Preliminary clinical studies with thromboxane synthase inhibitors and thromboxane receptor blockers. A review.

This review of the clinical studies of thromboxane synthase inhibitors (TXSIs) and thromboxane receptor blocking drugs (TXRBs) covers the years 1981 to the present. Clinical studies on TXSIs include those in normal volunteers as well as those in patients with angina, peripheral vascular disease and Raynaud's syndrome, pulmonary hypertension, cerebral vasospasm, hepatorenal syndrome, adult respiratory distress syndrome, and those on cardiopulmonary bypass and hemodialysis. The compounds studied include dazoxiben, dazmagrel, CGS 13080, CV 4151, OKY 1581, OKY 046, and U 63557A. In volunteers, single-dose studies have demonstrated inhibition of thromboxane A2 (TXA2) formation, with some small increases in bleeding time but no marked effect on platelet aggregation. In general, the compounds tested were ineffective in both chronic stable angina and vasospastic angina but caused symptomatic improvement in patients with unstable angina. The TXSIs studied were found to produce no consistent effects in any of the other clinical conditions. Since none of the compounds tested produced a sustained inhibition of TXA2 synthesis, the disappointing clinical results with this class of drugs may be due to an incomplete blockade of thromboxane synthase with the dosage regimens used. Possible alternative or additional reasons for the general lack of success with TXSIs could be that some of the diseases studied do not involve TXA2 or that accumulating prostaglandin endoperoxides in the presence of thromboxane synthase inhibition substitute for TXA2 in causing platelet aggregation. TXRBs rely for their efficacy only on blockade of the TXA2 receptor and antagonize the deleterious effects of both TXA2 and prostaglandin H2 equally, so they represent a simpler pharmacological approach than TXSIs. Such drugs include AH 23848, GR 32191, BM 13.177, BM 13.505, and SQ 28668. All of these compounds are inhibitors of platelet aggregation induced by TXA2 or by its stable mimetic, U-46619. AH 23848 was ineffective in patients with stable angina but did benefit patients with peripheral vascular disease. BM 13.177 has also proven effective in preventing restenosis after angioplasty, occlusion of coronary artery bypass grafts, and the deleterious effects of TXA2 in renal disease. From these preliminary studies, it would appear that TXRBs may offer greater clinical potential than TXSIs. Further studies currently underway with TXRBs to resolve this question include those in unstable angina, angioplasty, peripheral vascular disease, renovascular hypertension, and cyclosporine nephrotoxicity.

Total anomalous pulmonary venous drainage associated with tetralogy of Fallot: report of a case.

The association of total anomalous pulmonary venous drainage and Tetralogy of Fallot is a rare occurrence; only six cases have been reported and only in one of these was the pulmonary drainage by the infracardiac route. A further such case is reported in a girl twin, with cleft palate and umbilical hernia and a normal spleen, who died at the age of three weeks and the clinical and post mortem features are described. The masking effect of the pulmonary outflow stenosis on pulmonary venous obstruction is discussed together with the relevance to clinical diagnosis and surgical intervention as "palliative" surgery may be dangerous.

Calcification of glutaraldehyde-preserved porcine and bovine xenograft valves in young children.

Eight children (mean age, 7.6 years) had xenograft prosthetic valves inserted. All developed evidence of prosthetic valve obstruction requiring reoperation 18 to 55 months after insertion (mean, 32 months). At operation, all the valves were found to be heavily calcified. There were two perioperative deaths. Of two patients who had a second xenograft valve inserted, one died suddenly 12 months later. Gross calcification of the xenograft was found at postmortem examination. The other patient had evidence of mild xenograft calcification at follow-up 19 months postoperatively. Four of the ten calcified xenograft valves were of bovine origin (Ionescu-Shiley type); in these the calcific obstruction occurred significantly earlier than in the six porcine (Hancock) valves.

Balloon occlusion angiography in critically ill neonates.

The use of balloon occlusion of a vessel during angiography is described in small ill babies. There were no complications associated with the technique, and angiographic visualisation of structures proximal to the balloon was improved especially in aortic arch anomalies.

Anomalous connection of left atrial appendage with persistent left superior vena cava.

An unusual connection of the left atrial appendage with a persistent left superior vena cava was demonstrated at angiography in a child with a ventricular septal defect, aortic valve stenosis, and aortic isthmus stenosis; this was later confirmed at necropsy. No previous reports of this anomaly have been found.

Coeliac disease associated with congenital heart disease.

Six children with congenital heart disease are described in whom poor growth was found to be due to small-bowel villous atrophy; none was in heart failure and only one was severely cyanosed. Growth improved in all 6 on a gluten-free diet. Gluten enteropathy may be more common than is realised in children with congenital heart disease, and jejunal biopsy should be undertaken early in any patient with poor growth and no heart failure to exclude the coexistence of the condition.

Two chambered left ventricle. Three new varieties.

A short review of two chambered left ventricle is given, and this rare condition is briefly compared and contrasted with the more common condition involving the right ventricle. Three cases are described, each of which presents a new variety of subdivision of the left ventricle; in two of these the condition was first shown by angiocardiography. The first case had left heart hypoplasia with dysplastic stenosis of the mitral and aortic valves and severe endocardial fibroelastosis of the main left ventricular cavity. The second case also showed dysplasia of the left sided valves with pronounced endocardial fibroelastosis, and in addition there was a congenital malformation of the left lung. The third case showed a bizarre ventricular subdivision without other congenital malformations. The role of the intertrabecular myocardial sinusoids in the pathogenesis of some types of two chambered ventricle is discussed and this is considered to have been of significance in the first two cases. The third case possibly represented an intramyocardial aneurysm of obscure aetiology.

Cineangiocardiography in tetralogy of Fallot.

The advantages of angled angiographic projections are demonstrated in a review of 55 cases of tetralogy of Fallot. Particular attention was paid to the origins of the branch pulmonary arteries, whose diameter was measured and compared with that of the descending aorta, showing that in 12 per cent there was narrowing to below 40 per cent of descending aortic diameter. Right aortic arch was present in seven cases (13%) and a major coronary artery anomaly in two (4%).

Angiocardiography with metrizamide in the neonate and infant.

The non-ionic contrast medium metrizamide was compared with a routine ionic medium (sodium methyl-glucamine diatrizoate) in a series of 16 patients with congenital heart disease, all under 11 kg body weight, undergoing angiocardiography. Despite a higher viscosity, metrizamide yielded images of equal quality to those of the ionic medium, and was clinically better tolerated. Metrizamide produced a significantly lesser effect on plasma osmolality, a parameter closely related to contrast medium toxicity. Other biochemical parameters showed insignificant changes. Metrizamide is therefore a more suitable contrast medium for angiocardiography and despite its cost should be considered for patients with serious congenital heart disease who are in poor clinical condition.

Results of 24 hour ambulatory monitoring of electrocardiogram in 131 healthy boys aged 10 to 13 years.

Ambulatory monitoring of the electrocardiogram was performed in 131 healthy boys aged between 10 and 13 years for two consecutive periods of 24 hours. When awake the maximal heart rates ranged from 100 to 200 and the minimal from 45 to 80 beats per minute. During sleep maximal rates were 60 to 110 beats and minimal rates 30 to 70 beats per minute. Sinus arrhythmia was seen in every boy and in 36 (27.5%) no other changes were found. Sinuatrial block, Mobitz type I, was not seen. Sinuatrial block, Mobitz type II, occurred twice only. Complete sinuatrial block occurred in 8.4 per cent, never lasted more than one cycle, and was always followed by a junctional beat. First degree atrioventricular block occurred in 8.4 per cent and Mobitz type I atrioventricular block in 10.7 per cent. Premature beats were always single, atrial in 13 per cent, ventricular in 26 per cent, and except in two boys were never more than four in 24 hours. There were no episodes of ventricular or supraventricular tachycardia. Changes in P wave morphology were common and slow junctional rhythm occurred in 13 per cent during sleep.