Efficacy and safety of a new long-acting drug combination, trandolapril/verapamil as compared to monotherapy in primary hypertension. Swedish TARKA trialists.

OBJECTIVE: To evaluate the clinical efficacy and safety of a new antihypertensive drug combination of trandolapril/verapamil compared to monotherapy with verapamil or trandolapril, in patients with mild to moderate primary hypertension. DESIGN: A multicentre, prospective, randomized, double-blind, controlled cross-over study with specific statistical considerations. SETTINGS: Eighteen primary health care centres and out-patient hospital clinics in Sweden. PATIENTS: Two hundred and twenty-six outpatients with uncomplicated primary hypertension with a baseline sitting diastolic blood pressure (BP) between 95 and 115 mmHg. INTERVENTIONS: After a 4-week placebo period, patients were randomized to treatment for 8 weeks with trandolapril/verapamil (2 mg/180 mg) or each drug alone (verapamil 240 mg, trandolapril 2 mg) for 8 weeks. MAIN OUTCOME MEASURES: Treatment responses (blood pressure (BP) fall and rate pressure product) to the three regimens with statistical comparison and also in relation to plasma concentrations of active renin (AR). Adverse events and safety were also evaluated. RESULTS: The mean BP fall was significantly greater with the combination (20/15 mmHg), p < 0.00054, as compared to both trandolapril (14/11 mmHg) or verapamil (13/11) mmHg. The difference between verapamil and trandolapril was not significant. Rate pressure product decreased significantly more on the combination, p < 0.001, than on trandolapril or verapamil alone. Treatment response to trandolapril was positively correlated to initial AR (r = 0.30-0.43). All treatments were well tolerated and safe. CONCLUSIONS: The new fixed drug combination trandolapril/verapamil was superior to monotherapy with either of these drugs alone regarding reduction of both BP and rate pressure product. This combination can be safely and effectively used for the treatment of mild to moderate primary hypertension.

Nitrofurantoin produces oxidative stress and loss of glutathione and protein thiols in the isolated perfused rat liver.

The effects of 150, 600 or 1,200 nmol/ml of nitrofurantoin on glutathione (GSH), glutathione disulfide (GSSG), protein thiols (PSH) and cell integrity were studied in the isolated perfused rat liver. Nitrofurantoin produced a dose-dependent, up to 3-fold, increase in bile flow and a marked, up to 150-fold, increase in biliary excretion of GSSG. By the conclusion of the experiment, tissue levels of GSH had fallen to 81 +/- 14, 41 +/- 10 and 16 +/- 5% of control values at the three dose levels. Tissue levels of GSSG rose from 18.3 +/- 2.3 to 45.3 +/- 8.0 nmol/g and from 20.0 +/- 6.0 to 187 +/- 47 nmol/g within 15 min at the two higher doses, but fell to initial levels by the end of the experiment. Only at the 1,200-nmol/ml dose did the tissue levels of PSH decline, to 64 +/- 14% of initial values, by the end of the experiment. Lactate dehydrogenase and transaminases were found in the perfusate only after the GSH and PSH levels had fallen. After a 60-min exposure to 1,200 nmol/ml of NFT followed by blank perfusate for 3 h, massive engorgement of the liver was noted. Microscopic examination revealed extensive interstitial edema, nuclear pyknosis, cytoplasmic shrinkage and vacuolization, and mitochondrial dense deposits. We conclude that toxic doses of nitrofurantoin can produce cellular depletion of GSH and PSH which, if not the direct cause, at least signal the loss of cell viability.