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.     

Preservation of All Chordae Tendineae and Papillary Muscle During Mitral Valve Replacement with a Tilting Disc Valve

Mitral valve replacement was performed in 21 patients using a surgical technique that preserves the entire papillary muscle and chordal apparatus. With this technique, the anterior mitral leaflet is split from the center of the free edge toward the annulus. Bilateral incisions are made from the proximal end of this split to the two mitral commissures, detaching the anterior leaflet from the annulus. These two halves of the leaflet, with all chordae intact (corresponding to the anterolateral and posteromedial papillary muscles), are judiciously trimmed to remove areas of leaflet untethered by chordae tendineae and (when necessary) fibrous thickening; then swung posteriorly and sutured to the posterior mitral annulus using mattress sutures with pledgets. This surgical technique is expected to favor the preservation of left ventricular function and avoid occurrence of irreversible left ventricular dilation/dysfunction, and has been used successfully for calcific and degenerative etiologies, using both tilting disc valves and porcine bioprostheses. It is especially useful in the implantation of tilting disc and bileaflet mechanical prostheses because anterior subvalvular chordae tissue may interfere with the disc excursion and relocated to the posterior leaflet annulus.     

Cardiovascular risk factors in the population of 2 regions covered by the MONICA-France regions: Strasbourg and Toulouse

Cardiovascular risk factors were studied from 1985 to 1987 in two population samples from the French regions of the Bas-Rhin (BR) (Strasbourg) and the Haute-Garonne (HG) (Toulouse). 1,257 men and women in the BR and 1,323 in the HG, aged 35-64, participated in the survey. A common investigation methodology in harmony with the MONICA protocol, was used. The mean weight was higher among the male (5 kg) and female (6 kg) populations living in the BR than in the HG. Even after age, body mass index and tobacco consumption adjustments, arterial systolic blood pressure was higher in the male population of the BR (145 mm Hg) than in the HG (133 mm Hg). Similar differences were observed among the female population. A higher proportion of hypertensive subjects whatever the sex and the age group was noted in the BR. The proportion of smokers, and the quantity of tobacco they smoked, did not differ between the two centers. Adjusted total cholesterolemia was higher in the HG, with mean differences of 0.32 mmol/l among the men and 0.35 mmol/l among the women. In the case of HDL cholesterol, the differences were 0.23 mmol/l among the men and 0.34 mmol/l among the women, explaining in large part the differences of the mean levels of total cholesterol.     

Experimental epikeratophakia using tissue lathed at room temperature.

This report presents for the first time the results of carrying out epikeratophakia with tissue lathed at room temperature. Using an experimental model of epikeratophakia in the rabbit, we evaluated tissue handling techniques for the preparation of donor lenticules. Details of the technique are described and the in-vivo and histopathological findings reported.     

Neonatal Graves'' disease.

A newborn boy was noted by his mother to have a prominent left eye at birth, but an eye examination was delayed until age 7 months, at which time his ophthalmologist diagnosed exophthalmos. Computed tomography was interpreted as showing mild, diffuse, optic nerve thickening bilaterally suggestive of optic nerve gliomas. Subsequent examination in our clinic revealed pseudoproptosis secondary to retraction of the left upper eyelid. Magnetic resonance imaging demonstrated normal orbital structures. The mother was noted to be clinically hyperthyroid, and abnormal thyroid function tests confirmed the diagnosis. Although the infant was euthyroid, neonatal Graves' ophthalmopathy was diagnosed. He was managed by close observation while his mother was treated for her hyperthyroidism.