A microdose study of ¹4C-AR-709 in healthy men: pharmacokinetics, absolute bioavailability and concentrations in key compartments of the lung.

PURPOSE: To explore, in a microdose (phase-0) study, the pharmacokinetics, bioavailability and concentrations in key compartments of the lung, of AR-709, a novel diaminopyrimidine antibiotic for the treatment of respiratory infection. METHODS: Four healthy men each received two single, 100 µg microdoses of ¹4C-AR-709, 7 days apart: the first was administered intravenously (IV), the second orally. Plasma pharmacokinetics of ¹4C and unchanged AR-709 were obtained by high-performance liquid chromatography and accelerator mass spectrometry (AMS). Next, 15 healthy men received a single, 100 µg microdose of ¹4C-AR-709 IV. Plasma, bronchoalveolar lavage fluid, alveolar macrophages and bronchial mucosal biopsy samples were analysed by AMS. RESULTS: After IV administration, clearance of AR-709 was 496 mL/min, volume of distribution was 1,700 L and the absolute oral bioavailability was 2.5 %. Excretion in urine was negligible. At 8-12 h after IV dosing, ¹4C concentrations in lung samples were 15- (bronchial mucosa) to 200- (alveolar macrophages) fold higher than in plasma. In alveolar macrophages, ¹4C was still mostly associated with AR-709 at 12 h after dosing. CONCLUSIONS: The results of this microdose study indicate that AR-709 attains concentrations appreciably higher within the lung than in plasma. Its low oral bioavailability however, precludes oral administration. Although IV administration would appear to be an effective route of administration, this would limit the use of AR-709 to a clinical setting and would therefore be economically unsustainable. If further clinical development were to be undertaken, therefore, an alternative route of administration would be necessary.

Tolerability, pharmacokinetics and concentration-dependent hemodynamic effects of oral CF101, an A3 adenosine receptor agonist, in healthy young men.

OBJECTIVES: To assess safety, tolerability, pharmacokinetics and hemodynamic effects of oral CF 101, an A3 adenosine receptor (A3AR) agonist, in healthy men. METHODS: One single and 1 repeated dose, parallel-group, ascending dose, double-blind and placebo-controlled study in normal volunteers. In the single dose study, n = 15 subjects received 1, 5 or 10 mg oral CF101; in each group 1 subject received placebo, the remainder active CF101. In the repeat-dose study, n = 28 subjects received repeated 12-hourly oral doses of CF 101 (2, 3, 4 or 5 mg) for 7 days, in each group 2 subjects received placebo, the remainder active CF101. TEST MATERIALS: Single-dose study: CF101 in 30% Cremophor RH40. Multiple-dose sudy: CF101 in 0.5% methylcellulose suspension. Both studies: the corresponding vehicles were used as placebos. Galenicals were prepared remotely from the clinical study site to ensure double-blind nature of the study. RESULTS TOLERABILITY: Single doses up to 5 mg CF101 were safe and well-tolerated. However, the single dose of 10 mg CF101 was associated with flushing, tachycardia, nausea and vomiting, which were viewed as dose-limiting in normal volunteers. Single doses of CF101 (as well as the first of the multiple doses) were associated with increases in heart rate (8 - 24 beats/min after 5 mg and 18 - 55 beats/min after 10 mg). Multiple doses up to 4 mg 12-hourly for 7 days were safe and well-tolerated. However, the 5 mg multiple-dose group reported headache, drowsiness, hot flushes and dizziness on standing; this declined with dosing duration and was not dose-limiting in this study. Adverse events were commonest near t(max). RESULTS PHARMACOKINETICS: For oral CF101, the t(max) was always 1 - 2 h post-dose and t 1/2 about 9 h, in both the single- and multiple-dose studies. For a single 5 mg dose (mean +/- SD) C(max) = 81.6 +/- 23.6 ng/ml in the single dose study, and 63.6 +/- 22.0 ng/ml after the first of the multiple doses; AUC if was 904.0 +/- 221.9 ng.h/ml and 596.1 +/- 196.6 ng.h/ml for the 2 studies, respectively. After 7 days of multiple dosing there was little change, and AUC(0-24h) = 601.0 +/- 163.6 ng.h/ml. These pharmacokinetic parameters were linearly proportional to dose in the other treatment groups. RESULTS PHARMACODYNAMICS: Increases in heart rate were related to plasma concentration and evident only in the upper range of concentrations observed. There were no changes on ECG monitoring beyond sinus tachycardia, and, in particular, no evidence of PR prolongation in any subject (n = 43). In comparison with single doses, this response was almost absent after 7 days of dosing. Leucocytosis (increases up to about 1.5 x 10(9)/l after 5 and 10 mg) was similarly transient and reversible after multiple dosing. CONCLUSIONS: Single oral doses up to 5 mg CF101 and repeated doses up to 4 mg 12-hourly for 7 days were safe and well-tolerated. Multiple-dose CF101 pharmacokinetics were unchanged and predictable from single-dose estimates, and were linearly proportional to dose. Increases in heart rate and neutrophil count were reversible during multiple dosing and were not dose-limiting in the repeat dose study. CF101 warrants further study for its efficacy in treating human disease.

Safety, tolerability and pharmacokinetics of subcutaneous A6, an 8-amino acid peptide with anti-angiogenic properties, in healthy men.

AIMS: To assess the safety, tolerability and pharmacokinetics of subcutaneous A6, an 8-amino acid peptide with anti-angiogenic properties, in healthy men. METHODS: Double-blind, placebo-controlled, parallel-group, dose-rising, phase I study of single and repeated doses. In the single dose phase, successive groups of 5 subjects received A6 15, 35, 75, 150, 300 mg, or placebo, as subcutaneous injections in the upper thigh. In the repeat dose phase, 2 groups of 6 subjects received repeat doses of A6 35 mg and 75 mg, or placebo, and 1 group of 5 subjects received 150 mg, or placebo, 12-hourly for 6 days (11 doses in total). In each group, 4 subjects received active treatment, the remainder placebo. Pharmacokinetics of A6 were assessed up to 24 h after single doses, for 12 h after the first of the repeated doses, and up to 24 h after the last of the repeated doses. MATERIALS: A6 for subcutaneous injection in phosphate buffer, pH 5.6-6.0. Phosphate-buffered saline was used as placebo. RESULTS: All dose regimens of A6 were safe and well-tolerated, both systemically and locally. Time to peak plasma concentration was similar (0.5-2.1 h) in all dosage groups. Cmax and AUC(0-inf) were linearly proportional to dose. Mean Cmax ranged from 454-10,333 ng/ml and mean AUC(0-inf) from 1,690-43,371 ng x h/ml after the 15 and 300 mg single doses, respectively. Terminal t(1/2) was 1.4-1.8 h, and there was no evidence of unexpected drug accumulation. Urinary excretion of unchanged A6 was 94.6% (SD 20.7) after the 300 mg single dose (0-24 h collection), and 78.4% (SD 13.0) after the 150 mg repeated dose (0-12 h collection). A6 did not trigger production of anti-A6 IgG antibodies within 14 days of the first dose. CONCLUSION: Single doses of A6 up to 300 mg, and repeated doses up to 150 mg, were well-tolerated and safe in healthy young men. A6 was rapidly absorbed; it was eliminated, mainly unchanged, in urine. Plasma concentrations were dose-proportional. A6 did not trigger an early immunogenic response.

Pharmacokinetics, safety and tolerability of three dosage regimens of buccal adhesive testosterone tablets in healthy men suppressed with leuprorelin.

We used a randomised, double-blind, crossover design to evaluate the pharmacokinetics, safety and tolerability of three doses of buccal adhesive testosterone tablets (BATT). Twenty-four healthy men, whose endogenous testosterone was suppressed to

Effects of recombinant human interleukin-12 on eosinophils, airway hyper-responsiveness, and the late asthmatic response.

BACKGROUND: Interleukin-12 (IL-12) is a macrophage-derived cytokine that modulates T lymphocyte responses and has the capacity to suppress allergic and eosinophilic inflammation. METHODS: We carried out a double-blind, randomised, parallel group clinical study, in which patients with mild allergic asthma were given subcutaneous recombinant human IL-12 at increasing weekly injections of 0.1, 0.25, 0.5 microg/kg (n=19), or placebo (n=20). We compared responses to inhaled allergen challenge 24 h before the first injection and 24 h after the final injection. Airways hyper-responsiveness and concentrations of peripheral blood eosinophils and sputum eosinophils were also assessed. FINDINGS: IL-12 caused a significant decrease from baseline in the main peripheral blood eosinophil count 24 h after the fourth injection compared with placebo (p=0.0001). Sputum eosinophils were also significantly decreased 24 h after allergen challenge when treated with IL-12 compared with placebo (p=0.024). IL-12 caused a non-significant trend towards improvement in airway hyper-responsiveness to histamine, but had no significant effect on the late asthmatic reaction after inhaled allergen challenge. After administration of IL-12, four of 19 patients withdrew prematurely; two with cardiac arrhythmias, one with abnormal liver function, and a single patient with severe flu-like symptoms. INTERPRETATION: We have shown that IL-12 lowers numbers of blood and sputum eosinophils, but without any significant effects on airway hyper-responsiveness or the late asthmatic reaction. This questions the role of eosinophils in mediating these reactions, and has important implications for development of new anti-inflammatory treatments.

Pharmacokinetics of isosorbide dinitrate in healthy volunteers after 24-hour intravenous infusion.

No studies have examined the pharmacokinetics of isosorbide dinitrate (ISDN) after infusion of long duration, even though such infusions are used in patients. We therefore measured ISDN and its active metabolites, isosorbide-5-mononitrate (IS5MN) and isosorbide-2-mononitrate (IS2MN), in plasma of 9 healthy volunteers who received a continuous intravenous infusion of ISDN for 24 hours at a dose rate that lowered diastolic blood pressure by 10% during the first 30 minutes of infusion. All subjects tolerated the infusion except one who experienced intolerable headache. Five subjects received 1 microgram.min-1.kg-1, one 2 micrograms.min-1.kg-1, and two 4 micrograms.min-1.kg-1 ISDN, whereas the full rate of 6 micrograms.min-1.kg-1 was used continuously in one subject. At all infusion rates the plasma concentrations of ISDN were higher at 24 hours than at earlier times, suggesting that a steady-state condition had not been reached at that time. The same was true for the mononitrate metabolites, which reached higher plasma concentrations and were cleared more slowly than the parent compound after the end of the infusion. Apparent elimination half-lives of ISDN, IS2MN, and IS5MN were 67 +/- 10 minutes, 115 +/- 13 minutes, and 272 +/- 38 minutes, respectively. Comparison of low-rate infusions (1 and 2 micrograms.min-1.kg-1) with high-rate infusions (4 and 6 micrograms.min-1.kg-1) showed that the plasma concentration ratios at 24 hours of mononitrate metabolites to parent drug and apparent plasma clearance of ISDN were almost halved at the higher infusion rates.

The time course of binding to striatal dopamine D2 receptors by the neuroleptic ziprasidone (CP-88,059-01) determined by positron emission tomography.

Positron emission tomography (PET) and 11C-raclopride were used to assess the time course of binding to central dopamine D2 receptors by the novel neuroleptic ziprasidone. In a third party blind study, six healthy male control subjects received a predose of 40 mg ziprasidone and were scanned at an interval of between 4 and 36 h post-dose. One additional subject was assigned to placebo predose and was scanned at 4 h post-dose. Binding potential (BP) was compared with that seen in the subject predosed with placebo and with that seen in nine unmedicated normal volunteers. Subjects studied up to 12 h post-dose had BPs that were greater than 2 SD less than the mean BP, indicative of extensive D2 receptor binding by ziprasidone. With increasing time between dosing and PET scanning there was a curvilinear increase in BP, so that all studies performed at or after 18 h post-dose gave BPs in the normal range (mean +/- 2 SD). Elevated prolactin levels returned to within the normal range by 18 h post-dose. PET measures of binding potential correlated significantly with serum levels of ziprasidone at the time of scanning and less significantly with absolute prolactin levels at the same time.

Hemodynamic and humoral effects at rest and after head-up tilt tests during 24-hour infusion of a new nitrate ester, ITF 296, compared with ISDN and placebo in healthy volunteers: a double-blind, randomized, within-subject study.

A double-blind, randomized, three-way complete crossover study was carried out to compare pharmacodynamic effects and tolerability during a 24-h intravenous infusion of ITF 296, isosorbide dinitrate (ISDN), and placebo, in the supine position and during 70 degrees head-up tilt. Ten healthy men aged 21-34 years participated in the study to obtain complete data in nine. Dosing started at 1 microgram/kg/min and was titrated up during the first 30 min of infusion, to produce a 10% reduction in diastolic blood pressure (DBP). At least 6 days elapsed between consecutive treatments. Heart rate (HR) and blood pressure were measured at least half hourly throughout the infusion period and up to 2 h afterwards. Systolic time intervals were measured before and at 0.5, 1, 2, 3, and 24 h of infusion in the fasting state. Tilt tests (70 degrees head-up for 2 min) were performed at 1, 6, 12, and 24 h of infusion. From 60 min before tilt, during tilt, and up to 15 min after end of tilt, ECG was monitored and BP, HR, and b/a ratio were recorded by means of fingertip plethysmography. Plasma-renin activity and concentrations of epinephrine and norepinephrine were measured preinfusion, and before and after tilt tests. Subjects were questioned frequently about adverse events. General tolerability of ISDN in the nine subjects who completed the study was poor, with eight suffering from headache and four from symptoms suggesting postural hypotension during tilt tests. Tolerability of ITF 296 was better, with 5 of 10 subjects reporting headache and 2 of 10 symptoms of postural hypotension during the first tilt only. Both active treatments successfully reduced DBP by at least 10% in all subjects at similar dose levels (final infusion rates 2.8 and 2.3 micrograms/kg/min for ITF 296 and ISDN, respectively). Systolic blood pressure (SBP) was reduced by about 6-7 mm Hg by both treatments. HR was increased by about 5 beats/min by ISDN but not by ITF 296. Those changes in BP and HR persisted throughout the 24-h infusion and reversed when it was discontinued. Fingertip plethysmography showed a profound reduction of b/a ratio, which persisted throughout the 24-h infusion. ISDN had consistently greater effects than ITF 296, suggesting that ISDN has the greater effects on small arterial vessels. Both active treatments reduced QS2 index throughout the 24-h period. Both treatments also reduced left-ventricular ejection time (LVET) index up to 3 h of infusion, with ISDN having the greater effects on LVET index and ITF 296 being intermediate between ISDN and placebo. ISDN prolonged pre-ejection period (PEP) at 1 h, had no effect at 2 h, and shortened PEP at 3 and 24 h. ITF 296 decreased PEP consistently during the 24-h infusion. Plasma-renin activity, epinephrine, and norepinephrine were increased by ISDN substantially more than by ITF 296. These results show that both ITF 296 and ISDN had comparable effects on diastolic blood pressure at similar dose-levels. ISDN increased HR, whereas ITF 296 did not. b/a Ratio was reduced more by ISDN, suggesting a greater activity on small arterial vessels. Arterial effects were maintained throughout the 24-h infusion. ISDN had a greater effect on venous return than ITF 296. ITF 296 seemed to show more balanced effects on preload and afterload than ISDN. ISDN caused significantly greater neurohumoral counter-regulation than ITF 296. Hemodynamic response to tilt was attenuated, as judged by the fact that hypotension occurred only during the early hours of the infusion, but the variability in the response of BP to tilt does not allow any firm conclusions to be drawn about possible development of tolerance. Tolerability of ISDN was poor and that of ITF 296 was better.

Interrelationships between Helicobacter pylori infection, nonsteroidal antiinflammatory drugs and gastroduodenal disease. A prospective study in healthy volunteers.

Helicobacter pylori and nonsteroidal antiinflammatory drugs independently cause gastroduodenal mucosal injury but the relationship between them remains unclear. We have performed a double-blind, parallel-group, placebo-controlled prospective study in 77 healthy volunteers aged 19-35 years who were randomly allocated to indomethacin (N = 15), one of three oxicams (piroxicam, chlortenoxicam, or CHF 1194; N = 36), or placebo (N = 26). Esophagogastroduodenoscopy was performed before and after four weeks of treatment and the mucosal appearances graded. Colonization with H. pylori was established at each endoscopy and gastrointestinal symptoms were assessed by daily diary card. Seven subjects (9%) were positive for H. pylori before treatment (one placebo, one indomethacin, and five an oxicam); their H. pylori status remained unchanged. Two of 70 H. pylori-negative subjects became H. pylori-positive (2.9%), both of whom had received placebo. The endoscopic score deteriorated in 1/6 drug-treated H. pylori-positive subjects and in 0/1 taking placebo. Of the H. pylori-negative subjects whose endoscopic score deteriorated, three (13%) were taking placebo, four (28.6%) indomethacin, and eight (25.8%) an oxicam. Upper gastrointestinal symptoms were reported in eight (30.8%) of the subjects taking placebo (one subject negative for H. pylori became positive), eight (53.3%) indomethacin (one H. pylori-positive), and 10 (27.8%) an oxicam (one H. pylori-positive). There were no statistically significant differences between the H. pylori-negative and H. pylori-positive groups whether on drug or placebo.(ABSTRACT TRUNCATED AT 250 WORDS)

Renal and general tolerability of repeated doses of nimesulide in normal subjects.

The renal and general tolerability of nimesulide was studied in 16 healthy men, randomised to 4 groups of 4 subjects. The groups all underwent 2 treatment periods of 7 days each, separated by a washout period of 14 days. The second treatment period was always at a higher dosage level than the first. There were 4 dosage regimens: placebo, and nimesulide 200, 300 and 400mg, all given twice daily by mouth according to a double-blind design. The tolerability of nimesulide was assessed by regular clinical examination, nondirected questions about adverse events, haematological and biochemical screening, and daily urine testing. Plasma and urinary concentrations of Tamm-Horsfall glycoprotein (THG), urinary retinol-binding protein (RBP) and beta-N-acetyl glucosaminidase (NAG) on days 1, 3, 7, and 10 of each period were used as selective indicators of nephrotoxicity. The highest dose of nimesulide (800mg daily) was associated with abdominal pain and indigestion in 5 of 8 recipients. The 400 and 600mg daily dosages were well tolerated. There were no clinically significant alterations in the haematological or biochemical screening tests during the study, and daily urinalysis remained normal throughout. The renal toxicity tests showed no evidence of nephrotoxicity associated with the administration of nimesulide in 14 subjects. The other 2 subjects each had modest increases in either urinary THG or NAG concentrations during treatment with nimesulide 800mg daily, but the results of their other tests remained normal. The study, therefore, showed only equivocal evidence of minor renal toxicity with nimesulide 800mg daily. Nimesulide 400 and 600mg daily were well tolerated in all respects, even though these dosages are higher than those recommended for clinical use.

Dose dependent occupancy of central dopamine D2 receptors by the novel neuroleptic CP-88,059-01: a study using positron emission tomography and 11C-raclopride.

Positron emission tomography (PET) and 11C-raclopride were used to measure the occupancy of central dopamine D2 receptors by a new neuroleptic, CP-88,059-1. In a double blind dose escalation study, seven healthy male subjects received a predose of between 2 mg and 60 mg CP-88,059-1, 5 h before PET scanning. One additional subject was assigned to placebo predose. Receptor occupancy was defined as the percentage reduction in binding potential compared with that seen in the subject predosed with placebo and with that seen in seven unmedicated normal volunteers previously studied. Binding of 11C-raclopride decreased in a dose dependent manner, and 85% dopamine D2 receptor occupancy was achieved with the highest dose of CP-88,059-1. The findings confirm that brain dopamine D2 receptors are blocked by CP-88,059-1 and suggest that an effective antipsychotic dose will be between 20 mg and 40 mg. The study high-lights the potential of positron emission tomography in the preclinical evaluation of new drugs.

Clinical implications of the pharmacology of serotonin reuptake inhibitors.

The selective serotonin reuptake inhibitors (SSRIs) are a tribute to the ingenuity of pharmacologists and designers of molecules. Not only do these drugs have remarkable selectivity for the reuptake of serotonin compared with other monoamines, but also they have a commendable lack of affinity for receptors including the serotonin receptor. In contrast, the classical tricyclic antidepressants (TCAs) are less specific in their pharmacological action. In addition to inhibiting the reuptake of serotonin, TCAs inhibit the uptake of noradrenaline, dopamine and tyramine, and antagonize cholinergic (muscarinic), adrenergic and histaminergic receptors. Moreover, TCAs have quinidine-like anti-arrhythmic activity and lower the seizure threshold. Clinical investigations have shown that the SSRIs have equivalent therapeutic efficacy compared with the TCAs in the treatment of depression. However, the pharmacological specificity of the SSRIs is a clinical advantage since they lack the propensity to cause dry mouth, blurred vision, urinary hesitancy, constipation, hypotension and arrhythmia. Furthermore, the SSRIs are relatively safe in overdosage. The similarities between the SSRIs are more obvious than their differences: all are highly potent and selective inhibitors of serotonin reuptake with efficacy in the treatment of depression. Nevertheless, each has a distinctive pharmacological profile. In this review the characteristics desired in an "ideal" antidepressant are examined, and the ways in which the TCAs and SSRIs fit this ideal are compared.

Cardiovascular effects of antidepressants: studies of paroxetine in healthy men and depressed patients.

The classical tricyclic antidepressant drugs effectively relieve the symptoms of depression, but they have the potential to be severely toxic to the cardiovascular system--including postural hypotension after therapeutic doses and lethal arrhythmias after overdosage. Paroxetine has been shown to be of similar efficacy to the tricyclic antidepressants but has lower cardiovascular toxicity in animal models and has no effects on heart rate, blood pressure or the electrocardiogram in healthy men receiving single 20-40 mg doses. The results of two contrasting studies in depressive patients and healthy men provide strong evidence that therapeutic doses of paroxetine lack any important haemodynamic or electrophysiological effects.

Clinical implications of the pharmacology of sertraline.

Sertraline is slowly absorbed after oral administration, with peak plasma concentrations at 6-8 h. Plasma concentrations are linearly related to dose. The elimination half-life is about 32 h; metabolism is by demethylation to an inactive metabolite. Once-daily dosing is recommended, with steady state being reached after about 7 days. The kinetics of sertraline in the elderly and in patients with renal impairment are similar to those in young healthy female volunteers. In young male volunteers, peak plasma concentrations were lower, and elimination half-life shorter, than in elderly men or both groups of women. Nevertheless, no reduction in dosage is recommended for these groups. Sertraline is highly active in animal models of depression, and administration of the drug to healthy human beings causes a selective, dose-related inhibition of 5-hydroxytryptamine (5-HT) uptake into blood platelets. Single doses of sertraline in volunteers caused changes in the quantitative pharmaco-electroencephalogram suggesting antidepressant and anxiolytic actions, with sedative potential evident only at doses of 200 mg or more. Sertraline does not impair psychomotor performance, including simulated car driving, and overall seems neither stimulating nor sedating: an increase in critical flicker fusion threshold suggests a slight alerting effect, whereas subjective tests indicate an increase in perceived sedation at doses of 100 mg or more. No potentiation of the effects of ethanol has been noted in either young or elderly subjects. No adverse effects on the electrocardiogram, blood pressure, or systolic time intervals have been detected, and sertraline lacks anticholinergic action. These studies imply a low probability of adverse central nervous and cardiovascular effects. Sertraline is probably a weak inducer of hepatic microsomal enzyme activity. Sertraline does not affect the clearance of lithium but there may be a pharmacodynamic interaction which leads to increased tremor when the drugs are given together. No clinically relevant effects were noted in the interaction studies with digoxin, atenolol and diazepam. The pharmacokinetics and pharmacodynamics of sertraline are generally favourable. However, caution is needed when sertraline is given to patients receiving lithium or drugs with a low therapeutic ratio, such as corticosteroids, oral hypoglycaemic agents, and warfarin.

A pharmacokinetic and dynamic study of single nightly doses of conventional and controlled release formulations of trazodone.

We studied the pharmacokinetics and dynamics of single evening oral doses of conventional capsules (100 mg) and a controlled release formulation (150 mg) of trazodone in 12 fasting and non-fasting young healthy volunteers. When corrected for the different doses used, there was no significant difference among the areas under the plasma concentration-time curves (AUC) for the conventional capsules and the controlled release tablets under fasting and non-fasting conditions. Both conventional and controlled release formulations were followed by a reduction in critical flicker fusion threshold (CFFT) and this effect was not influenced by the administration of food before dosing. After both conventional and controlled release formulations, blood pressure was significantly lower when medication had been given in the fasting state than when it had been given after food. The frequency of adverse symptoms was greater after the controlled release (150 mg) than after the conventional (100 mg) formulation. We conclude that there is no obvious advantage to the controlled release formulation (150 mg) and that conventional trazodone (100 mg) should be taken after food when it is given at night.

Ethics of evaluation of new drugs in human volunteers.

Experiments in human volunteers are a vital part of the evaluation of most new drugs. Are such experiments ethical? This question is discussed in the light of four ethical principles: justice, beneficence, non-maleficence and respect for autonomy. Problem areas include recruitment of volunteers, obtaining consent, payment for participation and special groups such as students and staff of research institutions, the poor, women of child-bearing potential, children and elderly volunteers. Drug evaluation in volunteers does present ethical difficulties, but none of these is insurmountable.

Clinical pharmacology of moclobemide, a new reversible monoamine oxidase inhibitor.

The clinical pharmacology of the new reversible monoamine oxidase (MAO) inhibitor, moclobemide, was examined in three separate studies in healthy male volunteers. In a single oral dose study, moclobemide (25-150 mg) was rapidly absorbed from the gastrointestinal tract and had a relatively short plasma half-life (mean 1.3 h after 150 mg). A decrease in the plasma concentrations of the noradrenaline metabolite 4- hydroxy-3-methoxyphenylglycol (HMPG), however, indicated a longer time to peak pharmacodynamic effect and longer duration of activity. Assay of platelet MAO activity did not reveal any evidence of irreversible inhibition of the B form of the isoenzyme. Single oral doses of moclobemide (150 and 300 mg) significantly lowered the threshold to the cardiovascular effects ('cheese reaction') of intravenous tyramine. However, after repeated administration of 100 mg three times daily for over 2 weeks, moclobemide caused significantly less potentiation than did phenelzine (15 mg three times per day) on the cardiovascular effects of oral tyramine, a clinically more relevant model. The MAO-B inhibitor, selegiline (5 mg once daily), also lowered the oral tyramine threshold significantly. Moclobemide was generally well tolerated by these healthy volunteers.

Betaxolol and glucose-insulin relationships: studies in normal subjects taking glibenclamide or metformin.

1. The potential interaction between selective beta 1-adrenoceptor blockers and sulphonylureas or biguanides was studied by comparing the beta 1-adrenoceptor antagonist betaxolol with placebo in 12 normal subjects taking glibenclamide or metformin in a single-blind crossover group study. 2. After a 4 day run-in period on no treatment, six subjects took glibenclamide 2.5 mg twice daily, and six subjects took metformin 850 mg twice daily from day 5 to day 19. All subjects took betaxolol 20 mg daily from day 10 to day 13, and placebo from day 5 to day 10 and from day 13 to day 19. 3. Plasma glucose and insulin concentrations were measured fasting and 60 min after a standard breakfast for 3 successive days during each study treatment; plasma potassium, sodium and betaxolol concentrations were also measured. 4. Fasting glucose, insulin and potassium concentrations did not differ significantly between betaxolol and placebo treatment periods in either glibenclamide- or metformin-treated groups. Post-prandial glucose and insulin concentrations were lower and higher, respectively, relative to fasting concentrations but there was no significant difference between any of the treatment periods. Glibenclamide produced significant increases in insulin concentrations compared with drug-free periods (P less than 0.01). Plasma potassium and sodium concentrations were not affected by any of the treatments. 5. Plasma betaxolol concentrations were adequate for beta 1-adrenoceptor blockade. 6. This study suggests that selective beta 1-adrenoceptor blockade with betaxolol does not change fasting or post-prandial glucose-insulin relationships during simultaneous treatment with either the sulphonylurea glibenclamide or the biguanide metformin.

Lornoxicam, indomethacin and placebo: comparison of effects on faecal blood loss and upper gastrointestinal endoscopic appearances in healthy men.

Forty-five healthy men aged 21-34 years took part in a double-blind, parallel-group, placebo-controlled study of the effects of 28 days' treatment with lornoxicam 4 mg twice daily or indomethacin 50 mg twice daily on faecal blood loss and the endoscopic appearances of gastric and duodenal mucosa. After an initial endoscopic examination, subjects received, intravenously, on day 0, autologous erythrocytes labelled with 51Cr. Complete daily faecal collections were then made from days 6-12, 20-26 and 34-40. The drug treatments or placebo were given from days 13-41. Faecal blood loss was calculated from 51Cr-specific activity of blood and faeces. Endoscopy was repeated 4-8 hours after the last dose of medication; mucosal appearance was graded on a 5-point scale. Lornoxicam caused no more adverse events than placebo; indomethacin caused more indigestion and central nervous system effects, and one subject in this group was withdrawn from the study. Median total blood losses during the pre-treatment and the second and fourth weeks of treatment were respectively 3.33, 3.95 and 5.71 ml for lornoxicam, 2.87, 7.04 and 7.75 ml for indomethacin, and 4.55, 3.64 and 4.13 ml for placebo. Differences between treatments were not statistically significant (P = 0.081 for second week of treatment, P = 0.383 for fourth week of treatment; Kruskal-Wallis test). The effect of chlortenoxicam on faecal blood loss in this study was thus intermediate between placebo and indomethacin, but within- and between-subject variability was such that the differences were not statistically significant. Endoscopic findings were normal in most subjects before and after all treatments, but indomethacin was associated with a slightly greater deterioration in endoscopic score and was the only treatment associated with Grade 3 appearance (in a single patient) in post-treatment endoscopy.