Closure of the cleft palate in one or two stages: the surgical methods

The details of two consecutive groups of cleft palate patients treated with one- or two-stage palate repair are presented. The total number of patients is 237, with 128 operated in one stage, and 109 operated in two stages. In the two-stage group, the frequency of 'unintended' palatal fistulas decreased by 80%, and the use of blood transfusions was greatly reduced, but total operation time and hospital stay were longer. The results in terms of speech quality, facial growth and dental occlusion, will be reported on separately.     

Pharmacokinetics of terodiline and a major metabolite in dogs with a correlation to a pharmacodynamic effect

The pharmacokinetics and pharmacodynamics of the anticholinergic and calcium antagonistic drug terodiline, N-tert-butyl-1-methyl-3,3-diphenylpropylamine, have been studied in beagle dogs. The bioavailability was about 25% (0.15 and 0.5 mg/kg), the terminal half-life 3 hr, the systemic clearance 40 ml/min..kg, the volume of distribution (V beta) about 7 l/kg and the unbound fraction in serum 0.14. p-Hydroxyterodiline and p-hydroxy-m-methoxyterodiline were quantitated and constituted 15-40% and 25%, respectively, of the amount excreted in urine (about 60% of the dose) and were the main metabolites, as in man. The dog was used as an experimental model to study the chronotropic effect. An increased heart rate was observed after acute administration of high doses of terodiline as well as after p-hydroxyterodiline. A 20% increase in heart rate was observed at a mean serum concentration of 1086 and 1010 micrograms/l following intravenous injection of terodiline or p-hydroxyterodiline, respectively. The corresponding unbound concentrations were 150 and 474 micrograms/l. The potency ratios of terodiline/p-hydroxyterodiline was 0.9 +/- 0.2 (based on total concentrations) and 3.2 +/- 0.8 (based on unbound concentrations). The estimated potency of parent drug and main metabolite and the fact that p-hydroxyterodiline constitutes 10-20% of the terodiline steady-state level in man, indicate that the contribution of the metabolite to the chronotropic effect observed in clinical studies is minor.     

Synthesis and Evaluation of Azole-Substituted Tetrahydronaphthalenes as Inhibitors of P450 arom,P450 17, and P450 TxA2

In search of potential drugs for the treatment of estrogen- and androgen-dependent cancer as well as the prophylaxis of metastases, tetralones, tetralins, and dihydronaphthalenes bearing a OCH₃ substituent at the benzene nucleus and an imidazol-4-yl, imidazol-1-yl, or 1,2,4-triazol-1-yl substituent in 2-position were synthesized with and without C₁-spacer between the rings (compounds 2 – 26 ). The compounds were tested in vitro for inhibition of the three target enzymes P450 arom (human placental microsomes), P450 17 (rat testicular microsomes), and P450 TxA₂ (citrated human whole blood). To examine selectivity, some compounds were further tested in vitro for inhibition of P450 18 (bovine adrenal mitochondria), P450 see (bovine adrenal mitochondria) and corticoid formation (aldosterone, corticosterone; ACTH stimulated rat adrenal tissue). In vivo, selected compounds were examined in Sprague Dawley rats regarding P450 TxA₂ inhibition, reduction of plasma testosterone concentration, antiuterotrophic activity (inhibition of the uterotrophic activity of androstenedione), reduction of plasma estradiol concentration (pregnant mares' serum gonadotropin-primed rats), and mammary tumor inhibiting activity (dimethylbenzanthracene-induced tumor; pre- and postmenopausal model). In the series of imidazol-4-yl compounds, which represent a novelty in the field of azole inhibitors of steroidogenic P450 enzymes, strong inhibitors of P450 arom and/or P450 17 were found: 7-OCH₃-2-(imidazol-4-ylmethylene)-1-tetralone ( 4 ) and 7-OCH₃-2-(imidazol-4-ylmethyl)-tetralin ( 12 ) are among the most potent inhibitors of P450 arom in vitro known so far. Compound 4 is a selective inhibitor, whereas 12 shows in addition strong inhibition of P450 17. In contrast to 12 , the 6-OCH₃ derivative (compound 11 ) is a selective inhibitor of P450 17, being 50 times more potent than ketoconazole. Some imidazol-1-yl compounds show a marked inhibition of P450 TxA₂: 2-(imidazol-1-ylmethyl)-1-tetralone ( 13 ) is a selective inhibitor of P450 TxA₂, whereas 7-OCH₃-2-(imidazol-1-ylmethyl)-tetralin ( 17 ) as well as 2-(imidazol-1-ylmethyl)-tetralin ( 16 ) and 7-OCH₃-2-imidazol-1-yl-3,4-dihydronaphthalene ( 25 ) additionally show strong inhibition of P450 arom and P450 17. Regarding the other steroidogenic P450 enzymes as well as corticosterone formation, the compounds show only little inhibitory activity. Aldosterone formation, however, is inhibited at low concentrations. Nevertheless, 4 and 12 are more selective, i.e. inhibit aldosterone synthesis less than the well known inhibitor of P450 arom fadrozole. The compounds show activity in the aforementioned in vivo tests.     

Necrosis observed on CT enhancement is of prognostic value in soft tissue sarcoma.

Fifty-one patients with deep-seated soft tissue sarcoma of the extremities and trunk wall were examined with contrast-enhanced CT for presence of nonenhanced tumor areas (CT necrosis). After a median follow-up time of 3 years, 19 of the 41 patients with CT necrosis had developed metastases, compared to none of the 10 patients who had tumors without CT necrosis. Tumors with CT necrosis were larger than tumors without, but in tumors of similar size, absence of CT necrosis was a favorable prognostic sign.     

The echocardiographic evolution of left ventricular hypertrophy in treated hypertensive patients. A long-term follow-up]

In order to study the possible regressive changes of left ventricular hypertrophy in treated hypertensive patients and to correlate them either with the drugs they received and/or the blood pressure reduction obtained, a long-term (6 years) echocardiographic follow-up study was performed in 61 patients. B and M mode echocardiographic septum and posterior wall thickness and left ventricular mass index were measured yearly and the type of ventricular hypertrophy, asymmetric septal or concentric (symmetric), were compared before and after the follow-up. Sixteen patients received only diuretics; 14, only propranolol, and associated therapy was used in the remaining 31 patients. Average blood pressure was significantly reduced in the whole group of patients, but, individually, 30 of them achieved normal levels for the diastolic (90 mmHg), remaining it over this value in the other, although all of them experienced an average reduction 10 mmHg with therapy. Those patients with concentric hypertrophy at entry showed a significant septal, posterior wall thickness and total ventricular mass reduction during the follow-up, those with initial asymmetric septal hypertrophy, a significant septal thickness and ventricular mass reduction, and those without hypertrophy on admission, showed an average paradoxical increase in septal thickness. We conclude that left ventricular hypertrophy disappeared or decreased in 48% of the patients and that treatment seems to prevent its progression or development in the 43% of all patients. The regressive or favorable changes were significantly more frequent among patients with normal blood pressure after treatment as well as among patients treated only with propranolol in comparison to those treated only with diuretics.     

Late postpartum eclampsia. Apropos of a case

We report the case of a 32-year-old multipara who presented preeclampsia on the fourth day after childbirth without receiving proper treatment that progressed to eclampsia 4 days later. Pregnancy and delivery had been uneventful. The patient presented proteinuria (30 mg/dl), serum total proteins 5.3 g/dl and serum albumin 3.3 g/dl. Blood pressure was controlled with methyldopa, 500 mg at six-hour intervals by intravenous route. The patient presented hypoxemia secondary to bilateral pleural effusion and aspirative pneumonia requiring mechanical ventilation and invasive hemodynamic monitoring. Treatment with cefotaxime, 1 g at six-hour intervals by intravenous route and clindamycin, 600 mg at six-hour intervals by intravenous route was initiated. Sedation was maintained with thiopental sodium, 3 mg/kg/hour in continuous infusion. At dismission, the patient was completely recovered from her clinical picture and needed no antihypertensive therapy. Physiopathologic features and the aforementioned complications are discussed with particular reference to differential diagnosis.     

Perimetric variability: Importance of criterion level

Perimetry suffers from considerable variability of results. A new technique for estimating individual criterion levels in normal subjects exposes the important role of psychological variables. The analysis depends on features peculiar to acuity perimetry. It can be accommodated in the regular examination. The results can be used to compensate for practice effects in serial examinations and to tighten the range of normal limits. The reduction in variation between normal subjects amounted to 57 per cent.