No abstract

It has been shown previously that verapamil and other calcium antagonists and calmodulin inhibitors can reverse multidrug resistance. We compared the potency of the dihydropyridine derivatives (4R)-3-[3-(4,4-diphenyl-1-piperadinyl)-propyl]-5-methyl-1,4-dihydr o-2,6- dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate-hydrochloride (B859-35), a metabolite of B859-35, niguldipine and (R)-nitrendipine to that of (RS)-verapamil in reversing multidrug resistance. The accumulation of the fluorescent dye rhodamine 123, which is transported by the P-glycoprotein, was determined by a flow cytometer. Multidrug-resistant human HeLa KB-8-5 and Walker rat carcinoma cells were incubated in the presence and in absence of the drugs indicated above. We found that 0.1 microM B859-35 increases the accumulation of rhodamine 123 in multidrug-resistant KB-8-5 and Walker cells more effectively than 1 microM (RS)-verapamil. In sensitive KB-3-1 cells addition of the drugs had no significant influence on the accumulation of rhodamine 123. IN KB-8-5 cells, 10 nM Adriamycin caused a reduction of cell growth to 85% compared to untreated controls (= 100%). If 1 microM B859-35, B859-35 metabolite, niguldipine, verapamil or (R)-nitrendipine was added to 10 nM Adriamycin, growth reduction compared with untreated controls increased to 12%, 11%, 23%, 63%, and 82% respectively. The effect of 0.1 microM B859-35 was a reduction in proliferation to 38%, that of 0.1 microM verapamil to 72%. These data illustrate that B859-35, a compound with antitumor activity in several tumors, is at least ten times more potent than racemic verapamil in reversing multidrug resistance.

Summary The dose‐plasma level relationship of DPH was determined in 700 patients divided into carefully defined groups. Equivalent dosages of DPH (5.1 mg/kg) were compared in each group. A highly significant (p < 0.001) linear dose (per meter2)‐plasma level relationship was observed in 21 adult males receiving their total daily dose each morning. Mean plasma DPH levels were similar in children of either sex, but larger doses were required to attain a plasma level equivalent to adult males. The mean plasma level achieved in adult females (25 to 45 years) was lower than that of adult males (p < 0.05). A significant increase (p < 0.001) in the mean plasma DPH level was observed in females over 65. There was no difference in the response of obese patients though they tended to receive inadequate dosages. The mean plasma level of patients receiving phenobarbital or primidone concurrently was similar to that of those receiving DPH alone, but individual differences were frequently observed. Consistent alterations in plasma DPH levels were not observed during pregnancy. Hence age, sex, and body size should always be fully considered in the clinical interpretation of data obtained by periodic monitoring of plasma DPH levels. RÉsumé La relation entre la dose de diphénylhydantoine (DPH) et son taux plasmatique fut étudiée chez 700 sujets, appartenant a des groupes soigneusement définis. Des doses équivalentes de DPH furent compareées dans chaque groupe (5.1 mg/kg). Une relation linéaire, très significative, entre la dose (par métre5) et le taux plasmatique fut observée chez 21 adultes de sexe masculin recevant leur dose quotidienne totale le matin. Les taux plasmatiques moyens de DPH étaient similaires chez les enfants des deux sexes, mais des doses plus élevées étaient requises pour atteindre un taux plasmatique équivalent à celui des adultes de sexe masculin. Le taux plasmatique moyen obtenu chez les adultes de sexe feminin (25–45 ans) était plus bas que celui des adultes de sexe masculin (p < 0.05). Un accroissement significatif (p < 0.001) du taux plasmatique moyen de DPH fut observe chez les femmes de plus de 65 ans. II n'y avait pas de différence dans la réponse chez les subjets obèses. Le taux plasmatique moyen chez les patients recevant à la fois du phénobarbital et de la primidone était analogue à ceux qui ne recevaient que de la DPH, bien que des différences individuelles furent fréquemment observés. Des changements significatifs du niveau plasmatique de DPH n'ont pas été observées durant la grossesse. Done l'âge, le sexe et le poids sont des facteurs de grande importance dans l'interprétation de données cliniques obtenues par l'évaluation périodique des taux plasmatiques de DPH. RESUMEN La relación dosis‐nivel en plasma de DPH se determineó en 700 enfermos divididos en grupos bien definidos. Dosis equivalentes de DPH (5,1 mg/kg) se compararon en cada grupo; en 21 adultos varones que recibían la dosis total cada mañana, se observó una relación linear dosis‐nivel en plasma (dosis por m2) muy significativa (p < 0.00...