Therapeutic use of the natriuretic peptide ularitide in acute renal failure.

BACKGROUND: Ularitide is a member of the natriuretic peptide family. This hormone exhibits an N-terminal extension by four amino acids compared with atrial natriuretic peptide. Ularitide was shown to exert strong diuretic and natriuretic effects when infused intravenously. Its main action sites are the glomerulum, inducing preglomerular vasodilation and postglomerular vasoconstriction and thereby elevating the glomerular filtration rate, and the tubular system inhibiting Na(+)-reabsorption. In initial uncontrolled clinical trials, this peptide was shown to have beneficial effects in patients suffering from oliguric acute renal failure. METHODS: We conducted a double-blind, placebo-controlled, multicenter, dose-finding trial recruiting 176 patients randomized into 4 different Ularitide doses groups (U5, U20, U40, and U80 ng/kg/min) and a placebo group (U0). Ularitide/placebo infusion was performed for 5 days with half the originally infused dose on day 5. The primary objective of the study was to test various doses of Ularitide in patients suffering from oliguric acute renal failure to avoid mechanical renal replacement therapy during the first 12 hours. FINDINGS: The results indicate that Ularitide does not reduce the incidence of mechanical renal replacement therapy compared with placebo-treated patients during the first 12 h of treatment (U0: 36 (20), U5: 35 (11), U20: 36 (9), U40: 28 (8), U80: 41 (12), (% (n) (p = 0.87)). Diuresis increased in the Ularitide-treated groups and the placebo group after onset of infusion and did not show any significant difference in the first 12 h collection period (U0: 576, U5: 514, U20: 500, U40: 360, U80: 158 ML/12h (Median), (p = 0.16)). INTERPRETATION: In summary, the incidence of mechanical renal replacement therapy in critically ill patients suffering from oliguric acute renal failure could not be altered positively by Ularitide administration according to our protocol. Further prospective clinical trials are needed to answer the question whether a different patient collective or a prophylactic administration of Ularitide are more promising approaches in the clinical setting of oliguric acute renal failure.

Ularitide: from renal natriuretic peptide to clinical trials.

Ularitide is a member of the natriuretic peptide family which is presumably synthesized in the kidney. In physiological experiments a correlation between Ularitide excretion and natriuresis has been found. Ularitide infusions and bolus injections in animals initiated profound diuresis and natriuresis as the most prominent effects. On the basis of findings in in-vitro and in-vivo experiments, Ularitide was used in clinical trials, and the results indicate that it could be a promising new drug to prevent and treat acute renal failure in patients after cardiac surgery and organ transplantation.

[Urodilatin (INN: ularitide). A new peptide in the treatment of acute kidney failure following liver transplantation]. / Urodilatin (INN: Ularitide). Ein neues Peptid in der Intensivbehandlung des akuten Nierenversagens nach Lebertransplantation.

UNLABELLED: Acute renal failure (ARF) is a serious complication following liver transplantation. Many therapeutic regimens have been used so far but with limited success. Urodilatin (URO) is a new member of the atrial natriuretic peptide (ANP) family. When administered intravenously, URO induces strong diuresis and natriuresis with tolerable hemodynamic side effects. Preliminary non-controlled clinical studies demonstrate beneficial effects using URO as a therapeutic agent in patients suffering from ARF following heart and liver transplantation (HTx, LTx). These results prompted us to initiate this first controlled clinical trial to investigate whether URO infusion can improve renal function in patients with emerging ARF following LTx. METHOD: We initiated a randomized, double-blind, placebo-controlled study comparing five patients receiving i.v. URO infusion (20 ng/kg bw/min) with four placebo patients after informed consent was obtained. Optional inclusion criteria were oliguria/anuria ( < 0.5 ml/kg/h), refractory to conventional treatment including administration of furosemide and dopamine, increase of serum creatinine to a least 200% of preoperative values, and BUN levels > or = 25 mmol/l. The primary parameters for efficacy was the frequency of hemodialysis/hemofiltration. RESULTS: The frequency of hemodialysis/hemofiltration during URO or placebo infusion was significantly reduced (P = 0.03) in the URO-treated patients in comparison with placebo. BUN levels did not differ between two groups, but serum creatinine levels were consistently lower in the URO group. Diuresis tended to be stronger in the URO group, maintaining high levels despite a significant reduction in the administration of furosemide in comparison with placebo. CONCLUSION: We conclude that URO seems to be a new approach for the treatment of therapy-resistant postoperative ARF following LTx.

Significance of prophylactic urodilatin (INN: ularitide) infusion for the prevention of acute renal failure in patients after heart transplantation.

Acute renal failure is a serious problem following heart transplantation. In first uncontrolled clinical trials, Urodilatin revealed beneficial effects in the prophylaxis and therapy of acute renal failure following heart and liver transplantation. Here, we present the first randomized, placebo-controlled, double-blind study on 24 patients following heart transplantation to investigate whether prophylactic i.v. Urodilatin infusion can prevent acute renal failure requiring renal replacement therapy. Postoperative drug management was characterized by intravenous application of high furosemide, cyclosporine, and vancomycin doses. Urodilatin infusion was started postoperatively with a dose of 40 ng / kg bw / min for 6 days. 6 of the 12 patients in the Urodilatin group and 6 of the 12 patients in the placebo group had a stable diuresis (3 - 4 l / day) during the study period of 6 days. In contrast, the remaining 6 patients of each group developed oliguria / anuria and required subsequent hemofiltration / hemodialysis. Cumulative duration of hemofiltration (88 +/- 7.39 hours in the placebo treated patients versus 44 +/- 5.35 hours in the Urodilatin treated patients, p < 0. 05) as well as frequency of hemodialysis (3.0 +/- 0.49 times in the placebo group vs 1.2 +/- 0.29 times in the Urodilatin group, p < 0. 05) were significantly reduced using Urodilatin. Mean arterial blood pressure was stable during the Urodilatin infusion period and was not different to that observed in placebo patients. We conclude that Urodilatin does not reduce the incidence of acute renal failure and the subsequent requirement for hemofiltration / hemodialysis in our patient population, but seems to reduce the duration of hemofiltration and frequency of hemodialysis compared to the placebo group.

Treatment of chronic stable angina with carvedilol in comparison with nifedipine s.r.

Carvedilol 25 mg b.d. was compared with nifedipine s.r. 20 mg b.d. for subchronic treatment of patients with chronic stable angina. After washout and placebo run-in, 163 patients were randomly and double-blindly allocated to one of the two treatment groups. Two symptom-limited seated bicycle exercise tests were performed on placebo in order to confirm stable baseline conditions. After 4 weeks of active treatment, a further exercise test was performed in the morning, 12 h after the preceding dose. Diary cards were kept by the patients throughout the trial in order to record angina attacks and glyceryl trinitrate consumption. Carvedilol seemed to be somewhat more effective than nifedipine s.r. for improving exercise tolerance and exercise time to onset of angina and 1 mm ST-segment depression. Although there were highly statistically significant differences vs placebo, the two treatment groups did not differ significantly. No difference between treatment with carvedilol and nifedipine s.r. was found regarding angina symptoms and glyceryl trinitrate consumption during daily life. Adverse events were less frequently reported in the carvedilol group than in the nifedipine group. Generally, however, both agents were well tolerated. Carvedilol therapy for chronic stable angina seems to be both efficacious and safe.

Efficacy and safety of carvedilol in comparison with atenolol in hypertensive patients pretreated with hydrochlorothiazide.

Carvedilol [25 mg once daily] (o.d.) was compared to atenolol (50 mg o.d.) as an adjunct to pre-existing hydrochlorothiazide (HCTZ) monotherapy in patients with mild to moderate hypertension [diastolic blood pressure (DBP), 100-115 mm Hg]. After a placebo run-in phase of 2 weeks, 131 patients received 25 mg HCTZ o.d. for 4 weeks. In all, 122 patients were transferred to the double-blind phase, in which 25 mg carvedilol or 50 mg atenolol was randomly added to HCTZ. After an additional 6 weeks of treatment, 112 patients were evaluable for efficacy (C/HCTZ group, n = 54; A/HCTZ group, n = 58). Blood pressure was measured and the heart rate was counted before medication, at 2-week intervals throughout the trial, and 2 h after medication on the 1st and the last day of the combination treatment period. Serum lipids were measured in addition to routine laboratory variables. A therapeutic response was defined as a reduction in supine and standing diastolic blood pressure to values of less than 90 mm Hg. In a relatively low number of patients (6 of 131), a response as defined above was achieved with HCTZ alone. This may be accounted for by the fact that patients were required to have a diastolic blood pressure of at least 100 mg Hg and by the relatively short period of monotherapy. The two groups of patients receiving different combination treatments were well matched for demographic data and blood pressure values before the adjunct was added. In both groups there was a marked additional blood pressure decrease on the initiation of combined treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

An open, long-term, multi-centre study of the anti-anginal efficacy and safety of isosorbide 5-mononitrate at low doses in patients with coronary heart disease.

A total of 250 patients with coronary heart disease diagnosed clinically, by ECG and in some cases by coronary angiography, was treated with isosorbide 5-mononitrate, 221 of the patients being treated for up to 6 months. In 181 patients previously treated with isosorbide dinitrate (ISDN)-retard, the mean daily dosage of nitrate was reduced from 77 mg (200 mg maximum) ISDN to 45 mg (120 mg maximum) isosorbide 5-mononitrate in long-term treatment. During previous treatment with ISDN-retard (with high doses in some cases: 80 to 200 mg daily in 48.6% of patients and 40 mg or less daily in only 33.1%), 4.5% of the patients were totally free of angina pectoris attacks. In the same patients, this proportion was 53.6% after administration of isosorbide 5-mononitrate for 6 months (dosage 40 mg daily or less in 67.4% of patients, 80 mg or more in 8.8% of patients). A substantial increase in subjective exercise tolerance and the reduction in incidence of angina pectoris was associated with a marked reduction in nitrate consumption for acute attacks. Isosorbide 5-mononitrate lowered slightly the blood pressure and heart rate. Treatment with isosorbide 5-mononitrate was withdrawn in 22 (8.8%) patients due to nitrate intolerance (headache in 7.6%) and in a further 7 (2.8%) patients for other reasons. Of patients completing 6-months' treatment, 9.9% reported one or more reversible undesirable reactions typical of nitrates at the start of the trial (compared with 6.8% in the pre-trial period). The incidence of such effects decreased to 1.4% after 6 months. The incidence of tolerable headache was 7.7% during the first week on isosorbide 5-mononitrate, decreasing to 0.9% after 24 weeks (5.9% in the pre-trial period). The laboratory parameters and subjective tolerability data confirmed the therapeutic safety of isosorbide 5-mononitrate.