Onset and duration of action of single doses of formoterol inhaled via Turbuhaler.

The aim of the study was to investigate the time of onset and the duration of the bronchodilating effect of different doses of formoterol administered via Turbuhaler in patients with moderate asthma. Thirty-one patients (five women) with a mean forced expiratory volume in 1 s (FEV1) of 1.97 +/- 0.54 1 and a mean reversibility of 31 +/- 14% of baseline were included in this double-blind, randomized, placebo-controlled and cross-over study. The patients inhaled single doses of placebo, i.e. 6, 12, 24, or 48 micrograms formoterol fumarate, on 5 separate days. Serial measurements of specific airways conductance (SGAW) and FEV1 were performed at regular time intervals for 12 h. The majority of the patients had at least a 50% increase in SGAW within 1-4 min after administration of all active treatments. The maximum increase in FEV1 over placebo was dose-dependent: 12% (6 micrograms), 18% (12 micrograms), 19% (24 micrograms), and 26% (48 micrograms) (P < 0.001). Twelve hours after administration of 6, 12, 24, and 48 micrograms formoterol, the mean increase in FEV1 was still 7%, 15%, 18%, and 27%, respectively, above the value following placebo. Headache was the most frequently reported adverse event in all treatments including placebo. After inhalation of 48 micrograms, three patients experienced mild tremor lasting for less than 1 h; likewise, one patient experienced the same event for 3 h after placebo. Formoterol administered via Turbuhaler10 gave a rapid and dose-related bronchodilating effect lasting for 12 h and was well tolerated.

The inhalation device influences lung deposition and bronchodilating effect of terbutaline.

The development of new inhalation devices for asthma drugs raises the issue of the relationship between pulmonary deposition and therapeutic effect of inhaled drugs in patients with obstructive lung diseases. We thus conducted a randomized, double-blind and double-dummy, four-period crossover study in 13 patients with moderate asthma (mean age 36 yr; FEV1 59% of predicted), who inhaled 0.25 and 0.5 mg terbutaline sulphate on separate occasions either via a pressurized metered dose inhaler (pMDI) or Turbuhaler (TBH). Pulmonary deposition was 8.1 +/- 2.7% and 8.3 +/- 2.3%, respectively, of the nominal dose for pMDI and 19.0 +/- 7.3%, and 22.0 +/- 8.1% for TBH. The FEV1 increase after 0.25 mg terbutaline sulphate via TBH was significantly greater than after 0.25 mg via pMDI. No significant differences in FEV1 increase were observed between 0.25 mg via TBH, 0.5 mg via pMDI, or 0.5 mg via TBH. Other lung function variables showed similar dose- and device-related changes. We concluded that: (1) the dose of terbutaline sulphate deposited in the lungs is dependent on which inhalation system is used; (2) TBH delivers about twice the amount of drug to the lungs as the pMDI; and (3) the observed difference in deposition is reflected in the bronchodilating effect.

Intravenous enterostatin does not affect single meal food intake in man.

Enterostatin, a pentapeptide released with colipase from pancreatic procolipase in man, affects eating behaviour in animals. We report the first phase II study of intravenous (i.v.) enterostatin (D3800) in obese but otherwise healthy men. Eighteen men (mean age 37 years, mean body mass index 34.9 kg/m2) completed a double-blind, randomized, crossover placebo controlled trial. After in initial session, each man received i.v. 4 mg D3800, 16 mg D3800 or placebo in random order over three sessions, immediately before a test meal served on a universal eating monitor. No statistically significant effect of i.v. enterostatin on any uptake or rating variable was observed. Several factors may explain the lack of effect, e.g. the inability of i.v. enterostatin to reach a site of action, the time between i.v. administration and eating, and the possibility that the only human responders are those who express particular fat preferences.

Long-term effects of glipizide on insulin secretion and blood glucose control in patients with non-insulin-dependent diabetes mellitus.

Of 23 patients with non-insulin-dependent diabetes mellitus (NIDDM), whose fasting blood glucose had not reached less than or equal to 6.0 mmol.l-1 after 10 weeks of dietary regulation, 15, who had had a weight reduction of -2.8 kg by dietary control, did achieve a fasting blood glucose less than or equal to 6.0 mmol.l-1 after addition of less than or equal to 20 mg glipizide daily. They had a sustained (greater than or equal to 2 years) increase in meal-induced insulin secretion (32% increase in postprandial C-peptide AUC), and a sustained reduction in postprandial hyperglycaemia (34% reduction in AUC). Ten of the patients took a mean daily dose less than 5 mg (4.8 mg) and had a sustained increase in insulin secretion rate (increased C-peptide slope). The 15 patients had no elevation of basal insulin secretion and no impairment of weight reduction. The remaining 8 subjects, who showed little or no weight reduction on dietary control, had little or no reduction in fasting blood glucose despite long-term treatment with 20 mg glipizide daily, a less sustained increase in meal-induced insulin secretion, a smaller reduction of postprandial hyperglycaemia, and an increase in body weight. On diagnosis the 8 subjects did not differ from the other 15 subjects in age, body weight, blood glucose, HbA1c, C-peptide or insulin, nor in their glucose and insulin responses to a test dose of glipizide; the main reason for the apparent drug failure appeared to be deficient compliance with dietary regulation rather than a primary inability to respond to sulphonylurea treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Dose-dependent effects of glyburide on insulin secretion and glucose uptake in humans.

OBJECTIVE: To examine the relationship between plasma glyburide concentrations (0, 50, 100, 200, 400, and 800 nM) and the insulin response and glucose metabolism during euglycemic (4.6 +/- 0.1 mM) and hyperglycemic (11.6 +/- 0.2 mM) conditions. RESEARCH DESIGN AND METHODS: Nine healthy subjects participated in the study. Steady-state plasma glyburide concentrations were achieved by primed continuous intravenous infusion of glyburide. RESULTS: During both euglycemia and hyperglycemia, glyburide enhanced insulin secretion and glucose disposal only to drug levels of 100-200 nM corresponding to an oral dose less than or equal to 10 mg. CONCLUSIONS: The data suggest that glyburide (and probably other sulfonylureas), operates within a narrow range of plasma concentrations (50-200 nM), which can be achieved with very low doses of the drug. It remains to be shown whether the threshold of maximal effect also in clinical practice is achieved with lower sulfonylurea doses than that currently used.

Determination of glibenclamide and its two major metabolites in human serum and urine by column liquid chromatography.

A simple reversed-phase liquid chromatographic method for the measurement of low concentrations of glibenclamide (glyburide) and its two major metabolites, 4-trans- and 3-cis-hydroxyglibenclamide, in human serum and urine has been developed. The compounds were extracted with n-hexane-dichloromethane (1:1). The UV detection wavelength was 203 nm. The minimum detectable serum level of glibenclamide was 1 ng ml (2 nM), and the relative standard deviation was 8.9% (n = 9). When maximum sensitivity was desired the metabolites were chromatographed separately. Metabolites in urine were measured by the same method after five-fold sample dilution. The utility of the method was tested on a healthy volunteer who ingested 3.5 mg of glibenclamide. The parent drug was present in the serum for at least 18 h, and the metabolites in the urine for at least 24 h.

Will sulfonylurea treatment of impaired glucose tolerance delay development and complications of NIDDM?

The chronic hyperglycemia of non-insulin-dependent diabetes mellitus (NIDDM) evolves gradually and is usually preceded by more transient hyperglycemia, classified as impaired glucose tolerance (IGT). Already in this phase, there is an increased risk of cardiovascular complications, and many IGT subjects, like NIDDM patients, often display several of the metabolic and circulatory disturbances that are associated with hyperglycemia, e.g., insulin resistance, hyperinsulinemia and/or hyperproinsulinemia, delayed insulin release, dyslipidemia, and hypertension. Therefore, and because untreated hyperglycemia is a self-perpetuating condition, early detection and early intervention may be necessary to prevent the progression and complications of NIDDM. This in turn would necessitate screening procedures, and the therapeutic goal should include both euglycemia and normalization of plasma insulin, plasma lipids, and blood pressure. A study in the German Democratic Republic indicated that the mortality in screening-detected NIDDM patients did not differ from that in patients detected in routine care. In a Swedish study on screening-detected NIDDM subjects, only those who had IGT rather than manifest NIDDM could maintain fasting blood glucose less than or equal to 6 mM for 5 yr by hypocaloric dietary regulation alone. In those with screening-detected NIDDM, the delayed acute insulin release and net postprandial hyperglycemia were improved by addition of glipizide, and most managed to attain and maintain fasting blood glucose less than or equal to 6 mM for approximately 2 yr after such addition. However, after 4 yr, there was an increase in blood glucose, suggesting that preventive intervention either may not be possible or may have to start in the IGT phase.(ABSTRACT TRUNCATED AT 250 WORDS)

Mechanisms and variations in the food effect on propranolol bioavailability.

Mechanisms and variations in the food-induced increase in the bioavailability of propranolol were assessed by single-dose (80 mg) studies in healthy volunteers who took the drug on an empty stomach, immediately after a protein-rich breakfast, and together with a carbohydrate-rich, protein-poor breakfast. Concomitant intake of the protein-rich, but not the carbohydrate-rich, protein-poor breakfast, increased the bioavailability of propranolol in most, but not all, subjects. The food (protein) effect displayed much inter-individual variation, from a decrease to a 250% increase, which could be explained, at least in part, by a correlation between the oral clearance of propranolol and the food-induced increase in its bioavailability. The food effect was not associated with decreased total availability, but with delayed appearance, of the oxidative metabolites 4-OHP, NLA and PG. Hence the food (protein) effect does not seem to be caused by enzyme inhibition, but rather it is due to reduced hepatic extraction of propranolol, probably consequent to an increase hepatic entry rate. When taken together with the protein-rich breakfast, propranolol usually appeared in systemic blood at least as early as when taken on an empty stomach, implying that gastric absorption of propranolol may be possible in the presence of protein-rich food. Within the individual the food effect was reproducible, but its magnitude showed an intraindividual variation that may reflect its dependence upon the rates of gastrointestinal absorption and splanchnic-hepatic blood flow, and hence upon the rate of hepatic drug entry.

Influence of chronic diflunisal treatment on the plasma levels, metabolism and excretion of indomethacin.

The single-dose pharmacokinetics of indomethacin following 100 mg rectally was measured in two groups of 8 healthy subjects before and after diflunisal 500 mg p.o. once daily, or 500 mg in the morning and 1000 mg in the evening, until steady state conditions were reached. A further group of 8 healthy subjects was given 50 mg indomethacin rectally before and after diflunisal 500 mg p.o. twice daily. High dose diflunisal (1500 mg/day) decreased the renal clearance of indomethacin from 21.9 to 1.8 ml/min (92%) and reduced the renal excretion of both unchanged (63%) and conjugated (82%) indomethacin. The apparent total body clearance (0.12 l/h/kg), apparent volume of distribution (0.98 l/kg), and volume of distribution at steady state (0.80 l/kg) were decreased by 47%, 35% and 30%. The maximum plasma concentration (2.4 micrograms/ml) and total area under the curve (13.0 micrograms x h/ml) were increased by 40% and 119%, respectively. The terminal elimination half-life (5.7 h) and mean residence time (6.7 h) were slightly prolonged (7.0 h and 8.8 h) in the presence of diflunisal. The contribution of metabolism to the overall elimination of indomethacin was increased by only 2%. Similar results were obtained when the subjects were challenged with the low dose of diflunisal (500 mg/day), although the magnitude of the changes were smaller. The interaction between indomethacin and diflunisal may be due to competition both at the metabolic (conjugation) and the excretory (tubular secretion) levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of renal failure, rheumatoid arthritis and old age on the pharmacokinetics of diflunisal.

The single-dose plasma kinetics of diflunisal was studied in healthy young and old subjects, in patients with rheumatoid arthritis, and in patients with renal failure. The plasma and urine kinetics of the glucuronidated metabolites of diflunisal were studied in the healthy elderly subjects and in the patients with renal failure. In addition, the multiple-dose plasma kinetics of diflunisal was assessed in healthy volunteers and in patients with rheumatoid arthritis. After a single dose of diflunisal the terminal plasma half-life, mean residence time and apparent volume of distribution were higher in elderly subjects than in young adults. No difference was observed in any pharmacokinetic parameter between age-matched healthy subjects and patients with rheumatoid arthritis. The elimination half-life of unchanged diflunisal was correlated with the creatinine clearance (r = +0.89) and its apparent total body clearance exhibited linear dependence on creatinine clearance (r = +0.78). In patients with renal failure, the terminal plasma half-life and mean residence time of diflunisal were prolonged. The renal and apparent total body clearances were lower, the mean apparent volume of distribution was higher and the mean area under the concentration-time curve extrapolated to infinity (AUC) was greater in the renal failure patients than in controls. The plasma concentration of the glucuronidated metabolites rapidly rose to levels above those of unchanged drug in renal patients, whereas they were lower than those of unchanged diflunisal in controls. The AUC (0-96 h) of diflunisal glucuronides in the patients was four-times that in controls, and the terminal elimination half-life of the glucuronides was prolonged in them. The renal excretion and clearance of diflunisal glucuronides were reduced when renal function was impaired. After multiple dosing, the pre-dose steady-state plasma-concentration increased with decreasing creatinine clearance (r = -0.79). When the plasma concentration exceeded 200 mumols.l-1, the elimination half-life was doubled, due to partial saturation of diflunisal conjugation. This finding suggests that lower doses could be used in long-term treatment. Thus, old age and arthritic disease appear to have little influence on the kinetics of diflunisal in the absence of renal functional impairment. Ordinary doses can be given for short term treatment of elderly patients with or without RA. In patients with renal failure, however, reduced doses of diflunisal are recommended.

The influence of glipizide on early insulin release and glucose disposal before and after dietary regulation in diabetic patients with different degrees of hyperglycaemia.

An early defect in subjects with non-insulin-dependent diabetes mellitus (NIDDM) and the preceding phase of impaired glucose tolerance (IGT) is a reduction in early insulin release and hence a prolonged elevation of postprandial blood glucose. We therefore assessed whether a rapidly acting sulphonylurea (glipizide 5 mg 0.5 h before a test meal) could correct these disturbances in 38 IGT/NIDDM subjects, whose early insulin release and postprandial blood glucose elevations remained unimproved after 10 weeks of dietary regulation. We also assessed whether the efficacy of glipizide was dependent upon the ambient blood glucose concentration, and if early systemic availability of the drug was important for the blood glucose lowering effect. A single dose of glipizide normalized early insulin release and hence reduced the postprandial blood glucose increase that was not lowered by dietary regulation. The efficacy of glipizide was dependent upon the early systemic availability of the drug, but early systemic availability and efficacy were independent of the extent of blood glucose elevation, at least within a range of 6-12 mmol.l-1 of fasting blood glucose.

Interaction of ethanol and glipizide in humans.

The hypoglycemic effect of 2.5 mg glipizide and the potentiation of this effect by ethanol were studied in 10 normal-weight nondiabetic subjects. The reductions in blood glucose concentrations were similar in time of onset and extent (2 mM) whether glipizide was taken alone or in combination with ethanol. However, the return of blood glucose toward fasting level was delayed by ethanol. Beta-Cell secretory activity, evaluated from the concentrations of insulin and C-peptide, was unchanged by ethanol. The serum glipizide concentrations were reproducible within subjects, whereas there was a considerable interindividual variation. This heterogeneity in the rise in glipizide concentration was strongly correlated with blood glucose fall and insulin secretion. Thus, ethanol can prolong but does not augment the hypoglycemia induced by glipizide. The heterogeneity in glipizide concentration seems to be caused by an interindividual variation in kinetics.

Lack of primary effect of sulphonylurea (glipizide) on plasma lipoproteins and insulin action in former type 2 diabetics with attenuated insulin secretion.

A double-blind, placebo-controlled investigation has been made into the effects of 8 weeks of glipizide treatment in diabetics previously classified as Type 2 but with subsequent attenuation of insulin secretion and thence maintained on exogenous insulin. Although all patients were exposed to therapeutic plasma concentrations of glipizide, fasting blood glucose, haemoglobin A1 and plasma lipoproteins (HDL, LDL, total cholesterol and triglycerides) did not show any consistent improvement following this treatment. It appears unlikely that SU (glipizide) has any primary effect on insulin action or on plasma lipoproteins. Its primary action is to augment insulin release and availability, so, its use should be restricted to Type 2 diabetics who retain insulin secretion.

Reduction of paracetamol and aspirin metabolism during viral hepatitis.

The single-dose pharmacokinetics of two analgesic drugs, paracetamol (acetaminophen) and aspirin, were studied in healthy volunteers and in patients with viral hepatitis during the acute and the convalescent phase. Impaired elimination of paracetamol and aspirin was found in hepatitis patients, while plasma peak concentrations were unaffected. Recovered patients were not different from healthy controls in the rate of drug elimination. The data suggest normal single dosage for these drugs in acute viral hepatitis, and dosage modification only in severe cases.

Therapeutic equivalence of once- and thrice-daily glipizide.

Two cross-over studies were carried out in 23 patients with Type 2 diabetes, to examine whether glipizide, a potent sulphonylurea with fast and complete absorption and rapid elimination (t1/2 less than 5 h), can be given once-daily without loss of therapeutic effect. In both studies, patients were randomly assigned to an initial dose of 7.5 mg once daily or 2.5 mg three-times daily, which was increased to 15 mg o.d. or 5 mg t.i.d. if the fasting plasma glucose remained over 10 mmol/l on the lower dosage. In Study 1 (n = 11), administration once a day before breakfast was compared with intake before breakfast, lunch and early dinner (5 p.m.) and in Study 2 (n = 12) the comparison was between intake once-daily before breakfast and dosing before breakfast, lunch, and at bedtime (10 p.m.). Neither the 24-hour urinary glucose excretion nor HbA1, fasting plasma glucose, insulin or C-peptide levels differed between the once and three times daily administration with the third dose given before early dinner. The nadir plasma levels of glipizide were not significantly different and were often too low to be detected. Postponing the third dose until 10 p.m. did not produce any improvement in HbA1 or in fasting plasma glucose, insulin or C-peptide. The mean nadir glipizide levels following this schedule were twice as high as those after once-daily administration. As expected, the plasma glipizide after breakfast was higher when the whole dose was taken before breakfast than when it was divided. The corresponding plasma level of insulin was higher and that of plasma glucose was lower.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetic interaction of acetylsalicylic acid and dipyridamole.

It is often recommended that acetylsalicylic acid (ASA) and dipyridamole should be given together in order to obtain secondary prophylaxis against certain ischaemic diseases. Therefore, the possible pharmacokinetic interactions between these agents were assessed following single-dose exposures in 14 healthy volunteers. The plasma concentrations of ASA, salicylic acid (SA) and dipyridamole were measured by selective h.p.l.c. techniques. It was found that, while dipyridamole kinetics were unaffected by concurrent ASA, concurrent dipyridamole significantly enhanced the peak concentration (24%) and AUC (27%) of ASA. Thus, co-administered dipyridamole might influence the anti-platelet effect of ASA.

Pharmacokinetics and metabolic effects of glibenclamide and glipizide in type 2 diabetics.

Fifteen Type 2 diabetics were treated for 4-week periods with once daily (10 mg) glibenclamide, glipizide and placebo according to a double-blind cross-over protocol. Post-dose glipizide concentrations were three times higher than those of glibenclamide, due to the incomplete bioavailability of the latter. On the other hand, pre-dose drug levels were similar, as an expression of the slower absorption and/or elimination of glibenclamide. Both active treatments reduced postprandial blood glucose concentrations and 24-hour urinary glucose excretion to a similar degree, but fasting blood glucose concentrations were slightly lower during glibenclamide treatment. Both active treatments enhanced fasting and postprandial insulin and C-peptide concentrations, the C-peptide response being greater after glipizide than after glibenclamide. Plasma glucagon and GIP concentrations were not significantly affected. Insulin sensitivity was increased by glibenclamide but not by glipizide. Neither therapy affected insulin binding to erythrocytes. It appears that both glibenclamide and glipizide improved glucose metabolism by sustained stimulation of insulin secretion, which was most pronounced with glipizide. Only glibenclamide improved insulin sensitivity and was slightly more active than glipizide on fasting blood glucose levels. The differences may be consequences of the pharmacokinetics, but differences in pharmacodynamics cannot be excluded.

Pharmacokinetics of dixyrazine: low bioavailability, improved by food intake.

The single-dose kinetics of the psychotropic phenothiazine dixyrazine was assessed in eight young healthy volunteers given the drug at three occasions: 10 mg intravenously, 25 mg orally in the fasting state, and 25 mg orally together with a standardized breakfast of 1,840 kJ. The plasma concentrations of dixyrazine were measured by high-pressure liquid chromatography. Like some other lipophilic weakly basic drugs, dixyrazine showed a rapid disappearance from plasma, having an elimination half-life of 3.4 h, a clearance of about 1,200 ml/min, and an apparent volume of distribution of 5.9 l/kg. Dixyrazine was found to have a very low and interindividually varying bioavailability; in the fasting state, dixyrazine bioavailability was only 1% in one subject, 3-6% in five others, and 11 and 24% in the remaining two subjects. The mean fasting bioavailability was 7.4%. After intake with breakfast, the mean bioavailability was increased to 12.4% (p less than 0.01), with a range of 2-29%. Probably, the low oral bioavailability is due to extensive presystemic (hepatic) degradation, and the food effect to a reduction of this process.

Different effects of different nutrients on theophylline absorption in man.

The influence of concomitant intake of a standardized breakfast (1,840 kJ) and of carbohydrate (830 kJ), fat (645 kJ), and protein (365 kJ) on the absorption of theophylline (400 mg) from a modern formulation of choline theophylline (4 X 135 mg) was examined in 18 healthy volunteers. After fasting overnight, they ingested the drug both immediately after the meal/nutrient and on an empty stomach, fasting being continued for another 4 h. Theophylline concentrations in serum were analyzed by high-pressure liquid chromatography. The results indicate that carbohydrate and the complete breakfast, but not fat or protein, delayed the absorption of theophylline. This is of particular interest as previous animal studies suggest that theophylline may be partially absorbed by an active transport mechanism operating in glucose uptake, and as carbohydrate has been found to increase the absorption rate of phenytoin, another acidic drug with a pKa similar to that of theophylline. This emphasizes the complexity of factors regulating the absorption of drugs and their interactions with food and dietary components.

Indobufen interacts with the sulphonylurea, glipizide, but not with the beta-adrenergic receptor antagonists, propranolol and atenolol.

This study assessed the possible interactions of the cyclooxygenase inhibitor indobufen with one sulphonylurea, glipizide, and with two beta-adrenoceptor antagonists, one of which is extensively metabolised already in the first passage through the liver (propranolol) while the other essentially escapes biotransformation (atenolol). Indobufen was first given as a single 200 mg dose and then for a 5 day period in a dosage of 200 mg twice daily, to six healthy volunteers. Glipizide (5 mg), propranolol (80 mg) and atenolol (100 mg) were given as single doses before and during indobufen medication. The drug concentrations were measured by selective and sensitive h.p.l.c. methods. The findings suggest that the lipophilic acid indobufen can inhibit the metabolic inactivation of another lipophilic acid, glipizide, but does not interfere with the disposal of the two basic drugs, propranolol and atenolol. The increased glipizide concentrations following indobufen were associated with an enhanced blood glucose reduction. Hence, this interaction may be clinically relevant.