A 12-month randomized controlled study of the aldose reductase inhibitor ponalrestat in patients with chronic symptomatic diabetic neuropathy.

The effects of the aldose reductase inhibitor ponalrestat (600 mg day-1) on sensory, electrophysiological, and autonomic function were examined in 50 patients with chronic symptomatic, distal symmetrical diabetic neuropathy in a 52-week randomized, double-blind, parallel-group, placebo-controlled, single-centre study. In an endeavour to identify patients with a degree of neuropathy potentially amenable to pharmacological intervention, a minimum conduction velocity of 30 m s-1 was set for the peroneal motor nerve. At 52 weeks, no significant differences were observed between the ponalrestat and placebo groups in motor (ulnar, median, and peroneal) or sensory (ulnar and radial) nerve conduction velocities, vibration perception thresholds, adjectival symptom scores or tests of autonomic function (mean electrocardiographic R-R interval variability on deep breathing and orthostatic blood pressure response). Ponalrestat was clinically well tolerated and had no significant effect on glycaemic control. The lack of beneficial effects of ponalrestat may in part reflect the advanced stage of the neuropathic process in patients with established symptomatic disease, and the poor reproducibility of current neurophysiological techniques. Firmer knowledge of clinico-pathological correlates allied to improved non-invasive neurophysiological measurement techniques should facilitate the selection of patients for future therapeutic trials in diabetic neuropathy.

Peripheral and autonomic nerve function in 259 diabetic patients with peripheral neuropathy treated with ponalrestat (an aldose reductase inhibitor) or placebo for 18 months. United Kingdom/Scandinavian Ponalrestat Trial.

The potential of the aldose reductase inhibitor ponalrestat (600 mg daily) to ameliorate diabetic neuropathy was evaluated in 259 diabetes mellitus patients with peripheral neuropathy (defined by abnormal vibration perception threshold and abnormal peroneal motor conduction velocity) in a double-blind placebo-controlled clinical trial running for 18 months. Overall, no beneficial effect of ponalrestat on vibration perception thresholds, nerve conduction velocities, and nerve action potential amplitudes was detected. Because vibration perception thresholds and conduction velocities in median, peroneal, and sural nerves did not deteriorate in the placebo group, the potential of ponalrestat to prevent the expected deterioration in peripheral nerve function that occurs with an increased duration of diabetes was not tested. Patients with an abnormal heart rate reaction to standing (abnormal 30:15 ratio; n = 84) on ponalrestat did not deteriorate in this autonomic nerve function test as shown in those on placebo. In conclusion, ponalrestat did not improve peripheral nerve function in diabetes mellitus patients with signs of peripheral neuropathy, although it did ameliorate a deterioration in autonomic nerve function in diabetic patients with signs of autonomic neuropathy.

Metabolic effects of aldose reductase inhibition in diabetic man.

The metabolic effects of 52 weeks treatment with the aldose reductase inhibitor ponalrestat were examined in 32 diabetic patients (16 insulin treated) in a randomized, double-blind, placebo-controlled clinical trial. Twelve hour metabolic profiles were performed on two separate occasions in each patient (a) during a single-blind placebo run-in period and (b) after 52 weeks treatment with either ponalrestat 600 mg/day or matching placebo. No effects attributable to ponalrestat were evident in glucose, pyruvate, or alanine metabolism. A significant overall treatment effect was observed for lactate concentration (ponalrestat vs. placebo 12 h least square mean at 52 weeks: 1.35 vs. 1.65 mmol/l, p = 0.024). For glycerol (p = 0.018), non-esterified fatty acids (p = 0.003) and total ketone bodies (p = 0.045) there was evidence for a variation of treatment with time between the insulin treated and non-insulin treated patients, although no statistically significant overall treatment effects were observed for any metabolite. Fasting total ketone body concentration at 52 weeks was significantly elevated in the insulin-treated patients receiving ponalrestat (antilog LS mean: 0.12 vs. 0.01 mmol/l, p = 0.01). In conclusion, ponalrestat has no effect on glucose metabolism in diabetic patients. A potentially beneficial effect on lactate metabolism was accompanied by a minor ketogenic effect in insulin-treated patients.

A study of peripheral diabetic neuropathy. The application of age-related reference values.

The standardization of methodology and the provision of age-related reference values have been addressed for the design of and interpretation of data from a multicentre neuropathy trial. Age-related reference values were generated from 120 healthy volunteers. Vibration perception thresholds (VPT) deteriorated significantly with age (p less than 0.001). Patients were selected on the basis of age-related abnormal VPT and peroneal motor nerve conduction velocity. They were assessed at the beginning and end of a placebo run-in period (baseline data). The coefficients of variation (CV%) for VPT at the medial malleolus (16.81 per cent, n = 316) and great toe (19.23 per cent, n = 313) were lower compared to results in healthy volunteers (29.7 per cent and 20.8 per cent, respectively, n = 49). The CV% for expiratory:inspiratory (E:I) ratio (4.82 per cent, n = 215), Valsalva manoeuvre (10.84 per cent, n = 249) and 30:15 ratio (7.73 per cent, n = 292) from patients corresponded to those recorded in volunteers (7.6 per cent, n = 45 11.0 per cent, n = 49 9.5 per cent, n = 48, respectively). Most patient values for VPT at the great toe fell beyond the 95 centile line for volunteers. E:I ratio for volunteers showed a more variable relationship with age, although patient values appeared to be located below the 5 centile line for volunteer data.

The effect of indomethacin on breathlessness in patients with diffuse parenchymal disease of the lung.

We have shown in a previous study that indomethacin reduced breathlessness in normal subjects during exercise. In a double-blind randomized study we have determined the effects of both acute (50 mg) and chronic (25 mg twice daily for 7 days) oral treatment with indomethacin on breathlessness induced by exercise in patients with diffuse parenchymal disease of the lung. The relationship of breathlessness, as measured on a visual analogue scale, to ventilation was not significantly altered by either acute or chronic treatment with indomethacin compared to placebo. There was no significant change in the distance walked in 6 minutes after any of the treatments. Possible explanations for the differing effects on breathlessness observed in normal subjects and in patients are discussed.

The analysis of a sequential clinical trial for the comparison of two lung cancer treatments.

Methods adopted in the analysis of data from a randomized controlled trial of a new treatment for inoperable lung cancer are described. The trial design employed the sequential logrank test using length of survival from time of randomization as the principal outcome measure. We describe the practical arrangements for regular inspections of the accumulating data as required by the sequential design, and also for more extensive but less formal interim analyses, and present some of the results. On termination of the trial the survival patterns of the two treatment groups were compared using methods of analysis developed specifically to allow for the sequential nature of the trial design. The role of prognostic factors was investigated using fixed sample methods which are approximately independent of the sequential design.

Percutaneous absorption of chlorhexidine in neonatal cord care.

The percutaneous absorption of chlorhexidine during its routine use in topical antiseptic preparations used in umbilical cord care was investigated by determining plasma chlorhexidine concentrations at ages 5 and 9 days. These showed that percutaneous absorption of chlorhexidine occurred in preterm neonates treated with a 1% solution of chlorhexidine in ethanol, but not in term infants similarly treated, or in preterm infants treated only with a dusting powder containing 1% chlorhexidine and 3% zinc oxide.

Cardioselectivity of atenolol in asthmatic patients.

This double-blind, randomised, within patient, placebo-controlled study set out to investigate the effect of a cardioselective beta-blocker, atenolol, at different oral doses (50, 100 and 200 mg) and a non-selective agent, propranolol (40 mg), upon 1. airways resistance (forced expiratory volume at one second = FEV1) and 2. the bronchodilator action of increasing doses of inhaled isoprenaline, in patients with co-existent hypertension and reversible airways obstruction. In 10 patients, two hours after drug administration, the 3 doses of atenolol caused a significantly greater (P less than 0.05) degree of B1-blockade than propranolol. In contrast the 3 doses of atenolol caused significantly less (P less than 0.05 to 0.01) B2-blockade as evidenced by a smaller fall in FEV1. The isoprenaline FEV1 dose response curves were displaced progressively to the right of the placebo curve with increasing doses of atenolol, but the greatest displacement was with propranolol. It was concluded that patients with reversible airways obstruction who require beta-blockade should be given a low dose of a cardioselective agent in conjunction with, if required, a beta 2 stimulant such as isoprenaline. Such a treatment will be less likely to cause a troublesome increase in airways resistance and the bronchodilator action of the beta 2 stimulant will be almost fully preserved.

Bioavailability of sustained release propranolol formulations.

In this comparative bioavailability study two sustained release capsule formulations of propranolol, one a clinical trial formulation and the other the U.K. sales formulation ('Inderal' LA), were compared with a conventional 'Inderal' tablet. Twelve healthy adult male volunteers received, on cross-over basis, on three separate occasions, 160 mg oral doses of three formulations of 'Inderal'. Bioavailability was based on concentration of propranolol in whole blood. The peak blood level and area under the propranolol blood level curve fell as the dissolution time increased. The half-lives of the three formulations were inversely proportional to their dissolution rates, those of the sustained release formulations being considerably longer than that of the conventional tablet. The 160 mg 'Inderal' tablet produced a rapid 90-fold decline over 24 h in propranolol blood levels following a high initial peak. By comparison both sustained release formulations showed a less rapid fall in systemic levels and gave higher blood levels at the end of 24 h and plateau values between 8 and 14 ng ml-1. The 'Inderal' LA sustained release formulation gave consistently higher propranolol blood levels than the clinical trial sustained release formulation. This result is in good agreement with their dissolution profiles. The lowering of the systemic bioavailability as the dissolution time increases is thought to be due to an increased metabolism of propranolol.

Bioavailability of atenolol formulations.

In this comparative bioavailability study two tablet formulations of atenolol (sales and clinical trial) were compared with an oral solution. Twelve healthy adult male volunteers received, on a cross-over basis, on three separate occasions, 100 mg oral dose of the three formulations of atenolol. Bioavailability was based on concentrations of atenolol in whole blood and urine. The atenolol blood levels peaked at approximately 3 h after dosing, with individual values ranging from 0.21 to 0.92 microgram ml-1 (a four-fold difference), with all three formulations. Three-fold variations among subjects occurred in the areas under the curve (AUC) and urinary recoveries. The average elimination of half-life of atenolol was between 6 and 7 h for all three formulations. Some statistically significant differences were observed between the tablets and the aqueous solution: the AUC (infinity) and mean peak blood concentrations were significantly greater with the U.K. sales tablet than the solution, and the mean concentrations in the blood at certain specified times after administration were significantly greater with the two tablet formulations than the solution. The profiles of absorption and excretion of the two tablet formulations were similar. No adverse reactions were encountered in this study and all subjects completed the study without incidence.

Absorption of chlorhexidine from the intact skin of newborn infants.

34 newborn infants who had been bathed in a standard manner with Hibiscrub were studied to find out whether it was absorbed percutaneously. Low levels of chlorhexidine were found in the blood of all 10 babies sampled by heel prick, and 5 of 24 from whom venous blood was taken. The detection of chlorhexidine varied greatly with the method and timing of sampling, and no correlation was found between gestational or postnatal age and chlorhexidine levels.