Biomedical subjects
W P Jackson
Publications and source records attributed to W P Jackson.
Imidazolidin-2-one prostaglandin analogues.
The 5-desoxy analogue of BW245C, imidazolidin-2-one 3, has been synthesized by reduction of the N-benzyl hydantoin derivative 6. Compound 3 was found to be approximately equipotent with BW245C as an inhibitor of platelet aggregation and this result indicates that the 5-keto group of BW245C is not essential for platelet inhibitory activity.
Hydroxamic acids and hydroxyureas as novel, selective 5-lipoxygenase inhibitors for possible use in asthma.
Inhibition of 5-lipoxygenase (5-LO) is a potential target for therapeutic intervention in asthma. Acetohydroxamic acids such as BW A4C are potent and selective 5-LO inhibitors in vitro and also inhibit 5-LO activity in vivo following oral administration. In man, BW A4C is metabolised relatively rapidly (t1/2 = approx. 2h) but nevertheless inhibits 5-LO with reasonable persistence. Chemical modification of BW A4C has resulted in compounds, including the alpha-methyl analogues BW B218C and BW A360C and the hydroxyurea BW B70C, that retain high in vitro potency as selective 5-LO inhibitors and, compared to BW A4C, have a higher potency and longer duration of action in vivo. Members of both the hydroxamic acid and hydroxyurea series of 5-LO inhibitors are presently being considered as potential anti-asthma drugs.
Inhibition of 5-lipoxygenase: development of hydroxamic acids and hydroxyureas as potential therapeutic agents.
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The artificial beta cell.
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Gycosuria as an indication for glucose tolerance testing during pregnancy.
The indications for and results of all glucose tolerance tests (GTTs) performed at the Antenatal Clinic, Groote Schuur Hospital, Cape Town, over a period of 1 year, and the indications for a GTT in the first 80 newly diagnosed diabetics over a 4-year period are analysed. Out of 558 GTTs, only 17 tentative diagnoses of 'gestational diabetes' were made. The most rewarding single indication for a GTT was repeated glycosuria, which was an indication in 61 out of the 80 newly diagnosed diabetics. A combination of two indications in the same patient was related to twice as many abnormal GTTs as a single indication, while reported previous diabetes or hyperglycaemia certainly merited confirmation. Reasons for repeating GTTs are discussed, as well as the management of 'borderline' and 'potential' diabetics. It is emphasized that 'diabetes' or 'hyperglycaemia' diagnosed during pregnancy is not equivalent to a definite diagnosis of diabetes in the non-pregnant state.
Diabetes newly diagnosed during pregnancy: A 4-year study at Groote Schuur Hospital.
As a result of active screening for gestational diabetes of the population attending various antenatal clinics in the Cape Peninsula, 127 patients with a repeatedly diabetic glucose tolerance test (GTT) were discovered; in many the GTT was grossly abnormal. The most useful screening factor was repeated glycosuria. Because they had booked late, 22 patients received virtually no treatment, and 1 patient aborted. Treatment of the remaining 104 patients was achieved principally by regulating diet, but when this failed metformin or glibenclamide therapy was instituted. Insulin was used when diet and oral drugs failed. Diabetic control was considered adequate if fasting blood glucose levels remained below 5,5 mmol/l and if postprandial levels were below 7 mmol/l. Most patients (67) were well controlled on a strict dietary regimen, and there were no perinatal deaths in this group. Glibenclamide and metformin, judging from this small series, appear to be safe for use in gestational diabetics. The overall perinatal mortality in treated patients was 10/1 000 as compared with an effective perinatal mortality of 145/1 000 in the 'untreated' group. Neonatal morbidity was similar to that in other reported series. Hypoglycaemia was seldom a problem and 79% of birth weights were between the 10th and the 90th percentiles.
Effects of the sulphonylurea drugs gliclazide and glibenclamide on blood glucose control and platelet function.
Platelet aggregation and adhesion are commonly increased in diabetes mellitus. These abnormalities may in part be responsible for the increased incidence of vascular disease in diabetics. We have investigated the effects of diet, diet plus glibenclamide, and diet plus gliclazide on plasma glucose control and platelet function in 10 newly diagnosed maturity-onset diabetics who had not previously been treated. Before treatment, the mean postprandial plasma glucose value was 13,4 +/- 0,8 mmol/l, which fell insignificantly on dietary treatment, to 12,2 +/- 1,0 mmol/l (P greater than 0,05). Both glibenclamide and gliclazide, when added to the diet, significantly lowered mean plasma glucose values to 9,3 +/- 0,8 mmol/l and 7,8 +/- 0,8 mmol/l respectively (P less than 0,05). Platelet aggregation in response to 1 mumol adenosine diphosphate (ADP) was increased in the diet period, whereas aggregation in response to 10 mumol and 100 mumol was normal. This suggests an increased sensitivity of the platelets to ADP in diabetic patients. The addition of both glibenclamide and gliclazide reduced the magnitude of the response to within the normal range. Platelet aggregation in response to 10 mumol adrenaline and 750 micrograms/ml collagen was significantly reduced by glibenclamide (P less than 0,05). We conclude that sulphonylurea therapy appears to reduce the increased platelet aggregation which occurs in diabetics. This may play a role in the prevention of vascular disease.
The diabetic foot.
Modern thought regarding the pathogenesis, clinical features and management of the 'diabetic foot' is reviewed. The interplay of the triad of ischaemia, neuropathy and infection is emphasized throughout. Management is directed at maintaining or providing a pain-free, working foot.
Controversy in diabetes mellitus.
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Shortage of insulin.
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Metformin in management of pregnant insulin-independent diabetics.
Sixty pregnant "maturity-onset" (insulin-independent), established and gestational, diabetics were treated with Metformin in the second and third trimester after dietary treatment had failed. The incidence of Metformin failure was 53.8% in the established diabetics and 28.6% in the "gestational" diabetics. The 27 Metformin failures were transferred to other therapy, leaving for further analysis 33 patients who received Metformin up till delivery. Two neonatal deaths occurred in this group (1 congenital abnormality and 1 preterm infant) giving a perinatal mortality of 61/1000. This compares with a perinatal mortality of 103/1000 in the Metformin failure group and 105/1000 in a group of insulin-dependent diabetics treated during the same period. Apart from a high incidence of neonatal jaundice requiring phototherapy the infant morbidity in the Metformin group was low. The mothers of 3 infants with congenital abnormalities had received Metformin only during the last trimester of their pregnancy.
Insulin secretion and pancreatic exocrine function in patients with chronic pancreatitis.
The relationship between insulin responses to oral glucose and pancreatic exocrine function were examined in 15 patients with chronic pancreatitis. Good correlations were found between the insulin responses and exocrine pancreatic function measured as the concentrations of pancreatic enzymes in duodenal juice after intravenous cholecystokinin-pancreazymin (CCK-PZ). There appears to be a roughly parallel loss of endocrine and exocrine function in the course of chronic pancreatitis.
Studies on plasma glucagon concentration in maturity-onset diabetics with autonomic neuropathy.
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Is juvenile-onset diabetes more than one disease?
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Monitoring one's own blood glucose.
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Circulating antibodies in diabetics treated with conventional and purified insulins.
Conventional insulins contain impurities which are immunogenic; these include pancreatic polypeptide (PP), glucagon and somatostatin and intermediates of insulin synthesis co-extracted during purification. Monocomponent (MC) insulins are free of these contaminants. In 49 insulin-treated diabetic patients, antibodies were found to insulin (94%), pro-insulin (68%) and PP (68%). Antibodies to glucagon and somatostatin were not detected. There was a significantly lower mean maximum binding and titre of insulin and PP antibodies and total circulating insulin (i.e. antibody bound and free) in patients receiving MC insulin. In patients treated with MC insulins for longer than 2 years there was a significant fall in the mean maximum binding of insulin and total serum insulin, but no consistent change in diabetes control and daily insulin dose. It seems that except in the special instances of fat atrophy, insulin allergy and certain cases of insulin resistance, there is no need to resort to MC insulin.