Cigarette smoke extracts inhibit prostacyclin synthesis by the rat urinary bladder.

Since prostacyclin (PGI2) is known to have a cytoprotective effect on epithelia, and since cigarette smoking is associated with an increased risk of bladder cancer, we investigated the possibility that nicotine, cotinine (the principal metabolite of nicotine) and other components of cigarette smoke inhibit PGI2 secretion by the urinary bladder. Using the rat urinary bladder as a model, we found that cigarette smoke extracts, but not nicotine or cotinine, inhibit in vitro PGI2 synthesis. 2-Naphthylamine, a known bladder carcinogen, was also a potent inhibitor of PGI2 synthesis by the rat bladder.

Non-suppression of cortisol secretion by long term treatment with ketoconazole in patients with acute leukaemia.

Ketoconazole, a potent antifungal agent, inhibits adrenal steroidogenesis in normal subjects during short term treatment. Since this drug is used in the long term prophylaxis of fungal infections in patients with haematological malignancies, we have investigated whether such patients have evidence of adrenocortical suppression. Six patients on long term prophylaxis with ketoconazole were given tetracosactrin stimulation tests.

The effect of non-specific beta-blockade on metabolic and haemostatic variables during hypoglycaemia.

Several haemostatic and metabolic variables were monitored during insulin stress tests (ISTs), which were preceded by placebo, nadolol or propranolol ingestion for 10 days. Nadolol administration blocked the rise in plasma factor VIII: RAg concentrations, but no significant changes were observed in platelet aggregation/thromboxane A2 release. Propranolol administration reduced the significance, but not the magnitude, of the plasma factor VIII:Rag rise and also marginally inhibited platelet aggregation/TXA2 release.

Thrombocytopenia and lupus-like anticoagulant in a patient with peripheral vascular disease: response to infusion of prostacyclin.

A 46 year old man with intermittent claudication due to severe peripheral vascular disease had a circulating lupus like anticoagulant (LLAC), thrombocytopenia (79 X 109/1), markedly reduced platelet survival and a normal bone marrow. He was treated with intravenous prostacyclin (PGI2) infusions which resulted in improvement of the patient's exercise tolerance and normalisation of his platelet count (300 X 109/1) and platelet aggregation could then be assessed. The platelets were markedly hyperaggregable and generated supranormal quantities of thromboxane A2.

Stimulatory effect of immunoglobulins and Fc fragments on glucose oxidation and glucose transport by adipocytes.

Following our demonstration that human IgG, its Fc fragments and IgM stimulate lipogenesis in adipocytes, we embarked on a study to investigate whether these proteins stimulate the oxidation and transport of glucose by adipocytes, and whether such a stimulation is mediated through the insulin receptor. Using a simplified method for the measurement of [14C]-carbon dioxide produced from [U-14C]-glucose by rat adipocytes, we demonstrated that both IgG, Fc fragments and IgM produced a dose-dependent stimulation of oxidation of glucose by adipocytes. These proteins also produced a stimulation of 3-o-methylglucose uptake by adipocytes.

Thromboxane A2 analogue (U-46619) stimulates vascular PGI2 synthesis.

Since platelet release reaction products (e.g. serotonin, ADP) stimulate prostacyclin (PGI2) release in vitro, we have investigated whether thromboxane A2 (TXA2) also has a similar effect.

The effect of diflunisal administration on platelet aggregation and cerebral blood flow.

The effect of a high dose of diflunisal (750 mg twice daily) on platelet aggregation and cerebral blood flow was investigated in 8 healthy volunteers. Diflunisal inhibited platelet aggregation consistently; this effect on platelets was reversed within 24 hours after the last dose of diflunisal. There was, however, no correlation between the anti-aggregatory effect of diflunisal and its plasma concentration.

Diminished creatinine clearance in anorexia nervosa: reversal with weight gain.

To assess whether patients with anorexia nervosa have abnormalities in creatinine clearance, we measured plasma creatinine concentration, urinary creatinine excretion, and creatinine clearance in 10 patients with anorexia nervosa before and during treatment. Urinary creatinine excretion and creatinine clearance were diminished in all patients. Nine patients had significant decreases in their plasma creatinine and creatinine clearance was increased even when corrected for body weight and body surface area respectively.

An investigation into the effects of nifedipine and nimodipine on platelet function and vascular prostacyclin synthesis.

The effect of two calcium-channel blockers (nifedipine; nimodipine) on in vitro platelet function and prostacyclin (PGI2) synthesis was investigated. Platelet aggregation and thromboxane A2 release in platelet-rich plasma were inhibited by both drugs, but the effective concentrations (20 mg/l) were considerably higher than the reported therapeutic levels of the drugs (60 micrograms/l). Platelet impedance aggregometry (PIA) in whole blood was a more sensitive (4-fold) index of the effect of nifedipine on platelets, but inhibitory concentrations of the drug were still considerably higher (5 mg/l) than therapeutic concentrations.

The effect of tiaprofenic acid and indomethacin on vascular prostacyclin and platelet thromboxane A2 production.

Two experimental models were used to compare tiaprofenic acid and indomethacin. The first model involved assessing their effect on in vitro prostacyclin synthesis by rat aortic rings and human umbilical endothelial cells. The results showed that the inhibitory effect of the two drugs was similar.

Does human placenta produce prostacyclin?

We have previously demonstrated that the human placenta possesses potent platelet anti-aggregatory activity. This activity was exhibited only when aggregation was induced by adenosine diphosphate (ADP), but not when induced by adrenaline, ristocetin or collagen. We have also shown that placental extracts degrade ADP.