Insulin-dependent diabetes mellitus in homozygous sickle-cell anaemia.

Concurrent sickle-cell disease and diabetes mellitus is rare. The first case of the co-existence of these two disorders to be identified in Nigeria, West Africa, is presented.

Effect of reduced phytate wheat bran on zinc absorption.

The rise in plasma zinc after the ingestion of 765 mumol (50 mg) elemental zinc was measured over 6 h in three groups of healthy subjects who, in a second test, also consumed a standard wheat bran, a reduced phytate, high fibre processed bran or rice-based, low phytate, low fibre breakfast cereal (Rice Krispies). Standard bran, reduced phytate bran and Rice Krispies all significantly decreased the area under the plasma zinc time curve (AUC) compared to the zinc alone test. The AUC obtained with standard bran was significantly lower than that after reduced phytate bran (mean +/- s.e.: -5.9 +/- 2.7 vs 18.5 +/- 4.2 mumol.h/l, P less than 0.001). The percentage reductions in AUC produced by the test meals were: standard bran 106.4 +/- 2.4, reduced phytate bran 75.9 +/- 4.8, Rice Krispies 46.3 +/- 10.4 per cent, P less than 0.01). Histidine, taken with standard bran in a small subgroup of subjects, tended to improve zinc absorption but the difference was not statistically significant.

Effects of cimetidine and carbenoxolone on gastric mucus.

The effect of cimetidine on normal human gastric mucus has been compared with that of carbenoxolone, a drug believed to enhance mucus production. Each drug was given for two weeks, the gastric contents aspirated over a timed period and the results assessed in unstimulated and pentagastrin stimulated secretions. The volume, dry weight and the carbohydrate contents of non-diffusable glycoconjugates, high molecular mass glycoproteins and glycopolypeptides were investigated. Both drugs reduced the volumes of stimulated secretions. This was statistically significant after cimetidine. More importantly neither drug affected the amount of non-diffusable glycoconjugates, so that the concentration remained the same or increased. Both drugs reduced the monosaccharide content of the high molecular mass fractions. This reached significance for the stimulated secretion after cimetidine. As the carbohydrate content of the glycopolypeptides was unchanged this indicated the presence of a non-mucin glycoprotein or protein. Overall there was no fundamental difference between the results for cimetidine and carbenoxolone.

Pharmacokinetics of nifedipine after oral administration in chronic liver disease.

Presented are the results of a study in which ten healthy subjects and seven patients with hepatic cirrhosis were given 10 mg nifedipine orally; plasma concentrations of the drug were measured over 24 hours. The drug was also administered intravenously, but those results were unsatisfactory for presentation. The rate of absorption and peak plasma concentrations were similar in the two groups. There was a fourfold increase in the elimination half-life (434 +/- 74 minutes in the cirrhotics compared with 102 +/- 11 minutes in the healthy subjects). A twofold increase in the area under the plasma concentration-time curve occurred in the cirrhotic group. The study confirmed that there is clinically significant alteration in the kinetics of nifedipine in patients who have hepatic cirrhosis and that there is considerable risk of accumulation. No adverse effects were observed despite high plasma levels of nifedipine.

Anti-ulcer drugs and intrinsic factor secretion.

Twelve healthy volunteers were randomly allocated to take two of the following treatments; cimetidine, misoprostol (a prostaglandin E1 analogue) and carbenoxolone, for two weeks. A further four subjects took ranitidine. Gastric aspirates were collected before and on the 14th day of therapy for each drug, and analysed for intrinsic factor concentration and total output. Both randitine and cimetidine inhibited pentagastrin stimulated output by 47% and 27% respectively in comparison to control, but had no effect on stimulated mean intrinsic factor concentrations. No changes were observed with misoprostol and carbenoxolone treatment.

Some aspects of the glycoprotein and glycopolypeptide content of human gastric mucus.

The carbohydrate content of non-diffusable, glycoprotein and glycopolypeptide material has been studied in normal human gastric aspirates. Pentagastrin doubles the volume of secretions but has no effect on the amount of non-diffusable material. Only about 40% of the weight of the non-diffusable material is mucin in nature. Gel-permeation chromatography indicated that about half of the mucin survived as high molecular mass glycoprotein. Monosaccharide differences, for example between secretors and non-secretors, only became manifest at the glycopolypeptide stage. These results emphasize the dangers of attempting to assess mucin changes by simple carbohydrate analyses of unfractionated gastric aspirates.

The natriuresis following oral administration of the calcium antagonists--nifedipine and nitrendipine.

Ten healthy individuals received in random order placebo, nifedipine 10 mg, nifedipine 20 mg, nitrendipine 10 mg and nitrendipine 20 mg as single oral administrations at weekly intervals. On the day before each treatment placebo was administered. Urine was collected for 6 h and then for 18 h after each administration. There was a significant increase in urine volume and sodium excretion after the drugs, but no change in potassium excretion. The effect was most evident in the 6 h after drug administration. The effect was no greater at the higher doses of either drug. A natriuretic-diuretic action of nifedipine and nitrendipine has been confirmed in man. The mechanism of the effect remains unclear.

Do beta blockers differ in their effects on hepatic microsomal enzymes and liver blood flow?

The effects of three beta blockers on liver blood flow and hepatic enzyme activity were investigated. Eight healthy subjects received placebo, 100 mg metoprolol, 40 mg nadolol, and 60 mg propranolol orally three times a day for four days in a randomized block design. On the fourth day of each treatment, beta blockade was measured by inhibition of exercise-induced tachycardia and apparent liver blood flow was measured by indocyanine green clearance. Plasma concentrations of the beta blockers were measured 2 hours after the early morning dose. Metoprolol produced the greatest inhibition of exercise tachycardia. All three drugs appeared to reduce liver blood flow, but this was only statistically significant in the case of propranolol. Enzyme inhibition occurred but to a varying extent. Propranolol produced a 36 per cent fall in antipyrine clearance (P less than 0.1) while metoprolol and nadolol both caused a 12 per cent reduction (P less than 0.05 and P = 0.06, respectively). Wide interindividual variation in the plasma concentrations of the drugs limit interpretation, but the results suggest that at the doses used, metoprolol and nadolol may be less likely to cause significant drug interaction by enzyme inhibition than propranolol.

A study of the potential interactions between azapropazone and frusemide in man.

Ten healthy individuals received frusemide 40 mg orally for 7 days. Following a drug free period of 7 days they received azapropazone 600 mg twice daily for 7 days and then both treatments for a further 7 days. Sodium excretion fell from 141 +/- 16.8 mmol/day to 84.3 +/- 6.8 mmol/day (P less than 0.01) on initiation of azapropazone treatment. The natriuretic response to frusemide was unchanged by premedication with azapropazone. Urate excretion rose from 3.35 +/- 0.249 mmol/day to 4.98 +/- 0.365 mmol/day on initiation of azapropazone therapy but subsequently returned to baseline values. Plasma uric acid fell from 0.289 +/- 0.024 mmol/l to 0.167 +/- 0.0125 mmol/l (P less than 0.001) on azapropazone but rose to 0.186 +/- 0.0116 mmol/l (P less than 0.001) with the addition of frusemide. Azapropazone may cause sodium retention but after repeated administration frusemide still has a marked diuretic action. The hypouricaemic effect of azapropazone is only slightly antagonised by frusemide at the doses studied.

Systemic absorption of ketoconazole from vaginal pessaries.

Eight healthy female subjects were each given (a) ketoconazole 400 mg orally, (b) ketoconazole 400 mg as a single vaginal pessary, (c) ketoconazole 800 mg as two vaginal pessaries, and (d) ketoconazole 1200 mg as three vaginal pessaries. The area under the plasma concentration time curve (AUC) after the oral dose was 51.41 +/- 10.99 mg l-1 h (mean +/- s.d.) and the half-life of ketoconazole was 2.98 +/- 1.41 h. The AUCs after vaginal administration were 0.27 +/- 0.14, 0.52 +/- 0.25, and 0.43 +/- 0.22 mg-1 l h following the 400, 800 and 1200 mg pessaries respectively. Systemic absorption of single doses of vaginally administered ketoconazole appears to be negligible in the absence of vaginal infection. There were no local or systemic side effects related to ketoconazole in these healthy volunteers.

Effects of chronic oral cimetidine on apparent liver blood flow and hepatic microsomal enzyme activity in man.

Cimetidine 200 mg three times daily and 400 mg at night was given to 10 subjects for four weeks. Apparent liver blood flow was measured by indocyanine green clearance and microsomal enzyme activity by antipyrine clearance, before and after cimetidine. There was no reduction in indocyanine green clearance but antipyrine clearance, as expected, was significantly reduced by 15% at four weeks. Chronic cimetidine treatment does not reduce apparent liver blood flow and is therefore unlikely to be of use in the treatment of portal hypertension. The cimetidine associated hepatic enzyme inhibition appears to persist with prolonged treatment. Therefore patients on chronic cimetidine remain vulnerable to certain drug interactions.

Influence of food on the pharmacokinetics of ketoconazole.

Eight healthy adults were given single oral doses of ketoconazole (200, 400, 600, and 800 mg) in the fasting state and with a standard breakfast at weekly intervals according to a balanced block design. Concentrations in serum were measured up to 32 h after the dose. Food did not reduce ketoconazole absorption or significantly alter peak ketoconazole concentrations in serum, though there was a food-related delay in achieving peak concentrations. At the 400- and 600-mg doses, food appeared to enhance absorption, but this effect was not seen at the 800-mg dose. With an increase in dose, the half-life and area under the serum concentration-time curve increased disproportionately, suggesting that the pharmacokinetics of ketoconazole may be dose dependent. Up to the 800-mg dose, the elimination of ketoconazole did not appear to be saturable. Administration of the drug with food is unlikely to be a cause of therapeutic failure.

Multiple dose pharmacokinetics of ketoconazole and their effects on antipyrine kinetics in man.

Ketoconazole 200 mg was given twice daily for five days to eight subjects. The serum pharmacokinetics were examined with the first dose on day 1 and with the ninth dose on day 5. The serum half life of ketoconazole was 74.8 +/- 13.9 min (mean +/- S.D.) on day 1, and 155.9 +/- 32.7 min on day 5. On day 1 the area under the serum concentration time curve was 626.9 +/- 230.1 mg/l.min, and 1441 +/- 897.3 mg/l.min on day 5. Antipyrine kinetics were determined before and after the course of ketoconazole. There was no significant change in the clearance and half life of antipyrine. Ketoconazole in the doses used in this study does not appear to alter hepatic microsomal enzyme activity in man. The increased ketoconazole half life and area under the serum concentration time curve on day 5 were in part caused by food. Other mechanisms for these changes such as saturation of a tissue compartment or a change in the elimination of ketoconazole during chronic dosing, may also be responsible.

Fluorescein dilaurate--tubeless test for pancreatic exocrine failure.

The usefulness of fluorescein dilaurate as an indicator of pancreatic exocrine failure has been assessed in 70 patients and normal volunteers. The test consisted of a comparison of urinary fluorescein excretion after ingestion of fluorescein dilaurate with that after ingestion of unesterified fluorescein. The test was easy to perform and acceptable to the patients. The sensitivity of the test was 95%. There was a false-positive rate of 11% in a group of patients who had steatorrhoea which was non-pancreatic in origin. The test can be a useful screening test for the exclusion of pancreatic exocrine failure as a cause of steatorrhoea and can be conducted in outpatients.

A study of the inhibitory effects of SCH 28080 on gastric secretion in man.

1 SCH 28080 (2-methyl-8-(phenyl methoxy) imidazo-(1-2-a) pyrine-3-acetonitrile) is a novel drug unrelated to existing anti-ulcer agents. 2 The effect of placebo and increasing doses of the drug on gastric acid output and peptic activity was examined in four healthy men, in the resting state and following pentagastrin stimulation. 3 Significant inhibition of gastric acid secretion and peptic activity occurred with the 50 mg dose in both the stimulated and unstimulated states. Approximately 90% inhibition of acid output was achieved with the 200 mg dose. 4 Antisecretory activity of SCH 28080 is confirmed in man. This drug or an analogue may have potential in anti-ulcer therapy.