Phase I safety and pharmacokinetic studies of brequinar sodium after single ascending oral doses in stable renal, hepatic, and cardiac allograft recipients.

Brequinar sodium (BQR), a substituted 4-quinoline carboxylic acid, was in clinical development in combination with cyclosporine (CsA) as a potentially effective therapy for the treatment and prophylaxis of rejection in organ transplant patients. This phase I study was performed in stable renal, hepatic, and cardiac transplant patients receiving CsA and prednisone maintenance therapy for immunosuppression. The pharmacokinetic objectives of this study were to characterize the pharmacokinetics of (a) single oral 0.5- to 4-mg/kg doses of BQR when given in combination with CsA and prednisone to stable renal, hepatic, and cardiac transplant patients and (b) steady-state oral doses of CsA, with and without single oral doses of BQR. In all three patient populations, the pharmacokinetics of BQR were characterized by a lower oral clearance (12-19 mL/min) than that seen in previous studies in patients with cancer (approximately 30 mL/min at similar doses) and a long terminal half life (13-18 hrs). This slower oral clearance for BQR could be due either to a drug interaction between BQR and CsA or to altered clearance or metabolic processes in patients with transplants. Steady-state CsA trough levels and the oral clearance of CsA were not affected by BQR coadministration. Among the three transplant populations, the cardiac transplant patients had lower oral clearance values of BQR and of CsA. The cause of this lower clearance is not known. Safety results indicate that BQR was well tolerated by this patient population.

[Inflammatory lymphadenoid reactions around basocellular epitheliomas]. / Réactions inflammatoires lymphadénoïdes autour des épithéliomas baso-cellulaires.

The histological study of 3,960 basal cell epitheliomas (carcinomas) showed in 82 cases (2 p. 100) an inflammatory lymphoplasmocytic reaction of the lymphadenoid type characterized by the neoformation of differentiated germinative centers. These organoid structures are morphologically similar to those of normal lymphoid follicles of the lymph-nodes and occur most often around the basal cell carcinomas of the face and the neck (96 p. 100), mainly the temporal and peri-auricular skin areas (37,5 p. 100). The concerned tumours are mostly of the primordial type (90 p. 100); such a lymphadenoid reaction was never observed around morphea-like basal cell carcinomas and seldom around superficial spreading basaliomas of the trunk. In 85 p. 100 of the examined cases the tumours were ulcerated and invaded the depth of the reticular dermis (78 p. 100) or the subcutaneous fat (6 p. 100). The occurrence of a lymphadenoid stromal reaction seemingly does not limit the tumour growth and in most cases it concerns aggressive and ulcerated ulcus rodens of histologically nodular or large trabecular type (solid, pseudo-cystic or adenoid variants). It could account for the possible inhibition of the host T-cell mediated immune defense by the aggressive behaviour of the tumour and the induction of a B-lymphocytic secreting reaction with no evident efficiency on the proliferative pattern and activity of the tumour. Its prevalent occurrence around basal cell carcinomas of peri-auricular localization could be related to lymphopoietic remnants of this skin area.