[Acute liver failure ascribed to nefazodone: importance of 'postmarketing surveillance' for recently introduced drugs]. / Acuut leverfalen toegeschreven aan nefazodon: het belang van 'postmarketing surveillance' bij recentelijk geïntroduceerde geneesmiddelen.

A 50-year-old man developed acute liver failure 7 months after nefazodone treatment was initiated. There was no evidence of any aetiology apart from the exposure to the antidepressant drug nefazodone, while the results of repeated histological examinations of the liver were compatible with serious progressive drug-induced hepatitis. This diagnosis was initially disregarded because in the literature no patients with nefazodone-induced hepatitis were reported. However, the drug had only recently been introduced, which meant that relatively infrequent adverse drug reactions might not have been published. Further analyses of databases of the marketing pharmaceutical industry and of the World Health Organization revealed more cases of liver toxicity ascribed to nefazodone, which showed that liver failure may indeed be associated with nefazodone use. Consequently, prescribing doctors have been warned by the pharmaceutical company about this possible adverse drug reaction.

Efficacy and tolerance of three different calcium acetate formulations in hemodialysis patients.

BACKGROUND: Calcium acetate (CaAc) is an effective phosphate binder in patients with chronic renal failure. However, an important side effect is gastro-intestinal discomfort. Phos-ex (Cablon, The Netherlands) is the only commercially available non-coated CaAc formulation in our country. We developed two new CaAc formulations: neutral-coated CaAc (NCCaAc) and enteric-coated CaAc (ECCaAc). METHODS: In a randomised double-blinded cross-over trial we compared efficacy and tolerance of the three formulations in 19 stable hemodialysis patients, with a mean age of 63 years (range, 36-85), who had been on hemodialysis for 19 months (range, 6-47). Patients were randomised to receive NCCaAc or ECCaAc, with meals, for a period of 10 weeks and after cross-over for another 10 weeks. During a third non-blinded period, patients received Phos-ex for 10 weeks. RESULTS: Serum phosphate was significantly higher with ECCaAc compared to NCCaAc (1.89 +/- 0.07 vs. 1.70 +/- 0.08 mmol/l, P < 0.05). Serum Ca was significantly lower with ECCaAc compared to NCCaAc or Phos-ex (2.38 +/- 0.04, 2.47 +/- 0.04 and 2.48 +/- 0.04 mmol/l, P < 0.05). There were less hypercalcemic and more hyperphosphatemic events in the ECCaAc period, compared to the other periods. The daily CaAc dose and dietary intake of calcium, phosphate, protein and calories were comparable in all three periods. With Phos-ex, patients noticed more gastro-intestinal complaints than with to NCCaAc and ECCaAc. Two patients stopped taking Phos-ex because of side effects. CONCLUSIONS: In hemodialysis patients, phosphate control and tolerance were both influenced by the formulation of CaAc. Although phosphate control was adequate with all three formulations of CaAc, ECCaAc was less effective compared to NCCaAc or Phos-ex. NCCaAc and ECCaAc were better tolerated than Phos-ex. Regarding efficacy and tolerance, NCCaAc was the best calcium acetate formulation.

Calcium antagonists, a useful additional therapy in treatment resistant hypertension: comparison of felodipine ER and nifedipine Retard by 24-h ambulatory blood pressure monitoring.

OBJECTIVE: To compare the efficacy and tolerability of felodipine extended release (ER) 2.5 mg (F2.5) and 5 mg (F5) once daily with nifedipine Retard 10 mg (N20) and 20 mg (N40) twice daily as additional therapy in patients who remained hypertensive despite treatment with an ACE-inhibitor, beta-blocker or diuretic. DESIGN AND METHODS: In a multicentre, double-blind parallel study, 61 men and 54 women, aged 35-75, with a supine diastolic blood pressure between 95 and 115 mmHg were randomised to treatment with F2.5, F5, N20 or N40 for 8 weeks, with optional doubling of the dose after 4 weeks. Blood pressure was measured at the office after 0, 4 and 8 weeks and by 24-h ambulatory monitoring (ABPM) after 0 and 4 weeks. Spontaneously reported adverse events and a subjective symptom assessment questionnaire were used for side-effect profiling. RESULTS: Mean office systolic/diastolic blood pressure was clinically relevantly reduced in all treatment groups after 4 weeks by 8/7, 12/9, 11/9 and 18/11 mmHg for F2.5, F5, N20 and N40, respectively, and after 8 weeks (F2.5-5: 17/11 mmHg: F5-10: 18/14 mmHg; N20-40: 19/14 mmHg; N40-80: 25/14 mmHg) with no statistically significant differences between these groups. The lowest dose of felodipine (F2.5) was the least effective. After 4 weeks the ABPM showed consistent 24-h reductions in blood pressure (4/2; 8/5; 7/5; 10/6 mmHg, respectively) over 24 h for the felodipine ER 5 mg group only and for both nifedipine groups. No statistically significant difference between these groups was found. An office responder does not appear to be identical to an ambulatory one and vice versa. The adverse events, mostly oedema, flushing and headache, were dose-related. CONCLUSIONS: Both felodipine ER and nifedipine Retard are effective "add-on' drugs in patients with monotherapy-resistant hypertension. The blood-pressure-lowering effect is dose-dependent and tolerability is inversely related to efficacy. The results emphasize the benefits of combining two agents with low doses.

Identification of the component part in an epoetin alfa preparation that causes pain after subcutaneous injection.

The subcutaneous administration of epoetin alfa preparations may cause pain at the injection site. To identify the pain-causing substance in these formulations we performed two double-blind, placebo-controlled, randomized order, cross-over studies. Differences in pain experienced after subcutaneous injection of an epoetin alfa solution and its vehicle were assessed in 36 patients. The vehicle and its component parts, albumin and citrate, were compared in 36 volunteers. Normal saline served as a placebo control in both studies. Pain scores were obtained from visual analogue pain scales with no divisions and from five point verbal descriptive pain scales. Both the epoetin alfa solution and its vehicle caused significantly more pain than normal saline (P < 0.0001) in the patients studied. In volunteers the pain scores with the vehicle or its citrate component were significantly higher (P < 0.0001) when compared with normal saline or with the albumin component of the vehicle. In conclusion, the local pain experienced after subcutaneous administration of epoetin alfa preparations is mainly caused by the citrate component of the buffered solution. Epoetin alfa and the albumin component of the preparation do not play a role in this phenomenon.