The pulmonary deposition of two aerosol preparations of nedocromil sodium delivered by MDI assessed by single photon emission computed tomography.

The pulmonary deposition and pharmacokinetics of fine and coarse radioactive aerosols of nedocromil sodium, of mass median aerodynamic diameters 16 microns and 24 microns respectively, delivered by metered dose inhaler (MDI) have been investigated. The corresponding geometric standard deviations of the particle size distributions were 5.32 and 3.93. Pulmonary deposition was assessed by both planar radionuclide scintigraphy and multi-modality three dimensional imaging using single photon emission computed tomography (SPECT) and x-ray computed tomography (CT). The three dimensional data were analysed by transformation to a hemispherical shape based on the fractional radial distance of each point in the lung from the centre to the corresponding extrapolated point on the periphery. This enabled parameters on the variation of both concentration of deposition and total amount deposited with penetration distance to be calculated. For both planar and SPECT data the central to peripheral concentration ratio (C/P ratio) was calculated. The three dimensional C/P ratio showed a median value (3.21) which was significantly higher than for the planar imaging (2.03) (p < 0.001). The parameter used to express the variation of total amount deposited was the median dose position. This showed that for both aerosols 50% of the dose was deposited at sites with a percentage central to peripheral distance of greater than 68%. There was a trend for total percentage of the fine aerosol in the lungs to be higher than for the coarse and for its deposition to be more peripheral. In addition the mean concentrations in blood were measured to be greater for the fine aerosol. However these differences were relatively small and none were individually statistically significant. The technique of combined SPECT and CT imaging was shown to be valuable in obtaining more accurate information on pulmonary distribution of inhaled aerosol deposition. The merits, limitations and potential applications of the technique are discussed.

Comparison of the efficacy and acceptability of nicardipine and propranolol, alone and in combination, in mild to moderate hypertension.

1. We evaluated the relative efficacies and tolerability of various low-dose combinations of nicardipine and propranolol in patients with mild-moderate essential hypertension (DBP Phase V of greater than 90-125 mmHg; WHO Grades I and II) in order to select the best one. 2. Sixty patients completed the double-blind, balanced, randomised three-way cross-over protocol, with each phase lasting 4 weeks, and in which twice daily nicardipine 40 mg or propranolol 80 mg was compared with four twice daily combinations of nicardipine (20 or 30 mg) plus propranolol (40 or 80 mg). 3. At 'peak' effect time (i.e., 2 h post-dosing) all four treatment combinations were significantly more effective than propranolol, with effects ranging from 9-23 mmHg (systolic) and 5-15 mmHg (diastolic). Only the two 30 mg nicardipine combinations with propranolol were more effective than nicardipine monotherapy, further reducing BP by 8-13 mmHg (systolic) and 5-7 mmHg (diastolic); there were no significant differences between them. 4. 'Trough' diastolic pressures were not different between treatments and 'trough' BP control was sub-optimal on all treatments. 5. 70% of patients on nicardipine monotherapy, 33% of those on propranolol monotherapy and 30% of patients during the placebo run-in complained of symptoms. In terms of complaint rates, there was little to choose between the four combinations (27-33%). Serum potassium and creatinine levels were elevated following propranolol monotherapy by 0.19 mmol 1-1 and 6.5 mumol 1-1 respectively (P less than 0.01 for both) and following the nicardipine 30 mg/propranolol 80 mg combination. Nicardipine monotherapy elevated serum T4 levels by an average of 0.57 ng dl-1 (P less than 0.05). 6. The twice daily combination of nicardipine 30 mg plus propranolol 40 mg was therefore the optimum one in terms of its efficacy and tolerability. Further studies need to be performed to test the hypothesis that a higher dose of propranolol might ameliorate troublesome vasodilator side effects. However, none of the treatments studied was ideal for clinical use in the twice daily dosage used in this study.

Psychomotor effects of ketorolac in comparison with buprenorphine and diclofenac.

1. Ketorolac is an investigational non-opioid analgesic. Buprenorphine, an opioid compound and diclofenac, a non-steroidal anti-inflammatory, are analgesics used in clinical practise. 2. The psychomotor effects of ketorolac (30 mg), buprenorphine (0.3 mg), diclofenac (50 mg) and placebo all administered i.m., were examined in 12 healthy male volunteers (age 19-38 years), up to 8 h post-dose. 3. Creatine phosphokinase (CPK) was measured up to 24 h post-dose, providing an indication of local tissue damage following injection. 4. Buprenorphine caused significant psychomotor impairment in seven out of eight psychomotor tests. The effects consistently peaked 4 h post-dose and were still apparent in many cases 8 h post-dose. These psychomotor effects were supported by marked symptoms in all volunteers. 5. Ketorolac and diclofenac had no clinically significant effects on psychomotor tests and only minimal symptoms were reported. 6. Diclofenac caused a marked increased in CPK (mean Cmax 298 iu l-1) compared with ketorolac (mean Cmax 70 iu l-1) and buprenorphine (mean Cmax 68 iu l-1). 7. These results suggest that ketorolac and diclofenac are suitable for administration following day case surgery.

Atherogenesis in the White Carneau pigeon. Further studies of the role of carbon monoxide and dietary cholesterol.

Two experiments are described. In the first, 3 pairs of groups of 20 female White Carneau pigeons were fed on diets containing 0.5%, 1% or 2% cholesterol. Birds in one group from each pair were exposed to 150 ppm carbon monoxide (CO) for 6 h on 5 days of each week for 52 weeks, sufficient to raise their carboxyhaemoglobin (COHb) levels to approximately 10%, while those in the other group were sham-exposed under similar conditions. In the second experiment, 3 groups of 40 female pigeons were each fed on a diet containing 1% cholesterol, one group being exposed to CO to give COHb levels of 20%, one to give COHb levels of 10% and one being sham exposed. In addition, 20 birds in the second experiment were fed on the 1% cholesterol diet but were neither exposed to CO nor sham-exposed. Cholesterol enriched diets caused mean plasma cholesterol values in each group to rise sharply within 4 weeks of starting them, but the levels reached were as high with diets containing 0.5% cholesterol as for diets containing 1% or 2% added cholesterol. Exposure to CO increased plasma and aortic cholesterol levels, though this increase was only statistically significant for aortic levels in the second experiment. In both experiments combined exposure to the 1% cholesterol diet and CO resulted in a significant decrease in aortic triglyceride content. The incidence and severity of coronary artery atherosclerosis was associated with increasing dietary cholesterol. It was also associated with exposure to CO in birds given 0.5% or 1%, but not 2%, dietary cholesterol; the increase in birds given 1% was related to the dose of CO. Possible mechanisms are discussed for this effect of CO, which is not found in normally fed birds.