D. G. McDevitt

Observations on the efficacy and pharmacokinetics of sotalol after oral administration.

SummaryThe effects of sotalol after oral administration were measured on the tachycardia induced by strenuous exercise in normal subjects. Plasma sotalol levels were also determined. The oral administration of sotalol (50, 100, 200 and 400 mg) to 6 subjects produced a progressive reduction in the tachycardia induced by severe exercise. This was similar to the effects of 25, 50, 100, 200, 400 and 800 mg given to different subjects. Each increase in sotalol dose produced a successively greater reduction in exercise tachycardia. This did not appear to be maximum even with 800 mg. Oral sotalol was rapidly absorbed and produced peak blood levels in 2 – 3 hours. The plasma levels of sotalol measured 2 hours after the oral administration of 25 to 800 mg showed never more than a six-fold variation between different subjects. The half-life of sotalol in plasma was 12.7 ± SE 1.6 hours. There was a significant correlation between the logarithm of the plasma sotalol concentration and the percentage reduction of exercise heart rate. It is concluded that the oral administration of sotalol either once or twice daily (depending on dose level) will provide satisfactory 24-hour blockade of β-adrenoceptors.

Pharmacokinetics of Sotalol During Pregnancy

SummarySotalol, a beta-adrenoceptor blocking drug, was administered to 6 healthy pregnant volunteers between 32–36 weeks gestation and when at least 6 weeks post-partum. On both occasions, each volunteer was given sotalol 100 mg intravenously and 400 mg orally in randomised order with at least a 1 week washout period between. Plasma samples were analysed for sotalol using a fluorometric method and the pharmacokinetic profiles investigated. The systemic clearance of sotalol was significantly greater in the antenatal period (2.4±0.3 ml/min/kg) than in the post-natal phase (1.5±0.1 ml/min/kg). The apparent volume of distribution was similar in the two periods: the elimination half-life was 6.6±0.6h ante-natally and 9.3±0.7h post-natally after intravenous drug but the trend for faster elimination was not significant. The elimination half-life after oral administration (about 10h) and bioavailability (about 90%) were not altered significantly by pregnancy. It is suggested that the more rapid clearance of sotalol in pregnancy may be due to increases in renal plasma flow and glomerular filtration rate.

Validation of observed differences in the utilization of antihypertensive and antidiabetic drugs in Northern Ireland, Norway and Sweden

SummaryThe amount of antihypertensive and antidiabetic drugs based of defined daily doses per 1000 inhabitants per day varies two to three fold between Northern Ireland, Norway, and Sweden. We explored whether variations based on the universally applied defined daily doses might be accounted for by national differences in the actual average prescribed daily doses. Use of prescribed daily doses for antihypertensive drugs resulted in Northern Irish and Norwegian consumption figures which were respectively 40 and 21% lower than the Swedish one, compared to 38 and 25% when defined daily doses were used. The effect of population age-sex differences on the gross defined daily doses per 1000 inhabitants per day figures was determined by applying the Northern Irish or Norwegian age-sex group proportions to Swedish age-sex specific sales data. Taking population differences into account would have resulted in antihypertensive drug use being 21 rather than 38% less in Northern Ireland and 18 rather than 25% less in Norway. Also adjustment for prescribed daily doses left an unexplained difference of 23% between Sweden and Northern Ireland and 14% between Sweden and Norway. For oral antidiabetics use of prescribed daily doses resulted in a Northern Irish — Swedish difference of 62% compared to 67% when defined daily doses were used. Simultaneous adjustment for population differences and prescribed to defined daily dose variations left a 52% difference.

Therapeutic traditions in Northern Ireland, Norway and Sweden: I. Diabetes

SummaryA questionnaire survey was carried out to explore differences in the approach to treatment of patients with Type II diabetes between physicians in Northern Ireland, Norway and Sweden, and to discover to what extent it could account for the three-fold difference in drug use between the countries. A representative sample of 400 physicians in each country was asked to give their opinions on the choice of therapy for three model cases designed to cover the spectrum of treatment — from diet alone to insulin. Significantly more Swedish (65%) than Northern Irish (51%) and Norwegian (52%) doctors suggested diet alone for uncomplicated diabetes recently discovered in a middle aged, overweight man. For symptomatic diabetes in a 76 year old overweight woman with few retinal microaneurysms, the majority of physicians in all three countries suggested treatment with sulphonylureas. Biguanides were here a more common alternative in Northern Ireland than in Scandinavia. For suspected secondary treatment failure in a 63 year old woman with no signs of complications, insulin was suggested by 71% of the Norwegian doctors but only by 44 and 49% of those in Northern Ireland and Sweden, respectively. General practitioners tended to suggest oral treatment earlier and to maintain it longer than hospital physicians. The study has demonstrated significant differences in the approach to treatment of Type II diabetes mellitus between physicians in the three countries. However, the differences were more prominent in the choice of drugs than in the threshold of drug treatment. The results also fit with qualitative but not with quantitative differences in drug sales between the countries, suggesting that important differences may exist in the prevalence of clinically recognized Type II diabetes.

Pharmacokinetics of propranolol during pregnancy

SummaryPropranolol, a beta-adrenoceptor blocking drug, was administered to 6 healthy pregnant volunteers between 32 and 36 weeks gestation and when at least 6 weeks postparum. On both occasions, subjects were given propranolol 120 mg orally or 10 mg intravenously in randomised order with a minimum washout period of 1 week. Propranolol was assayed in plasma by gas-liquid chromatography with electron-capture detection and the pharmacokinetic parameters were investigated. There were no significant alterations in elimination half-life, clearance or apparent volume of distribution per kilogram antenatally compared with postnatally: bioavailability was also unchanged. It is concluded that the disposition of propranolol is not altered during pregnancy.

Pharmacokinetics of a microcrystalline theophylline preparation in patients with chronic obstructive airways disease.

SummaryPlasma theophylline concentrations have been measured in 9 patients with chronic obstructive airways disease following the oral administration of a microcrystalline theophylline preparation. Some measurements of FEV1 were also made. Four patients were given 375 mg as a single dose and then subsequently 375 mg stat and 125 mg 4 times daily for 3 days, (Group I). A further 5 patients took 250 mg as a single dose and then 250 mg 4 times daily for 3 days, (Group II). In both groups, following the single dose and again after the last dose of chronic administration, blood samples were obtained at frequent intervals up to 24 h for plasma drug estimation. During the 3-day course, blood samples were drawn before and 2 h after each morning dose. In Group I patients, substantial plasma theophylline concentrations were seen only after the loading dose. Thereafter, the mean concentrations before or 2 h after the morning doese were always less than 4.0 µg/ml. Trough concentrations were usually below 2.0 µg/ml. In contrast patients in Group II achieved substantially higher plasma theophylline concentrations, with mean peak concentrations always 10 µg/ml or greater, and trough concentrations greater than 5 µg/ml on at least one occasion in every subject. The elimination half-lives after chronic administration in both groups were not significantly different from those obtained after single doses. Mean drug accumulation, measured as AUCss/AUC1, was 0.87±0.07 in Group I and 0.72±0.14 in Group II, indicating that accumulation had not occurred with either regimen. The mean increase in FEV1 2 h after the administration of a single dose was 19.2% after 375 mg and 16.7% after 250 mg. These results indicate that the recommended dosage regimen for microcrystalline theophylline preparation (375 mg stat and 125 mg 4 times daily) produces inadequate plasma theophylline concentrations: 250 mg 4 times daily would appear to be likely to result in satisfactory theophylline levels in more patients.

Plasma theophylline concentrations following the oral administration of microcrystalline theophylline and a new sustained-release theophylline preparation to normal subjects

SummaryPlasma theophylline concentrations have been measured in 14 normal subjects following the oral administration of a microcrystalline theophylline preparation (MT) 187.5 mg every 6 h and a sustained-release theophylline preparation (SRT) 375 mg every 12 h for 5 days. During the 5 days, blood samples were drawn before and 2 h after each morning dose with MT, and before and 4.5 h after each morning dose of SRT. On days 1 and 5, more frequent samples were taken during the dose interval. With both preparations, steady-state plasma concentrations were achieved by the third day. The trough levels were significantly higher with SRT than with MT on days 3 and 4, and the levels at 4.5 h after SRT were significantly higher than those measured 2 h after MT on days 3, 4 and 5. Over the terminal 3 days of the study, mean theophylline concentrations with SRT ranged between 11.2 and 15.5 µg/ml at measured trough and peak times, whereas the mean trough levels with MT were always below 10 µg/ml. With adjustment for the dosage differences, the mean ratio of the areas under the plasma concentration/time curves for the final dosage interval for the two formulations (AUCSRT/AUCMT) was 1.29±0.56, suggesting that the SRT preparation was well absorbed. The “mean” steady-state plasma theophylline concentrations (AUC/dose interval) on day 5 were 11.5±4.7 µg/ml with MT and 13.7±5.7 µg/ml with SRT. Nine subjects experienced a total of 35 side-effects whilst taking MT, compared with 10 subjects complaining of 23 side-effects on SRT. These results indicate that, in normal subjects, SRT 375 mg every 12 h exhibited satisfactory sustained-release properties and achieved adequate mean plasma theophylline concentrations during chronic administration. It produced higher plasma levels and a lower incidence of side-effects than the same daily dose of MT.

Biliary excretion and enterohepatic recirculation of practolol in man

SummaryThe elimination of practolol in bile was studied in six patients who received a single oral dose of 400 mg within six days of undergoing biliary surgery. Bile collections were made from a T-tube drain left in the common bile duct after removal of multiple biliary calculi. There was wide variation in the concentration of practolol in bile and in the total amount of practolol excreted in bile during the 48 hour period after dosage. Two patients excreted 23 per cent and 41 per cent of the 400 mg dose in bile, whereas the excretion in the other four patients was only one per cent to four per cent of the oral dose. The mean urinary excretion of practolol in 48 hours was 74.2±S.E. 8.4 per cent of the ingested dose, and the total elimination (biliary plus urinary) was 86.5±S.E. 7.6 per cent. The total elimination ranged from 92 per cent to 105 per cent in four of the patients. The mean elimination half-life of practolol in blood was 6.4±S.E. 0.5 hours. This was significantly less than the half-life in normal subjects receiving the same practolol dose. Since complete or near-complete urinary excretion of practolol is found in normal subjects, the presence of large amounts of drug in the bile suggests that enterohepatic recirculation of the drug occurred in some of the patients at least. This is a possible explanation of the shortened half-life in these patients in whom drug was being removed with bile. The four patients with low excretion of practolol in bile were receiving other drugs at the time of the study. These included nitrazepam, diazepam and tetracycline which are known to have substantial biliary elimination either in animals or man. It is suggested that competition for biliary excretion may have occurred and this may represent a drug interaction of possible clinical significance.The elimination of practolol in bile was studied in six patients who received a single oral dose of 400 mg within six days of undergoing biliary surgery. Bile collections were made from a T-tube drain left in the common bile duct after removal of multiple biliary calculi. There was wide variation in the concentration of practolol in bile and in the total amount of practolol excreted in bile during the 48 hour period after dosage. Two patients excreted 23 per cent and 41 per cent of the 400 mg dose in bile, whereas the excretion in the other four patients was only one per cent to four per cent of the oral dose. The mean urinary excretion of practolol in 48 hours was 74.2±S.E. 8.4 per cent of the ingested dose, and the total elimination (biliary plus urinary) was 86.5±S.E. 7.6 per cent. The total elimination ranged from 92 per cent to 105 per cent in four of the patients. The mean elimination half-life of practolol in blood was 6.4±S.E. 0.5 hours. This was significantly less than the half-life in normal subjects receiving the same practolol dose. Since complete or near-complete urinary excretion of practolol is found in normal subjects, the presence of large amounts of drug in the bile suggests that enterohepatic recirculation of the drug occurred in some of the patients at least. This is a possible explanation of the shortened half-life in these patients in whom drug was being removed with bile. The four patients with low excretion of practolol in bile were receiving other drugs at the time of the study. These included nitrazepam, diazepam and tetracycline which are known to have substantial biliary elimination either in animals or man. It is suggested that competition for biliary excretion may have occurred and this may represent a drug interaction of possible clinical significance.

Erroneous plasma "cortisol" values in Addison's disease : A problem of the fluorimetric assay of 11-OH corticosteroids.

SummaryA case is described in which a woman, being investigated for Addison’s disease, had what appeared initially to be plasma cortisol levels within the normal range. Subsequent investigations including ACTH stimulation and an immunofluorescent test for adrenal cortical antibodies showed the diagnosis to be correct. Attention is drawn to the lack of specificity of the fluorimetric plasma 11-OH corticosteroid assay and, therefore, to the danger of using plasma “cortisol” as a screening test for adrenocortical hypofunction.

The clinical importance of brucellosis in veterinary surgeons in private practice

SummaryA survey of veterinary surgeons in ordinary (private) practice covering 97% of the total 125 was made to determine the amount of illness and to assess the extent to which this was attributable to brucellosis.19 (15%) were already diagnosed as having brucellosis and there seemed good grounds for this. 25 (20%) were complaining of symptoms at the time of the survey of whom only 7 were already diagnosed as having brucellosis. Of the 18 cases with symptoms not already diagnosed as having brucellosis, 6 were probably suffering from another disease and 2 had negative serological tests. Most of the 17 (14%) who were probably suffering from symptomatic brucellosis, had illnesses consisting of repeated episodes resembling mild influenza.It was found essential to interview individuals personally rather than by questionnaire to determine the precise nature of their work and the nature of their illnesses.In spite of the fact that eradication of brucellosis from cattle in Northern Ireland has reached an advanced stage, it still seems an important source of illness amongst veterinary surgeons in private practice. The survey also revealed a high incidence of skin lesions resulting from animal midwifery which was not all related to brucellosis.