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Biomedical subjects

R Latini

Publications and source records attributed to R Latini.

At least 109 records · Page 6Linked to original sources
PubMed1986

Amiodarone and desethylamiodarone distribution in the atrium and adipose tissue of patients undergoing short- and long-term treatment with amiodarone.

The time to onset of action of amiodarone is often long in patients treated for arrhythmias; one reason might be a slow entry of the drug into the target organ, the heart. Amiodarone and desethylamiodarone, its active metabolite, were measured in the plasma, atrial tissue and pericardial fat of patients undergoing cardiac surgery. Two groups were studied: patients treated with amiodarone for less than 28 days (short-term group) and those treated for 28 days or more (long-term group). Plasma levels of amiodarone in the two groups were not different, whereas levels of desethylamiodarone were significantly higher in the long-term group. Average concentrations of amiodarone in the atrium were higher with longer treatment periods (30.2 +/- 5.6 versus 13.2 +/- 2.5 micrograms/g wet weight of tissue); the same was true for desethylamiodarone (40.3 +/- 7.7 versus 15.7 +/- 3.7 micrograms/g). Amiodarone concentrations in fat were also significantly higher in the long-term than in the short-term group. Atrium/plasma concentration ratios of desethylamiodarone were higher than those of amiodarone, whereas fat plasma concentration ratios of desethylamiodarone were lower. In conclusion, the equilibration of amiodarone and desethylamiodarone concentrations between myocardium and plasma appears to occur slowly in patients undergoing long-term treatment with amiodarone.(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose Tissue↗
PubMed1986

Comparative bioavailability of aspirin from buffered, enteric-coated and plain preparations.

The bioavailability and pharmacokinetics of acetylsalicylic acid were studied in 6 volunteers, under a cross-over design, using plain compressed aspirin, two buffered preparations and an enteric-coated tablet. Absorption, calculated from urinary excretion, was complete for all the formulations. The buffered forms gave higher peak concentrations and AUC for acetylsalicylic acid than the other forms. Absorption from the enteric-coated tablet was the slowest. Acetylsalicylic acid was not measurable in plasma (less than 0.1 micrograms/ml) at any time in 3 subjects after plain and in 2 after enteric-coated aspirin. Acetylsalicylic acid was no longer measurable in plasma after 4 hours, irrespective of the preparation given.

Administration, Oral↗
PubMed1985

Aspirin kinetics and inhibition of platelet thromboxane generation-relevance for a solution of the "aspirin dilemma".

Six healthy male volunteers received aspirin (ASA) in a compressed (320 mg) and an enteric-coated (800 mg) formulation as single oral doses ten days apart. Ten plasma samples were obtained from each volunteer between 5 and 120 min after compressed ASA, and seven between 10 and 240 min after enteric-coated ASA. ASA was undetectable (less than 100 ng/ml) in plasma from three subjects receiving compressed ASA and two receiving the enteric-coated preparation. Plasma levels and kinetic parameters of salicylate were the same in subjects with undetectable and detectable ASA plasma levels. More than 98% inhibition of pre-drug serum TXB2 was noted in all samples collected one and four hours after either ASA preparation. TXB2 generation recovered on average by 3.5% at 24 hr with both preparations. Thus inhibition of platelet TXB2 generation occurred independently of the amount of ASA reaching the peripheral circulation. If this is due to inhibition of platelet function in the enterohepatic circulation followed by extensive first-pass deacetylation of ASA, vascular PGI2 synthesis could be spared. A better knowledge of the kinetic parameters of ASA for each of the formulations used in thrombosis prevention trials might help in solving the "aspirin dilemma".

Adult↗
PubMed1985

Pharmacology of platelet inhibition in humans: implications of the salicylate-aspirin interaction.

The current dispute over the effects of "low" vs "high" doses of aspirin should take into consideration the pharmacokinetics of this drug. In fact, different pharmaceutical formulations of aspirin may deliver little or no aspirin to the systemic blood. This was the case, for instance, in healthy volunteers taking 320 mg of compressed aspirin or 800 mg of enteric-coated aspirin. In all instances thromboxane B2 generation in serum was fully inhibited. Platelet cyclooxygenase might therefore be effectively acetylated by exposure to aspirin in the portal circulation, whereas vascular cyclooxygenase could be spared. Thus aspirin formulations ensuring complete first-pass deacetylation should be sought rather than "low" or "high" doses of unspecified aspirin formulations. Regardless of the type and dose of aspirin administered, salicylate is formed and accumulates in the circulation. It may antagonize the effects of aspirin on cyclooxygenase, at least in acute conditions. As an example, after administration of 1 g of salicylate to healthy volunteers, when plasma levels of the drug were about 75 micrograms/ml, the effect of 40 mg iv aspirin (given 40 min later) on platelet cyclooxygenase and aggregation was significantly diminished. In contrast, in patients undergoing saphenectomy, the same dose of salicylate (1 g) gave plasma drug levels of about 25 micrograms/ml; salicylate was unable to prevent the inhibitory effect on platelets of 40 mg iv aspirin (given 1 hr later) but did act on vascular prostacyclin. Thus the combination of salicylate with aspirin at an appropriate dose and blood level ratio may result in almost complete dissociation of the drug's effect on platelets and vessels in man.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Kinetics and metabolism of theobromine in male rats.

On the basis of general pharmacological information (blood cells/plasma partition, plasma protein binding) and using HPLC as the principal analytical method, we investigated the kinetics and metabolism of theobromine (a caffeine metabolite) in male rats after a single dose and after a 2 week chronic application. Doses in both conditions varied between 1 and 100 mg/kg. In in vitro and in vivo the fraction of theobromine unbound to plasma proteins averaged 0.90 over a wide range of concentrations. No significant difference was found in the pharmacokinetic profile of the drug after acute or chronic treatment at different doses except for a reduction in the absorption rate constant as the dose increased. AUC values increased in proportion to the dose. The 2 treatment schedules were also similar as regards metabolism, at least 50% of the administered dose of theobromine being excreted unchanged, and 25% as 6-amino-5-[N-methyl- formylamino ]1-methyluracil. Only at the highest doses was there a tendency for theobromine to accumulate at the expense of its major metabolite (a uracil compound).

Animals↗
PubMed1984

Kinetics and metabolism of theobromine in male and female non-pregnant and pregnant rabbits.

The kinetics and metabolism of theobromine (3,7- DMX ) were investigated in male rabbits after a single oral dose and 14 days oral dosing at 1, 5, 10, 50 and 100 mg/kg/day. Female non-pregnant and pregnant rabbits were also studied after single oral doses of 1, 5 and 50 mg/kg. No significant difference was found in the pharmacokinetic profile of 3,7- DMX due to either sex, pregnancy or after chronic oral administration for 14 days. Intravenous (i.v.) administration of 3,7- DMX at 1 and 5 mg/kg resulted in calculated kinetic parameters in close agreement with oral doses. Irrespective of sex, there was a reduction in the absorption rate constant as the dose increased, coupled with a linear dose-related increase in AUC values. No qualitative difference in the metabolism of 3,7- DMX in the rabbit was observed as linked to sex, pregnancy or treatment schedule. Twenty-five percent of the administered dose of 3,7- DMX was excreted unchanged, the major metabolite being 7-methylxanthine (40%). There appeared to be a shift in the metabolic pathway at 100 mg/kg/day in the males and at 50 mg/kg/day in the females with more unchanged 3,7- DMX excreted. Only at these highest doses (100 mg/kg for males and 50 mg/kg for pregnant rabbits) was there a tendency toward accumulation.

Animals↗
PubMed1984

High-performance liquid chromatographic isolation and fast atom bombardment mass spectrometric identification of Di-N-desethylamiodarone, a new metabolite of amiodarone in the dog.

Amiodarone is an antiarrhythmic drug which has received considerable attention in recent years. It has been suggested that the unusual pharmacodynamic characteristics of this drug may be due in part to the influence of active metabolites. Using fast atom bombardment (FAB) mass spectrometry we have identified a new metabolite of amiodarone, the di-N-desethyl analog (DDEA). This metabolite was present in the blood of dogs treated with the parent drug, and showed a greater affinity for myocardium than did the parent drug. The unique features of FAB mass spectrometry over electron impact mass spectrometry was an essential element in facilitating the identification of this new metabolite. Whether or not this metabolite has pharmacologic activity or is responsible for some of the side effects occurring during amiodarone administration is not known.

Amiodarone↗
PubMed1984

Amiodarone kinetics after single i.v. bolus and multiple dosing in healthy volunteers.

We studied three healthy volunteers after a single i.v. bolus of amiodarone, during 1 month of chronic oral dosing and after the discontinuation of the drug. Blood concentrations of amiodarone declined rapidly in a bi-exponential fashion after i.v. bolus. The terminal half-life ranged from 10 to 17 h; after discontinuation of chronic treatment the terminal half-lives were 8-21 days. The i.v. data, the trough levels during multiple dosing and the washout phase could be simultaneously fitted using a triexponential equation. The subjects were carefully monitored for cardiac and thyroid function. One subject had to stop taking amiodarone because of profound bradycardia. A reduction of serum TT3 and FT3 concentrations and an increase of serum rT3 and FT4 was found.

Adult↗
PubMed1984

Kinetics of caffeine metabolism in control and 3-methylcholanthrene induced rat liver microsomes.

The kinetics of formation of primary metabolites of caffeine (paraxanthine, theophylline, theobromine and 1,3,7-trimethyluric acid) was studied in control (CO) and 3-methylcholanthrene-induced (MC) rat liver microsomes. Vmax was similar but Km was 16 times lower for total caffeine metabolism in CO and MC microsomes, respectively. Similar behavior was observed in the formation of each metabolite. Single metabolites showed different degrees of induction at non-saturating concentrations of caffeine. Kinetics was non-linear in CO microsomes.

Animals↗
PubMed1984

Blood levels and electrophysiological effects of intravenous amiodarone in patients with junctional reciprocating tachycardia. Preliminary observations.

The time course and the mode of antiarrhythmic action of Amiodarone was studied after acute i.v. injection of the drug (5 mg/kg in 5 min) to four patients with junctional reciprocating tachycardia. Electrophysiological studies were performed before and 1 and 2 hours after Amiodarone injection. It was impossible or considerably more difficult to induce junctional reciprocating tachycardia after Amiodarone, and the drug's effect was detectable mainly on the AV node. Kinetic analysis of blood levels of Amiodarone during the electrophysiological study did not support a direct association between blood concentration and its effects.

Adult↗
PubMed1983

Myocardial disposition of amiodarone in the dog.

The time course of myocardial uptake and disposition of amiodarone was studied after both acute i.v. and chronic oral administration. In addition, the myocardial disposition of a metabolite, N-desethylamiodarone, was studied after chronic oral amiodarone administration. After i.v. administration, the plasma concentrations of amiodarone fell rapidly; however, peak myocardial concentrations were not observed until 10 to 30 min after administration. Amiodarone was highly concentrated in the myocardium; the average (+/- S.D.) myocardial/plasma concentration ratio between 2 and 6 hr after administration was 89 +/- 32. Although there was significant interanimal variability, there was relative consistency over time in the ratio for each dog during this time period. Although no metabolite (N-desethylamiodarone) was detected in the plasma after the single i.v. dose, it was present in both plasma and myocardial samples after chronic oral therapy. Mean steady-state plasma concentrations of amiodarone and N-desethylamiodarone ranged from 0.62 to 1.63 micrograms/ml and 0.19 to 0.43 micrograms/ml, respectively. These studies show that the myocardial disposition kinetics of amiodarone are different from other drugs studied and both amiodarone and its N-desethyl metabolite accumulate extensively in the myocardium.

Administration, Oral↗
PubMed1982

Simple estimate of the true right to left shunt (Qs/Qt) at maintenance F1O2 by sulphur hexafluoride retention.

Differentiating Qs/Qt over Qva/Q (as measured by the standard O2 content formula) appears to be of great interest in applying and evaluating different therapeutic approaches. The estimation of Qs/Qt by 100% O2 breathing may alter "per se" the lung condition and is unsatisfactory. We used Sulphur Hexafluoride (SF6; lambda = 6.10(-3) ml ml-1 760 mmHg-1) to identify the true shunt (VA/Q less than 0.05) at maintenance F1O2. A simple and rapid determination of SF6 retention is performed by ECD gas chromatography from contemporaneous arterial and mixed venous blood samples, taken during i.v. infusion of an SF6 containing solution. QS/Qt estimate is then given by the ratio: PaSF6/PvSF6. It is not necessary to know the absolute gas partial pressures or concentration, hence absolute gas calibrations are not required. This method is suggested as feasible and satisfactory for clinical use, allowing the determination of QS/Qt at the maintenance F1O2.

Fluorides↗
PubMed1982

Caffeine disposition after oral doses.

Caffeine (TMX) disposition was studied in mean after 1, 5, and 10 mg/kg in water, as mocha coffee (1.54 mg/kg) and as a soft drink (0.22 mg/kg). TMX and its metabolites were analyzed in plasma and urine by high-pressure liquid chromatography. The design permitted confirmation of most of the partial results in various experimental settings and contributed new data on the metabolic disposition of TMX, with specific reference to main dimethylxanthine metabolite found in plasma, paraxanthine (1,7-dimethylxanthine). Different analysis methods were compared for the calculated parameters (absorption and elimination rate constants and renal clearance)to assess the consistency of results. The kinetics of TMX and of its dimethylated metabolites in plasma were described with a model that used an analogdigital hybrid computing system. In addition to providing a comprehensive profile of TMS disposition in the healthy adult, the results indicate tha TMX exhibits dose-independent kinetics at the levels at which man normally takes TMX.

Administration, Oral↗