Impact of a high-dose nitrate strategy on cardiac stress in acute heart failure: a pilot study.

BACKGROUND: Intravenous nitrate therapy has been shown to improve short-term outcome of acute heart failure patients treated in the intensive care unit. The potential of a noninvasive high-dose nitrate strategy in the Emergency Department and the general ward remains unknown. METHODS: A total of 128 consecutive acute heart failure patients were either treated with standard therapy or high-dose sublingual and transdermal nitrates on top of standard of care treatment. Cardiac recovery, quantified by B-type natriuretic peptide (BNP) levels during the first 48 h, was the primary endpoint. Secondary endpoints ascertained the safety of the nitrate therapy. RESULTS: The high nitrate group received higher doses of nitrates during the first 48 h compared to the standard therapy group [82.4 mg (46.2-120.6) vs. 20 mg (10-30) respectively, P < 0.001]. The amount of diuretics given in both groups was similar. BNP levels decreased in all patients (P < 0.0001). However, the BNP decrease was larger in the high-dose nitrate group (P < 0.0001). The larger decrease in BNP in the high-dose nitrate group was already apparent 12 h after the initiation of treatment. After 48 h BNP values decreased by an average of 29 +/- 4.9% in the high-dose nitrate strategy group compared to 15 +/- 5.4% during standard therapy. There was a strong trend towards fewer ICU admissions in the high-dose nitrate group [high-dose nitrates: 2 cases (4%) vs. standard therapy: 9 cases (13%); P = 0.06]. During the study period, no intergroup changes were observed in blood pressure, RIFLE classes of acute kidney injury or troponin T. In-hospital and 90-day outcome was similar amongst the two groups. CONCLUSIONS: A noninvasive high-dose nitrate strategy on top of standard therapy is safe and notably accelerates cardiac recovery in patients observed on the general ward.

[Constancy check of the radiation output of Linac: comparison with diodes and ionization chamber]. / Konstanzprüfung des dosisproportionalen Outputs am Linearbeschleuniger: Vergleich zwischen Dioden und Ionisationskammer.

For routine QA measurements of the radiation output of a linear accelerator, an ionization chamber is usually used, the type of which may depend on the radiation quality. In this study, a comparison of the standard ionization chamber and the central diodes of an array, was performed both used simultaneously for the constancy check of the radiation output. It was investigated to which degree the two detectors deviate from each other over a long period of time for different radiation qualities. The aim of the study was to show whether the radiation output can be checked using the diode array, which is usually used for measuring beam profiles, by averaging the values of the central diodes within a reasonable accuracy. The results showed a maximum deviation of the two detectors of 0.9-2.2%, whereas the mean deviation is 0.4-0.8%, both depending on the radiation quality.

Metabolic studies on BMS-200475, a new antiviral compound active against hepatitis B virus.

BMS-200475 was recently shown to have potent antiviral activity against hepatitis B virus (50% effective concentration = 3.7 nM; 50% cytotoxic concentration = 30 microM). In metabolic studies in both HepG2 and hepatitis B virus-transfected 2.2.15 human hepatoma cell lines, the metabolism was similar, the primary products being the di- and triphosphates. The accumulation of triphosphate was rapid and detectable down to a 5 nM concentration of added drug. When cells were labeled at 25 microM, the intracellular triphosphate concentration attained 30 pmol/10(6) cells ( approximately 30 microM). The intracellular half-life of the triphosphate was about 15 h. Compared with five other nucleoside analogs of medical interest (lamivudine, penciclovir, ganciclovir, acyclovir, and lobucavir), BMS-200475 was most efficiently phosphorylated to the triphosphate in HepG2 cells.

Characterisation of [3H]ceranapril recognition sites in rat and human brain tissue.

The present studies assessed the nature of the recognition site for [3H]ceranapril in tissue from rat and human brain. [3H]Ceranapril exhibited high affinity saturable specific (defined by 1 microM captopril) binding to homogenates of tissue from both rat and human brain (mean pKd values between 8.42 and 8.69). High binding densities were observed in rat striatum and homogenates of tissue from human caudate (Bmax values 3317 +/- 192 and 1900 +/- 110 fmol/mg protein respectively), with comparatively low densities in cortical tissues. In kinetic experiments, association of [3H]ceranapril to homogenates of rat and human cortex was found to be rapid and fully reversible (K+1 = 6 x 10(5) M-1 sec-1 and 2.4 x 10(6) M-1 sec-1, K-1 = 7.6 x 10(-3) sec-1 and 4.5 x 10(-3) sec-1 respectively). In competition studies, lisinopril, captopril, unlabelled ceranapril, epicaptopril and fosinopril, all competed to a similar extent and with similar rank order of potency for the binding of [3H]ceranapril to homogenates of both rat and human brain. In in vivo studies, pretreatment of rats with either captopril or lisinopril (15 micrograms/250 g) significantly reduced the content of tritium in brain, as measured 20 min after intravenous administration of [3H]ceranapril. From these experiments [3H]ceranpril appears to selectively label, with high affinity, the inhibitor binding site of angiotensin converting enzyme and this site appears to be similar in both species studied.

The ACE inhibitor [3H]SQ29,852 identifies a high affinity recognition site located in the human temporal cortex.

The angiotensin converting enzyme (ACE) inhibitor [3H]SQ29,852 identified a single high affinity recognition site (defined by 10.0 microM captopril) in the human temporal cortex (pKD 8.62 +/- 0.03; Bmax 248 +/- 24 fmol mg-1 protein, mean +/- S.E.M., n = 4). ACE inhibitors and thiorphan competed to a similar level for the [3H]SQ29,852 binding site in the human temporal cortex with a rank order of affinity (pKi values mean +/- S.E.M., n = 3), lisinopril (9.49 +/- 0.02), captopril (9.16 +/- 0.08), SQ29,852 (8.58 +/- 0.04), epicaptopril (7.09 +/- 0.08), fosinopril (7.08 +/- 0.05) and thiorphan (6.40 +/- 0.04). Since this rank order of affinity is similar to the affinity of these compounds to inhibit brain ACE activity it is concluded that [3H]SQ29,852 selectively labels the inhibitor recognition site of ACE in the human temporal cortex.

Captopril: pharmacology, metabolism and disposition.

By inhibiting ACE, captopril blocks the conversion of AI or AII and augments the effects of bradykinin both in vitro and in vivo. In rats, dogs, and monkeys with 2-kidney renal hypertension, orally administered captopril rapidly and markedly reduces blood pressure; this antihypertensive effect apparently occurs via a renin-dependent mechanism; that is, the inhibition of ACE. In 1-kidney renal hypertension studies in rats and dogs, it was determined that oral doses of captopril markedly lowered blood pressure, but only after several days of dosing; the mechanism is thought to be non-renin dependent. In SHR, daily oral doses of captopril progressively lowered blood pressure; normal levels were attained by the sixth month. In all species studied, the reduction in blood pressure resulted from a reduction in total peripheral resistance; cardiac output remained unchanged or increased. In humans, captopril reduces blood pressure in patients with essential hypertension with low, normal, and high renin levels, and in patients with renovascular hypertension and hypertension associated with chronic renal failure. In hypertensive patients with high plasma renin activity, captopril apparently exerts most of its pharmacologic effects through inhibition of ACE. The means by which captopril reduces high blood pressure associated with low or normal PRA is not known, but it is clear that captopril does not act on an overactive plasma renin-angiotensin system in these cases. The antihypertensive effect of captopril is enhanced when it is given in combination with a diuretic or after salt depletion. Captopril was rapidly and well absorbed in all species tested, including man. Studies in rodents indicated that ingestion of food caused a reduction in the extent of absorption and bioavailability of captopril. Captopril and/or its metabolites were distributed extensively and rapidly throughout most tissues of normal rats; no radioactivity was detected in the brain. In vitro and in vivo, captopril formed disulfide bonds with albumin and other proteins. This binding was reversible in nature. In vitro studies in blood indicates that the disulfide dimer of captopril and mixed disulfides of captopril with L-cysteine and glutathione were formed. In intact blood cells, captopril remained in the reduced form (sulfhydryl), whereas in whole blood or plasma, captopril was converted to its disulfide dimer and other oxidative products. Biotransformation of captopril may involve both enzymatic and nonenzymatic processes.(ABSTRACT TRUNCATED AT 400 WORDS)

Biotransformation in the monkey of cartazolate (SQ 65,396), a substituted pyrazolopyridine having anxiolytic activity.

1. The metabolism of cartazolate (SQ 65,396), an anxiolytic agent, was studied in four male rhesus monkeys after oral administration. 2. Seven metabolites were identified in the pooled urine of the four monkeys. These resulted from a combination of (1) hydrolysis of the 5-carboxylic acid ethyl ester; (2) N-de-ethylation of the pyrazole ring; (3) gamma-hydroxylation of the n-butylamino side-chain; (4) removal of the n-butyl group; and (5) conjugation with beta-glucuronic acid.

Metabolism of tritium- and carbon-14-labeled tiamulin in dogs, rats, and pigs.

The metabolism of tiamulin hydrogen fumarate, labeled with 3H, 14C, or both, was studied in dogs, rats, and weanling pigs. After a dose of radiolabeled tiamulin, all three species excreted more radioactivity in feces (via bile) than in urine. Dogs absorbed 86% of a single oral dose of tiamulin-3H, and the disposition of the compound was similar after a single or multiple dosage regimen. The ratio of antimicrobial activity to total radioactivity in dog plasma was only about 0.25, and was still less in dog urine. After dosing with tiamulin-14C, rats and pigs excreted at least 1% of the dose as 14CO2 in expired air. In dual-labeled studies, pigs excreted less total 14C than 3H and had greater residues of 14C than 3H in edible tissues, blood, and plasma. After the administration of tiamulin-14C to pigs, radioactivity was incorporated into liver glycogen, indicating metabolic cleavage of the side chain of tiamulin. Tiamulin-3H is the isotopically-labeled compound of choice for studying metabolism and tissue residues in animals.

Inversion of optical configuration of alpha-methylfluorene-2-acetic acid (cicloprofen) in rats and monkeys.

A simple and sensitive radiometric method to determine the individual enantiomers of cicloprofen has been developed. 14C-Cicloprofen was converted to its L-leucine diastereoisomers, which were separated by thin-layer chromatography and quantified by measuring the radioactivity in the area corresponding to each individual diastereoisomer. This technique has also been used to measure the enantiomers of unlabeled cicloprofen by condensing with 14C-labeled L-leucine. By using the radiometric method, a unique biotransformation process, the inversion of the (-)-enantiomer of alpha-methylfluorene-2-acetic acid to its (+)-enantiomer, has been demonstrated in the rat and monkey. The rate of (-)- to (+)-inversion was found to be faster in the rat than in the monkey. After single or repeated oral adminstration of the racemic modification or the (-)-enantiomer of cicloprofen to both species, the ratio of (+)- to (-)-enantiomers of cicloprofen in plasma, urine, or bile increased with time. At 5, 22, and 48 hr after oral administration of a single 50-mg/kg dose of the (-)-enantiomer, 14C-cicloprofen in rat plasma contained 20, 50, and 79%, respectively, of the (+)-enantiomer. After receiving the same dose of (-)-enantiomer, monkey plasma contained 16.5% and 32% of (+)-enantiomer at 8 and 24 hr, respectively. After oral administration of a single 50-mg/kg dose of the (+)-enantiomer of 14C-cicloprofen to rats and monkeys, the percentage of (-)-enantiomer in plasma varied from 2 to 15%. Since the administered (+)-enantiomer contained 4% of (-)-enantiomer and the (+)-enantiomer was excreted at a faster rate than its (-)-antipode by rats or monkeys, it is not known whether an occasional small percentage increase of (-)-enantiomer in plasma resulted from the (+)-to-(-) inversion, or from faster elimination of the (+)-enantiomer. Nevertheless, if (+)-to-(-) inversion does occur in these two species, the rate is much slower than for the (-)-to-(+) inversion.