Physiological effects of intravenous fructose 1.6-diphosphate on diaphragmatic function in malnourished patients with COPD.

BACKGROUND: A low body mass index is one of the strongest predictors of mortality in Chronic Obstructive Pulmonary Disease (COPD) patients. Under-nutrition is often associated with skeletal muscle wasting and hypophosphatemia. AIM AND METHODS: In a pilot, randomised, double-blind placebo-controlled study, we assessed the physiological effects of phosphorous administration in 17 stable undernourished COPD patients, on diaphragmatic function, breathing pattern, neuromuscular drive (P0.1) and dyspnea score. Fructose 1.6-diphosphate (FDP) or placebo was administered i.v. for 7 consecutive days. RESULTS: FDP administration was associated with a marked increase in inspiratory time (Ti) that induced a significant rise (p < 0.05) in the Pressure Time Product of the diaphragm per breath (PTPdi/b). However, since breathing frequency also decreased, the Pressure Time Product per minute of the diaphragm (PTPdi/min), index of diaphragmatic energy expenditure was markedly reduced. The efficiency of the respiratory pump in clearing CO2 was also improved, although not significantly, in the FDP group (p = 0.09) as well as the maximal transdiaphragmatic pressure during the sniff manoeuvre (Pdi,sniff). CONCLUSIONS: This pilot physiological study showed that phosphorus replacement in undernourished, stable COPD patients, may be associated with a complex modification in respiratory pattern and diaphragmatic functions, leading to a marked although not significant reduction in PTPdi/min.

Prevention of exercise-induced bronchoconstriction by a new leukotriene antagonist (SK&F 104353). A double-blind study versus disodium cromoglycate and placebo.

The effects of 800 micrograms of inhaled SK&F 104353, a peptidoleukotriene receptor antagonist, and of 20 mg disodium cromoglycate (DSCG) on exercise-induced bronchoconstriction were compared in 18 asthmatic patients. The study was conducted according to a double-blind, crossover, randomized, placebo-controlled design. Two baseline exercise tests were carried out, and pulmonary function tests were done before and at 1, 5, 10, 15, 20, and 30 min after completion of the exercise. Patients showing a 20% or greater decrease in FEV1 in both exercise challenges entered the blinded portion of the study. When placebo was administered before exercise, FEV1 fell to the same extent as during the baseline phase. After SK&F 104353 and DSCG, the bronchoconstriction was attenuated. The mean maximal percentage fall in FEV1 after exercise was 29% after placebo and 20% after SK&F 104353 and DSCG. The differences between the two active treatments did not reach the 5% level of statistical significance, though at 20 min SK&F 104353 showed a more pronounced effect than DSCG. The protective effect suggests an important role of leukotrienes in the pathogenesis of exercise-induced bronchoconstriction.

Ibopamine as a substitute for digitalis in patients with congestive heart failure on chronic digoxin therapy. Smith Kline and French Ibopamine Group.

The substitution of digoxin with ibopamine, a new inotropic and vasodilating agent, was evaluated in a multicenter study in 58 patients with mild-to-moderate congestive heart failure, stabilized on diuretics, and digoxin therapy. The study was a parallel, double-blind, randomized trial of four weeks duration in which half of the group continued the pre-study medication (diuretics and digoxin) and half of the group was treated with diuretics and ibopamine (100 mg, three times a day). At baseline evaluation, the two groups were similar for age, sex, underlying cardiac disease, duration of congestive heart failure, symptom score, cardiothoracic ratio, echocardiographic parameters of left ventricular function and exercise tolerance as measured by bicycle ergometry. After four weeks, no clinical deterioration was found in the patients treated with ibopamine in any measured parameter. There were two deaths during the study: a sudden death and one following an acute myocardial infarction. Both patients were on digoxin. This study suggests that in patients with mild-to-moderate congestive heart failure, ibopamine therapy may effectively and safely substitute digoxin therapy for up to four weeks, representing an option for patients requiring inotropic support but are at risk for potential digoxin toxicity.

Interaction study of fenoldopam--digoxin in congestive heart failure.

The potential interaction between fenoldopam, a DA1 selective agonist, and digoxin has been studied in 10 patients with heart failure (NYHA Class II or III) on chronic digoxin treatment. Plasma levels and urinary recovery of the glycoside were monitored for 24 h before and after 9 days of treatment with fenoldopam 100 mg tid. Fenoldopam caused a small, non-significant decrease in the mean steady state plasma concentration and area under the plasma concentration curve of digoxin. As the clearance of digoxin was unchanged there does not appear to be an interaction between fenoldopam and digoxin at the level of the renal tubule.

Ibopamine: long-term safety study in patients with congestive heart failure. The Italian Ibopamine Working Group.

Ibopamine is a new orally active dopamine analogue with positive inotropic and vasodilating activity. The tolerability of the drug administered at the dose of 100 mg thrice daily for 12 months was studied in 302 patients with congestive heart failure, New York Heart Association (NYHA) class II and III. Of the 302 patients, 198 completed the study (65%); 59 patients (19%) were withdrawn for clinical events; 27 of them died (9%); 35 patients (12%) did not complete the study for non-compliance and 10 (3%) for protocol violations. Clinical events were generally related to the cardiovascular system and 85% of deaths were from cardiovascular causes. None of the deaths was considered related to treatment by the investigators. Clinically significant laboratory abnormalities were observed during the study in four patients only. This trial suggests that ibopamine is well tolerated in patients with congestive heart failure, NYHA class II and III, at the dose of 100 mg thrice daily for up to one year.

Pharmacokinetics and metabolism of premazepam, a new potential anxiolytic, in humans.

Premazepam, a pyrrolodiazepine with potential anxiolytic properties, behaves as a partial antagonist to diazepam in animal tests. Its pharmacokinetics and metabolism were studied in four healthy volunteers. After oral administration of 30 mg [6-14C] premazepam, the plasma levels of total radioactivity reached maximum concentrations 1-4 h (mean 2 h) following administration. The plasma curve was described by an open one-compartment model, and half-life was 11.5 +/- 1.3 h. Levels of the unchanged compound accounted for about 80% of the total radioactivity up to 24 h. Half-life of the unchanged compound was 7.9 +/- 1.2 h. On the average, 89.6% of the administered radioactivity was recovered in the urine and 2.3% in the feces during the 5 days following administration. Unchanged premazepam accounted for about 70% of the total radioactivity excreted in the urine. Of the three metabolites identified in the urine, none was active in vitro in displacing 3H-diazepam from its forebrain receptors in the rat, indicating that only the parent compound has definite pharmacologic activity.

Reduced triglyceridemia and increased high density lipoprotein cholesterol levels after treatment with acipimox, a new inhibitor of lipolysis.

Acipimox (5-methylpyrazine carboxylic acid 4-oxide) is a new inhibitor of lipolysis with long-lasting activity, whose plasma lipid lowering potential was demonstrated in early clinical trials. The hypolipidemic effect of acipimox was investigated in two double-blind cross-over trials versus placebo. The first trial, carried out in 12 type IV patients, showed a significant triglyceride lowering effect (-35%) following 4 weeks of drug administration at a 250 tid dose. The same regimen, maintained for 9 weeks in 18 type IIA patients, failed to induce a significant reduction of total cholesterolemia. However, in 10 subjects, in whom lipoprotein cholesterol fractionation was carried out, a significant reduction of low density and highly significant increase in high density lipoprotein cholesterol levels (respectively -11% and +20%) were observed.

Inhibition of platelet aggregation in man by indobufen (K 3920).

A complete crossover trial was undertaken in six healthy volunteers to gain information on dose-effect responses to indobufen by assessing the intensity and duration of the effect of 3 single oral doses of the drug on platelet aggregation induced by threshold concentration of ADP and by 3 added doses of collagen. The results of the study confirm that the activity is dose-related and is reversible since 24 hours after administration it has practically disappeared. The effect of the same dose of indobufen differed significantly according to the amount of collagen added to plasma, whereas increasing doses of indobufen provoked a significantly more marked effect when the amount of inducer employed was the same.

Inhibition of lipolysis by nicotinic acid and by acipimox.

Acipimox (5-methylpyrazinecarboxylic acid 4-oxide) is a new lipolysis inhibitor that has a distant chemical relationship with nicotinic acid (NA). The tritiated compound (100 mg) is rapidly absorbed, peak plasma radioactivity being reached after 2 hr, with an almost total elimination unchanged in urine. A comparison of th antilipolytic activity of three doses of acipimox and three doses of NA showed acipimox to be 20 times as potent as NA. There was a correlation between intensity and duration of effect for acipimox, but not for NA. Plasma acipimox levels correlated with inhibition of lipolysis. In consideration of the very good subjective tolerability of acipimox at all doses tested, this drug may be suitable for control of lipolysis in hyperlipidemias.

Clinical pharmacology studies with indobufen (K 3920): inhibitor of platelet aggregation.

When given to 12 subjects at single oral doses of 100 and 300 mg, indobufen caused clear-cut, dose-dependent, reversible inhibition of epinephrine- and collagen-induced platelet aggregation. Platelet factor 3 availability and platelet factor 4 release were not affected by the lower dose but were markedly reduced by the 300-mg dose. Bleeding time was slightly influenced by 100 mg, and 300 mg had a more pronounced effect. Indobufen 300 mg was also intravenously injected to five subjects. When washed platelets obtained before indobufen were resuspended in plasma obtained after indobufen, aggregation was inhibited. This was not the case when washed platelets obtained after indobufen were resuspended in plasma obtained before indobufen. These experiments indicate tha indobufen causes reversible inhibition of platelet functions unlike the effect of acetylsalicylic acid.

Pharmacokinetic, bioavailability and pharmacodynamic study of indobufen (K 3920), an inhibitor of platelet aggregation, after a single dose in man.

Six healthy volunteers received single iv and oral doses of 2-[p-(1-oxo-2-isoindolinyl)phenyl] butyric acid 100 mg (indobufen; K 3920), an inhibitor of platelet aggregation. Plasma levels and urinary excretion of the drug were determined by GLC. Collagen-induced platelet aggregation was assessed turbidimetrically at various intervals after administration. The plasma half-life of the drug was 7--8 h and more than 70% of the administered dose was recovered within 48 h in urine, as unchanged drug and as the glucuronide of indobufen. After oral administration of tablets of two different formulations, the drug was completely absorbed, but one formulation showed faster absorption. The maximal inhibitory effect on platelet aggregation was observed 1 to 4 h after iv administration, and it had decreased by 8h. After tablets, peak effect and the time of the peak were similar, but activity was significantly prolonged, in accordance with the higher plasma levels found at 8 h. The data suggest that the effect of indobufen on platelets is reversible, and that for this drug platelets behave as a compartment that slowly equilibrates with plasma.

Indobufen (K 3920), a new inhibitor of platelet aggregation: effect of food on bioavailability, pharmacokinetic and pharmacodynamic study during repeated oral administration to man.

The effect of food on bioavailability of indobufen tablets was investigated in 6 healthy volunteers. Subsequently, the same subjects took 100 mg b.i.d. for 7 days. Plasma levels and urinary excretion of indobufen were determined by GLC. Platelet aggregation induced by several concentrations of adrenaline was determined turbidimetrically at various times after the first and last doses. The absorption of indobufen tablets was not substantially impaired by the presence of food in the GI tract, although peak plasma levels and AUCs were slightly reduced after food. Pharmacokinetic analysis of plasma and urinary levels of indobufen did not indicate any change in drug disposition after repeated dosing. Adrenaline-induced platelet aggregation was markedly inhibited for up to 12 h after the first dose and the intensity and duration of this effect did not change after repeated administration. A twice-daily dosing appears suitable for clinical trials.

Bioavailability of temazepam in soft gelatin capsules.

1 Healthy volunteers received single doses of temazepam 30 mg in conventional gelatin capsules, suppositories or in solution. They experienced marked sedation and sleepiness. The onset of sleepiness was prompt after the administration of the solution; this latter showed the fastest absorption and gave the highest peak plasma levels. This observation led to the development of the soft gelatin capsule. 2 To assess bioavailability of the formulation, plasma levels of temazepam were determined in healthy volunteers after single oral administration of soft and hard capsules, and after seven consecutive night-time doses of the soft capsule. Absorption from the soft gelatin capsule was faster and produced earlier and higher peak plasma levels. There were no differences in relative availability. 3 The apparent half-life of temazepam after night-time administration was shorter than after morning administration, but no change was observed between the first and seventh night-time doses.

Human pharmacokinetics and bioavailability of temazepam administered in soft gelatin capsules.

Plasma levels of temazepam were determined in healthy subjects after single oral administration of soft and hard gelatin capsules, and after 7 consecutive night-time doses in soft capsules. Absorption from soft gelatin capsules was significantly faster and produced earlier and higher peak plasma levels. The two pharmaceutical forms did not show any significant difference in relative availability. The apparent half-life of temazepam after night-time administration was significantly shorter than after morning administration, but no change in half-life was observed between the first and seventh night-time doses.

Pharmacokinetic studies of indoprofen in healthy volunteers and in patients.

The pharmacokinetics of indoprofen in healthy subjects after single oral and i.v. administrations is reviewed. During repeated administration of indoprofen to 6 normal subjects (200-mg tablet every 8 hours for 6 days) no variations in the disposition of the drug were found in comparison with single dose administration. In 6 inpatients, with rheumatoid arthritis, the pharmacokinetics of indoprofen was studied after single oral (tablet) and i.m. administration. As for oral doses, no difference in main kinetic parameters was detected between the patients and normal subjects except for a higher volume of distribution in the former population. The bioavailability of the drug given by i.m. injection was not significantly different from that observed after oral administration.

Effect of food on absorption of indoprofen administered orally to man in two dosage forms.

The influence of food on the bioavailability of two oral dosage forms (100-mg capsules and 200-mg tablets) of indoprofen, a new propionic acid derivative with marked anti-inflammatory and analgesic properties, has been investigated. Plasma levels and urinary excretion of indoprofen were determined both in the fasting state and after a standard meal in healthy volunteers after administration of two 100-mg capsules (4 subjects) and of one 200-mg tablet (6 subjects). Indoprofen in biological fluids was determined by gas-liquid chromatography. The extent of absorption from tablets was not affected by food as indicated from the values of the total area under plasma level curves and urinary excretion of the drug. The rate of absorption was faster after meal than in the fasting state. The opposite was found for capsules, which showed a slightly delayed absorption after food. The results suggest that food may differently influence the absorption pattern of different pharmaceutical forms of the same drug.

Application of nonparametric procedure for bioassay data to the evaluation of analgesics in man.

Parametric tests for bioassay data are commonly applied to scores of pain intensity and relief for the assessment of potency ratios of analgesic drugs. It has been demonstrated, however, that scores derived from semiquantitative scales often deviate from normal distribution. In addition, when scores decrease as a consequence of analgesic treatment, the variances may be nonhomogenous. Both parametric and nonparametric procedures have been employed in this study for the evaluation of results of a double-blind multicenter trial of the analgesic effect of indoprofen and ASA (both drugs at three dose levels) and placebo in episiotomy pain. There was a good agreement between potency ratios obtained with the two assays. Peak PID appeared a less efficient means of estimating potency ratio than other measurements such as SPID and TOTPAR. The nonparametric test for quantitative bioassay appears to be a valid statistical procedure for evaluating results of clinical trials, and it does not imply any assumptions as to the type of distribution of the data.