Serial topoisomerase II expression in primary breast cancer and response to neoadjuvant anthracycline-based chemotherapy.

OBJECTIVE: We analyzed the value of topoisomerase IIalpha (Topo II) in predicting the clinical response to anthracycline-based neoadjuvant chemotherapy in breast cancers and the potential changes in Topo II after chemotherapy. In parallel, HER2, which is commonly coexpressed with Topo II, and p53, a modulator of chemotherapy activity, were also analyzed. METHODS: Forty-one patients with primary breast cancer and treated with neoadjuvant anthracycline-based chemotherapy (FAC or FEC) were included for the present study. Topo II, HER2 and p53 expression were measured by immunohistochemistry in pre and post chemotherapy (at the time of surgery), tumor specimens and the results were correlated with the clinical response. RESULTS: Topo II was overexpressed in 16 of 41 (31%) tumors before treatment, and this overexpression was significantly associated with clinical response (p = 0.03). HER2 and p53 were unrelated to response. Notably, Topo II overexpression, but not HER2 or p53, was lost in specimens after chemotherapy (p = 0.01). CONCLUSION: The observed link between Topo II and the clinical response to neoadjuvant anthracycline-based chemotherapy, together with its loss after chemotherapy, implies that Topo II deserves further testing in a prospective setting as a predictive marker.

Use of crossover trials to obtain antihypertensive dose-response curves and to study combination therapy during the development of benazepril.

When a new drug is developed, one of the first requirements is to establish the correct dose. Unfortunately, in dose-determination studies, not enough lessons have been learned from the past. Pilot studies are often planned without sufficient statistical power, due to an insufficient number of patients and highly variable blood pressure measurements. In the development of the new angiotensin converting enzyme (ACE) inhibitor benazepril, crossover trials were used to obtain useful information. At the end of phase II of the benazepril development, a double-blind crossover study was carried out with 25 patients, and the results made it possible to redefine the 12- and 24-h effects of benazepril in comparison with placebo. Moreover, the crossover trial allowed an investigation of the biological effects of the treatment. In further work, the efficacy of 10 mg benazepril, administered once a day, was confirmed in comparison with captopril and enalapril, with a beta-risk of less than 20%. Since this crossover study yielded reliable data, and there was no carryover effect, a similar crossover design was used to study the interaction between benazepril and nifedipine. In the past, mistakes were made and many antihypertensive drugs were administered in high doses, with no further beneficial effect on blood pressure and an increased risk of side effects. Work described in this paper shows that fewer but better designed and implemented studies can improve the efficiency and value of dose-finding studies for antihypertensive drugs.

First-step treatment of mild to moderate uncomplicated essential hypertension by a new calcium antagonist: nicardipine.

Nicardipine, a new calcium antagonist, was tested in a 14-week double-blind trial including 15 outpatients with uncomplicated essential hypertension. They were randomly assigned to nicardipine (20-30 mg three times daily) or placebo as first-step treatment. When necessary but always after a minimum of 4 weeks, pindolol (15 mg/day) was combined with nicardipine or placebo. At the end of step 1 (85 +/- 6 days with nicardipine vs. 58 +/- 6 days with placebo, p less than 0.01), nicardipine induced larger drops in supine systolic and diastolic blood pressure (SBP and DBP) than the placebo (21 +/- 2.5 vs 1.4 +/- 3 mm Hg, p less than 0.001, and 13 +/- 2 vs. 3.5 +/- 1.5 mm Hg, p less than 0.001, respectively). In the nicardipine group (n = 57), 53% of patients had controlled blood pressure (SBP less than 160 mm Hg and DBP less than 95 mm Hg) versus 17% in the placebo group (n = 47), p less than 0.001. There was no significant correlation between the decrease in blood pressure and the age of patients. The most common side effects in the nicardipine group were flushes (12%), headache (8%), ankle edema (5%), and asthenia (4%). When blood pressure was not brought under control and pindolol was prescribed as the second-step treatment, the nicardipine group (n = 52) displayed larger drops in SBP and DBP than the placebo group (n = 40) (27 +/- 5 vs. 15 +/- 3 mm Hg, p less than 0.01, and 18 +/- 1 vs. 9 +/- 2 mm Hg, p less than 0.001, respectively). These results show that a calcium antagonist is useful for first-step treatment of hypertension.

[Acute and chronic effects of a new calcium blocker, nicardipine, on renal hemodynamics in arterial hypertension]. / Effets aigus et chroniques d'un nouvel inhibiteur calcique, la nicardipine, sur l'hémodynamique rénale dans l'hypertension artérielle.

Renal hemodynamics and natriuresis were studied in 9 hypertensive patients without renal failure, 2 hours and 4 hours after oral intake of Nicardipine 30 mg; sodium intake was kept constant during the study (100 mmol per day). Then, Nicardipine was given at a dose of 30 mg three times a day and the hemodynamic study was repeated on the 6th day (2 hours after the morning dose). Renal blood flow (RBF) and glomerular filtration rate (GFR) were measured by the clearance methods using 131I-hippuran and 125I-iothalamate respectively. Results are as follows: (Table: see text). These results confirm the potent renal vasodilatory effect of Nicardipine; GFR was not significantly altered while RBF and FF returned to normal levels. An early and transient natriuretic effect was observed after the first dose of Nicardipine and body weight showed a significant decrease during the study indicating that no sodium retention was induced by Nicardipine.

Effect of nicardipine in elderly hypertensive patients.

The purpose of this study was to test tolerance and the antihypertensive effect of nicardipine, a new calcium antagonist, in 31 elderly patients aged 57-95 years. The study was conducted as a double-blind trial. The patients were allocated randomly to either active or placebo treatment. Sixteen patients were given 10-30 mg of nicardipine three times a day (mean dose, 69.4 mg per day); 15 other patients received a matching placebo. After 4 weeks, nicardipine lowered mean blood pressure, and the changes in systolic and diastolic blood pressure were significantly greater in the nicardipine group than in the placebo group. Nicardipine was tolerated very well, and orthostatic hypotension was never observed. There was no change in heart rate. Plasma renin activity (PRA) was measured in eight patients. There was no correlation between PRA and the antihypertensive effect of nicardipine. A pharmacokinetic study performed in 15 elderly patients showed a fast rate of absorption and also higher plasma levels than those observed in hypertensive adults (mean age, 54 years). This trial demonstrates the effectiveness of nicardipine in elderly hypertensive patients.

[Treatment of arterial hypertension in the aged with a calcium antagonist: nicardipine]. / Traitement de l'hypertension artérielle du sujet âgé par un inhibiteur calcique: la nicardipine.

The purpose of this study was to test in double-blind trial the tolerance and antihypertensive effect of nicardipine versus placebo in 32 elderly patients (mean age: 84 years). Nicardipine was given three times a day (mean dose: 69.4 mg per day). After four weeks, nicardipine lowered blood pressure (BP) from 186 +/- 4 mmHg/99.5 +/- 3 mmHg to 150 +/- 6/84 +/- 3 mmHg (p less than 0.001). 10 out of 16 patients were normalized (BP less than 160-95 mmHg). The placebo group remained hypertensive: 181 +/- 7/96 +/- 4 mmHg versus 183 +/- 4/101 +/- 3 mmHg (NS). 3 placebo treated patients were nevertheless normalized. The changes in systolic BP and diastolic BP were significantly greater in the Nicardipine group: respectively -36 +/- 4 versus -2 +/- 6 mmHg (p less than 0.001), -16 +/- 3 versus -5 +/- 4 mmHg (p less than 0.05). Treatment was very well tolerated. Orthostatic hypotension, change in heart rate, variation in biological parameters were never observed. These data agree with Buhler's statement suggesting that calcium channel inhibitors can represent an interesting alternative to diuretics as first line monotherapy in the treatment of hypertension in the elderly.