Effects of sphygmomanometer type and position of the arm on blood pressure measurement.

Random zero and standard sphygmomanometers were compared in a balanced study performed by 36 members of a General Practitioner Clinical Research Group. In addition the influence of arm position, supported versus dependent, was examined. There was minimal difference between the mean blood pressures measured by the two sphygmomanometers, although the results from the random zero were more variable. The mean blood pressures with the arm supported were consistently lower than with the arm dependent: 127/79 mmHg arm supported vs 131/83 mmHg arm dependent. It is recommended that the position of the arm should be standardised to that of being supported roughly horizontally at heart level. The random zero machine should be used for clinical trial work where the elimination of observer bias is important, and when proper training of observers can be undertaken.

An evaluation of the relative importance of formulation and process variables using factorial design.

A factorial design method for assessing the relative importance of various formulation and process factors and their interactions in model paracetamol tablets is described. The design was a 2 X 2 X 2 X 3 type using mixing time, starch concentration, drug particle size and compaction pressure respectively. The starch concentration was the most significant factor in affecting the dissolution rate but the larger drug particle size also gave a significant increase in drug release rate. Interactions between starch concentration and drug size and between these and mixing time were also observed. The most significant factor affecting the tensile fracture stress of the tablets was the mixing time, followed in order by the drug particle size, starch concentration and compaction pressure.

The effect of molecular size on the nasal absorption of water-soluble compounds in the albino rat.

The nasal absorption of a range of water-soluble compounds with different molecular weights, 4-oxo-4H-1-benzopyran-2-carboxylic acid (mol. wt 190), p-aminohippuric acid (mol. wt 194), inulin (mol. wt 5200) and dextran (mol. wt 70,000), has been investigated in the male Wistar rat. Compounds were instilled into the nasal cavities of anaesthetized animals, and for comparison, similar doses were administered intravenously. Serial samples of bile and urine were collected for up to 6 h. Nasal absorption, estimated by comparison of the extent of excretion in bile and urine following intranasal and intravenous administration, was 100% for 4-oxo-4H-1-benzopyran-2-carboxylic acid (1 mg kg-1), 75% for p-aminohippuric acid (1 mg kg-1), 15% for inulin (0.1 mg kg-1) and 2.8% for dextran (0.25 mg kg-1). The log molecular weight gave a good linear correlation with the log per cent intranasally absorbed (correlation coefficient of -0.996). From the molecular weight relationship, these data infer aqueous channel mechanisms for the nasal absorption of water-soluble compounds.

The nasal absorption of sodium cromoglycate in the albino rat.

The intranasal absorption of sodium cromoglycate has been investigated in the adult male COBS/Wistar rat. Sodium cromoglycate (1 mg kg-1) was instilled into the nasal cavities and for comparison animals were also similarly dosed intravenously or sub-lingually. Serial samples of blood or bile were collected. After intravenous administration, the area under the plasma concentration curve (AUC0-infinity) was 32 micrograms min ml-1 corresponding to a plasma clearance of 13 ml min-1 and an elimination rate constant of 0.049 min-1. Plasma concentrations of radioactivity after intranasal administration rose to a mean peak of 0.3 micrograms ml-1 approximately 20 min after dosing and fell to 0.03 micrograms min ml-1 at 3 h. The AUC0-3 was 19 micrograms min ml-1 corresponding to an absorption of 60% over 3 h. The absorption rate constant (ka) was 0.059 min-1. The total amount of sodium cromoglycate excreted in bile after intravenous administration was 56%. The amount of compound excreted in the bile was 30% after intranasal administration corresponding to an absorption of 53%. Plasma and bile data therefore show good agreement. Total excretion in the bile over 3 h after sub-lingual administration was 3%, demonstrating that this route made no significant contribution to the intranasal results. The absorption of sodium cromoglycate is independent of variations in the technique including changes in the orientation of the rat or blocking of the nasopalatine. The techniques used minimized other competing nasal clearance processes such as mucociliary clearance.

Towards the safer use of medicines.

In Britain the tools are now available to provide better information on safety of medicines in both hospital and community settings, and this could be done at relatively modest cost. The needs of patients, doctors, and pharmacists are changing; although more research is needed, such information as is presently available must be both better and more widely publicised and understood. Universities, government, the pharmaceutical industry, and educated journalism all have an important part to play in this process.

Oral Fabrol (oral N-acetyl-cysteine) in chronic bronchitis.

Five hundred and twenty-six patients suffering from chronic bronchitis were randomized to receive either N-acetylcysteine (NAC) or placebo during a 6-month period. The aim was to compare the number of acute exacerbations in the two groups. General practitioners were asked to enter patients with a diagnosis of chronic bronchitis, based on the MRC criteria. We failed to find any statistically significant difference in the number of exacerbations between the two treatment groups although there was a slight trend towards improvement in the NAC group during the first 3 months of the trial. The tolerability was similar for both treatments. Patients taking NAC showed a reduction in number of days on which they were incapacitated and this result was statistically significant.

Pharmacokinetics of chlorthalidone. Dependence of biological half life on blood carbonic anhydrase levels.

The relationship between the whole blood concentration of carbonic anhydrase and the biological half life of chlorthalidone has been investigated in six volunteers. A linear relationship was observed and on the basis of this, a pharmacokinetic model to explain the long and variable biological half life of chlorthalidone is proposed and discussed.

A reversed-phase high-performance liquid chromatography assay procedure for progabide and its related metabolic derivatives.

A reversed-phase high-performance liquid chromatography (HPLC) assay procedure for Progabide, its active acid metabolite (PGA), and its hydrolytic degradation product (SL79.182) has been developed. This highly specific technique has allowed the simultaneous determination of these drugs in aqueous samples, and when coupled with a single and easy extraction step, spiked plasma samples could also be analyzed. The method had a sensitivity of about 30, 45, and 100 ng/ml for Progabide, SL79.182, and PGA, respectively.

The stability and solubility of progabide and its related metabolic derivatives.

The stability-pH profile of the gamma-aminobutyric acid prodrug. Progabide, was found to be bell shaped, with maximum stability occurring at pH 6 to 7 with a t1/2 of 126 min. Of its metabolic derivatives, the deamidated product PGA degraded in a similar fashion to Progabide, whereas the hydrolytic degradation product SL79.182 was, a expected, a stable compound. Progabide behaved as a typical weak base, with its solubility increasing with a decrease in pH. SL79.182 behaved as a typical phenolic weak acid, with its solubility increasing with an increase in pH. Both compounds displayed low intrinsic solubilities of 14.5 x 10(-5) M for Progabide and 33.4 x 10(-6) M for SL79.182. An increase in temperature resulted in an increase in the solubility but a decrease in the stability of Progabide. The data obtained indicate that the gastric pH and gastric emptying rate will have a profound effect on the oral bioavailability of Progabide.

Placental transfer of chlorthalidone and its elimination in maternal milk.

A gas chromatographic method has been used to determine chlorthalidone in amniotic fluid, maternal and foetal blood at delivery, and in maternal milk and blood three days after delivery, following the administration of chlorthalidone to nine pregnant women suffering from toxaemia of pregnancy. Placental transfer of chlorthalidone and elimination in maternal milk have been shown and the implications of these factors are discussed. An explanation has been proposed for our observations that foetal blood levels of the drug are about 15% of those in maternal blood.

Relationship between the rate of appearance of oxprenolol in the systemic circulation and the location of an oxprenolol Oros 16/260 drug delivery system within the gastrointestinal tract as determined by scintigraphy.

1. The position in the gastrointestinal tract of an orally administered oxprenolol Oros drug delivery system labelled with technetium-99m DTPA was followed by gamma scintigraphy, and the corresponding plasma drug concentration-time profiles after oral and i.v. administration were used to relate pharmacokinetic and transit data. 2. Gastric emptying time (0.8 +/- 0.4 h, mean +/- s.d.), and the time to arrival in the colon (3.8 +/- 0.7 h) were reasonably consistent after administration of the Oros system to fasted subjects, as were the calculated small intestine transit times (3.0 +/- 0.7 h). As expected there were wide individual variations in colonic transit, so that recorded values for total transit ranged from 6 to 32 h (median, 24.7 h). 3. Absorption of oxprenolol occurred throughout the GI tract including the colon. Plasma drug concentration-time profiles and input functions (calculated by deconvolution) could be related to transit behaviour and in vitro release. Inflexions in the calculated rate of drug input when the Oros system was located in the colon corresponded with periods of stagnation at the hepatic and splenic flexures in two subjects and the ileocaecal junction in two others. The mechanism of these changes is unclear.