Immunosuppressant FK506 does not exert beneficial effects in symptomatic G93A superoxide dismutase-1 transgenic mice.

The immunosuppressant drug FK506 has been shown to exert neuroprotective effects in various model systems via inhibition of the protein phosphatase calcineurin (CN). The enzyme Cu/Zn-superoxide dismutase (SOD1), which is mutated in a familial form of amyotrophic lateral sclerosis (ALS), is an endogenous regulator of CN. Altered function of CN may therefore be involved in the pathogenesis of ALS. We tested FK506 in a transgenic mouse model expressing mutated SOD1 for potential beneficial effects. This treatment, initiated after onset of symptoms, did not cause a reduction in the decline of motor function nor did it prolong survival. These results argue against a crucial role of CN in the process leading to motoneuronal degeneration in SOD1-mutated mice.

Quinapril hydrochloride effects on renal function in patients with renal dysfunction and hypertension: a drug-withdrawal study.

Patients with mild to moderate hypertension (diastolic blood pressure > or = 95 and < or = 115 mmHg) and renal dysfunction entered one of two studies to assess the safety of efficacious daily doses of quinapril on renal function and blood pressure. Twenty-four patients with moderate renal impairment (MRI) (creatinine clearance > 30 and < or = 60 ml/min) entered 24 weeks of open-label quinapril treatment; 31 patients with chronic renal failure (CRF) (creatinine clearance < 30 ml/min) entered 16 weeks of open-label quinapril treatment. Patients with MRI initially received quinapril 5 mg once daily (qd) followed by titration to a maximum dosage of 40 mg/day (furosemide optional at 40 mg only). Patients with CRF initially received quinapril 2.5 mg qd and were titrated up to 20 mg/day (furosemide optional). Open-label quinapril treatment resulted in significant decreases in mean systolic (SBP) and diastolic (DBP) blood pressure. The 20 patients with MRI and the 28 with CRF who completed the open-label phase were then randomly assigned to continue active drug or to receive placebo in a 4-week, double-blind, drug-withdrawal phase. During the double-blind withdrawal phase, placebo-treated patients had significant increases in mean SBP and DBP from the end of open label. Creatinine clearance was essentially unchanged following open-label quinapril treatment or quinapril withdrawal. In conclusion, in patients with mild to moderate hypertension and renal dysfunction, quinapril in dosages of 5-40 mg qd for patients with MRI and 2.5 to 20 mg qd for patients with CRF significantly reduces blood pressure without adversely affecting renal function.