Objectives: To assess safety, tolerability, pharmacokinetics and hemodynamic effects of oral CF101, 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 12hourly oral doses of CF101 (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 study: 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 doselimiting 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 welltolerated. 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 inf 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 × 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 welltolerated. 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 du...

RESULTSMorning normal ranges of testosterone for men aged £ 40 years were 10.07-38.76 nmol/ L (2.90-11.18 m g/L), and for men age ≥ 40 years, 7.41-24.13 (2.14-6.96); the respective evening normal ranges were 6.69-31.51 (1.93-9.09) and 6.46-21.93 (1.86-6.33). Both morning and evening serum testosterone declined significantly with increasing age and BMI. LH was significantly higher in the morning than in the evening, but did not vary between the age groups or with BMI. The calculated normal ranges of LH were 0.9-7.0 IU/L (morning) and 0.7-6.8 IU/L (evening). CONCLUSIONSThe lower limit of normal for serum testosterone was 3-4 nmol/L (0.86-1.15 m g/L) lower than that of published ranges. The results have important implications for the diagnosis of hypogonadism and use of testosterone replacement therapy.

1. Ten studies were performed on nine patients with haematological disorders but with normal lungs, who required intermittent blood transfusions. The transfer factor for carbon monoxide and uptake of carbon monoxide per unit lung volume (KCO) were measured with the single breath technique before and at various intervals after transfusion. 2. The mean haemoglobin concentration increased from 7.7 to 11.1 g/dl. 3. The TLCO increased according to a formula based on the Roughton & Forster (1957) diffusion equations. TLCO (standardized) = TLCO (observed). (10.2 + Hb)/1.7 Hb, where haemoglobin (Hb) is expressed as g/dl. 4. The correlation between measured and predicted values was slightly better if changes in alveolar volume were taken into account, by using the KCO value.

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