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.

Selective inhibition of arachidonate 5-lipoxygenase by novel acetohydroxamic acids: biochemical assessment in vitro and ex vivo.

1. The chemically novel acetohydroxamic acids, BW A4C, BW A137C and BW A797C, are potent inhibitors of the synthesis of leukotriene B4 (LTB4) from arachidonic acid by human leucocyte homogenates: the concentrations required for 50% inhibition (IC50) were 0.1 microM, 0.8 microM and 0.5 microM respectively. Inhibition was less at higher concentrations of arachidonic acid. 2. These compounds also inhibited the synthesis of [14C]-5-HETE from [14C]-arachidonic acid and the calcium-dependent synthesis of LTB4 from 5-HPETE. This, therefore, suggests that they inhibit 5-lipoxygenase and LTA4 synthase. 3. Concentrations of acetohydroxamic acids required to inhibit metabolism of arachidonic acid by cyclo-oxygenase, 12-lipoxygenase and 15-lipoxygenase were 10 to 100 times higher than those required to inhibit 5-lipoxygenase. 4. The compounds were potent inhibitors of LTB4 synthesis induced by the ionophore, A23187, in human intact leucocytes. This inhibition was reversed by washing the cells. They were also potent, selective inhibitors of LTB4 synthesis induced by A23187 in whole rat blood: binding to rat plasma proteins did not greatly reduce the effectiveness of the compounds. 5. The effects of the acetohydroxamic acids, administered either intravenously or orally to rats, on the synthesis of LTB4, and thromboxane B2 (TXB2) in A23187-stimulated blood ex vivo was studied. The three compounds caused dose-dependent inhibition of the synthesis of LTB4 but not TXB2. Inhibition of LTB4 synthesis persisted for up to 6 h after a single oral dose of 50 mg kg-1. 6. The plasma concentrations of unchanged compound determined by h.p.l.c. correlated with the inhibition of LTB4 synthesis ex vivo.

The effects of a novel series of selective inhibitors of arachidonate 5-lipoxygenase on anaphylactic and inflammatory responses.

In conclusion, we have described a novel series of acetohydroxamic acids that are potent and selective inhibitors of arachidonate 5-lipoxygenase in vitro and in vivo. In addition, we have shown that these compounds attenuate "leukotriene-dependent" anaphylactic bronchospasm, the accumulation of inflammatory leukocytes, and the development of fever in experimental models. It now remains to be determined if these compounds have any therapeutic value in man.

The management of non-insulin-dependent diabetes during pregnancy.

We propose a rational regimen for management of non-insulin-dependent pregnant diabetics (NIDD), using appropriately constituted calorie-restricted diets with the oral agents metformin and glibenclamide as may be necessary, with rapid recourse to insulin if the latter do not produce excellent control of blood glucose. Using this regimen between June 1974 and December 1983 we have managed 423 new diabetics (ND, diagnosed during pregnancy) with a perinatal mortality (PNM) of 14 per 1000 and 268 established diabetics (known diabetics, KD) with a PNM of 70/1000 (57/1000 since 1978). A further 80 NIDDs were 'untreated', i.e., not seen by us until near term; these suffered a PNM of 313/1000. Side-effects of the drugs have been few and mild, they are not teratogenic; 'starvation ketosis' does not occur; neonatal hypoglycaemia is preventable by using continuous insulin infusion during delivery. We suggest that the regimen outlined here is acceptable to the patients, is safe, gives excellent results and furthermore teaches the diabetic mother proper dietary control and combats lifelong obesity. It should be useful especially in developing countries in which pregnant, overweight NIDDs are common. Precise control of the blood glucose is essential.

Oral hypoglycaemics in the first trimester and fetal outcome.

During a 5 1/2-year period we saw 171 pregnant women with established non-insulin-dependent diabetes; 78 patients received oral hypoglycaemic drugs during the 1st trimester and 93 did not. The outcome of pregnancy in these two groups is compared. Only two major congenital anomalies were seen in the tablet-taking group and the number of abortions (4) was not excessive. The perinatal mortality (PNM) rate was initially high after large doses of chlorpropamide or metformin had been given during the 1st trimester, but this was clearly related to inadequate diabetic control in later pregnancy. Among the last 50 of the total of 75 viable infants whose mothers received oral drugs early in pregnancy, the PNM rate was 40/1 000. We conclude that modern oral hypoglycaemic drugs are safe and useful, not only during later pregnancy but also during the 1st trimester, provided excellent control of blood glucose levels is achieved.

The effect of long-term high-fibre diets in diabetic outpatients.

Diets containing large amounts of dietary fibre have been shown to be beneficial in improving diabetic control. We investigated the practical aspects of administering a high-fibre diet to diabetic outpatients in Cape Town, using readily available, low-cost foodstuffs with a high dietary fibre content. Ten patients were followed up over a period of 9 months, for 3 months of which a high-fibre diet was prescribed. Although only 3 patients approached the projected dietary fibre intake, significant negative correlations were found between the mean plasma glucose changes and the dietary fibre increments (r = 0,704; P less than 0,05) and between the mean serum triglyceride changes and the dietary fibre increments (r = -0,741; P less than 0,05). These findings suggest that, were it not for poor dietary compliance, a high-fibre diet might result in significant improvement in diabetic control, and that education and motivation are of prime importance when making major changes to patients' eating habits.

Guar biscuits in the diabetic diet.

A new type of guar-containing biscuit has been developed and incorporated into the diabetic diet in both short- and medium-term studies. It has been found to be effective in reducing the postprandial rise in the blood glucose level and in improving glycaemic control, as shown by reduced fasting blood glucose values and decreased 24-hour urinary glucose excretion. This form of guar has proved to be palatable and acceptable to patients. It was effective in smaller quantities than have previously been tested and may prove a valuable adjunct in the treatment of diabetes.

Pregnancy in insulin-dependent diabetics. A 5 1/2-year study at Groote Schuur Hospital.

During a 5 1/2-year period we have seen only 39 pregnant women with insulin-dependent diabetes, as opposed to 171 with established insulin-independent diabetes. Tight control with two injections of mixed insulins per day was attempted, but satisfactory blood glucose values were obtained in only 16 cases. Nevertheless the overall perinatal mortality rate was 77/1000; of the 3 infants which died 2 had lethal congenital abnormalities and 1 was born to a mother whom we had been seeing for only 4 weeks. Perinatal morbidity was similar to that in other series, except that few of our infants were oversized, hyaline membrane disease was uncommon, and only 2 had a low Apgar score. Fourteen infants weighed less than 2500 g. Hypoglycaemia in the newborn appears to be much reduced by the use of continuous low-dose intravenous insulin infusion during labour or caesarean section. To reduce perinatal mortality further, we conclude that exact blood glucose control should be attained before conception.

Sulfonylureas and platelet function.

The platelets of many patients with diabetes mellitus are abnormally sensitive to the effects of aggregatory agents in vitro. It has been proposed that this abnormal platelet function may play a role in the pathogenesis of vascular disease in diabetic subjects. We have investigated the effects of six weeks of treatment with the sulfonylurea agents gliclazide and glyburide on platelet aggregation in 10 noninsulin-dependent diabetic subjects. During treatment with diet alone, the platelets of these patients were abnormally sensitive to aggregation in response to 1 microM of adenosine diphosphate, as compared with those in normal controls. Treatment with both drugs normalized ADP-induced aggregation in these patients. Treatment with glyburide significantly reduced aggregation in response to 10 microM of epinephrine and collagen at 750 microgram/ml. The alteration in platelet function did not correlate with the improvement in plasma glucose concentration, thus suggesting that this may be an effect of the drug. Although one must be cautious in extrapolating these in vitro findings to the clinical situation, this alteration in platelet aggregatory function may be of importance in the prevention of vascular disease in diabetic subjects.

Pregnancy in established non-insulin-dependent diabetics. A five-and-a-half year study at Groote Schuur Hospital.

During a 5 1/2-year period we have seen 171 pregnant women with established insulin-independent diabetes. Eleven of them booked late and received virtually no treatment. The remaining 160 patients were managed primarily by regulating diet; 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 post-prandial levels were below 6,7 mmol/l. Twenty-five per cent of patients were well controlled on diet only during the duration of their pregnancies, with 1 perinatal death. Glibenclamide and metformin appear to be safe drugs during pregnancy when properly used. The overall perinatal mortality rate was 78/1 000; 42/1 000 since January 1978, as compared with 364/1 000 in the 'untreated' group. Only 18 babies were large (> 4 000 g), respiratory distress rarely occurred and hyaline membrane disease was virtually absent. Hypoglycaemia of the neonate was seldom a problem, but was most frequently related to the use of glibenclamide. Neonatal hypoglycaemia may be abolished if patients receiving tablets or insulin are given continuous, intravenous low-dose insulin 24 hours before planned delivery. The prevalence of major abnormalities was as least double that among infants of non-diabetic mothers.

The effect of dietary fiber on glucose and hormone responses to a mixed meal in normal subjects and in diabetic subjects with and without autonomic neuropathy.

We investigated the effects of fiber on responses of blood glucose, serum insulin, gastric inhibitory polypeptide (GIP), and immunoreactive pancreatic glucagon (IRG) to ingestion of mixed meal with and without added fiber (5 g guar and 5 g pectin) in 12 normal, healthy subjects and in 12 age-, sex-, and weight-matched non-insulin-dependent, maturity-onset diabetic subjects (NIDDM). Fiber markedly enhanced glucose tolerance in the normal subjects without a change in insulin or GIP but with a significant reduction in glucagon responses. Fiber also markedly improved glucose tolerance in the NIDDMs without changing insulin or GIP but with a significant reduction in the glucagon responses. The NIDDMs were divided into two groups of six subjects, with and without autonomic neuropathy (AN). In NIDDMs without AN, glucose tolerance was improved by fiber without a change in insulin, IRG, or GIP. In diabetic subjects with AN, glucose tolerance was not improved, although glucagon levels were lowered and insulin and GIP responses were unchanged. It appears, therefore, that fiber improves glucose tolerance by altering factors other than insulin. It seems also that autonomic nervous supply to the gastrointestinal tract is important in mediating the effect.

Ketonuria in pregnancy--with special reference to calorie-restricted food intake in obese diabetics.

Early morning ketonuria, as judged by Ketostix testing, occurred in 19% of urine samples from insulin-independent diabetic pregnant women eating 1000 calorie diets, in 14% from diabetics on higher calorie diets, and in 7% of urines from nondiabetic pregnant women. Ketostix test was never found to be positive in blood, even when it was 2+ in urine samples, and acetoacetate levels were always below 1 mmol/L. Enzymatic estimations of acetoacetate (AA) and beta-hydroxybutyrate (BB) in urine and plasma samples revealed (1) no significant differences in range or mean between the groups receiving different restricted diets or full diets, the highest value observed for plasma AA being 0.34 mmol/L; (2) that Ketostix became positive at a concentration of AA above 1 mmol/L and that such a value in urine corresponded to plasma levels of between 0.06 and 0.1 mmol/L, i.e., double the normal; and (3) a 50-100-fold increase in urine AA when blood levels exceeded 0.08 mmol/L. Neonates born to diabetic mothers with ketonuria had no fetal distress or asphyxia neonatorum. The lowest Apgar score at 5 min was 8; 80% of neonates had a score of 10. Hence, positive Ketostix tests in urine samples do not indicate toxic levels in the blood, and a 1000 calorie diet for obese pregnant diabetics appears to be safe as regards neonatal outcome.