-
J F Bergmann,
J de Bruijne,
D M Hotho,
R J de Knegt,
A Boonstra,
C J Weegink, A A van Vliet,
J van de Wetering,
S P Fletcher,
L A Bauman,
M Rahimy,
J R Appleman,
J L Freddo,
H L A Janssen,
H W Reesink
[show abstract]
[hide abstract]
ABSTRACT: The ANA773 is an oral prodrug of a small-molecule toll-like receptor (TLR)7 agonist. Preclinical and healthy volunteer clinical studies with ANA773 have demonstrated induction of endogenous interferon-α (IFN-α) of multiple subtypes, which supports the potential utility in the treatment of chronic hepatitis C virus (HCV) infection.
To examine safety, tolerability, pharmacodynamics, pharmacokinetics and anti-viral activity of ANA773.
The ANA773 was investigated in a double-blind, placebo-controlled study in 34 patients chronically infected with HCV of any genotype. Patients were treatment-naïve or had relapsed following previous interferon-based treatment. This dose escalation study was composed of four dose groups (800, 1200, 1600 and 2000mg). In each group, six to eight patients received ANA773 and two received placebo. Patients were dosed with ANA773 every-other-day for either 28 days (800, 1200 or 1600mg) or 10days (2000mg).
Mild to moderate adverse events were reported, with an increase in frequency and intensity with increasing dose. No serious AEs were reported and there were no early discontinuations. There were dose-related increases in various markers of IFN-α response. The mean maximum change in serum HCV RNA level from baseline was -0.34, -0.29, -0.40, -0.97 and -1.26log(10) in the placebo, 800, 1200, 1600 and 2000mg cohorts, respectively. At the 2000mg dose, ANA773 significantly (P=0.037) reduced serum HCV RNA levels (range: 0.14 to -3.10log(10) ).
The ANA773 was generally well tolerated and resulted in a dose-related IFN-dependent response leading to a significant decrease in serum HCV RNA levels in the 2000mg dose group.
Alimentary Pharmacology & Therapeutics 06/2011; 34(4):443-53. · 3.77 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: (1) To assess plasma renin activity (PRA) and plasma aldosterone concentration (PAC) in patients with inferior vena cava syndrome (IVCS). (2) To study in an open fashion the efficacy of loop diuretic treatment, single, or in combination with an ACE-inhibitor or with spironolactone.
In 13 patients PRA and PAC were measured and related to urinary sodium excretion (UNa).
Highly elevated PRA and PAC were found in recently developed IVCS. The correlation coefficient between PAC and UNa was -0.61, p < 0.05. In 10 patients the influence of captopril (C)] at maximum tolerable doses with or without furosemide (F) was evaluated. Mean tolerated dose of C amounted to 8.8 mg t.i.d. (range 2-25), achieving a PAC reduction of 26%. Efficacy of F was severely blunted when PAC exceeded the low-normal range. Spironolactone addition at 100 mg/day in non-responders to F or to F and C, induced immediate natriuretic responses except in a patient with 7-70 fold increase in PAC.
(1) In IVCS loop diuretic efficacy is attenuated by aldosterone activation; (2) complete aldosterone suppression with captopril is difficult to achieve due to dose restriction; (3) spironolactone is favoured for a synergistic response.
The Netherlands Journal of Medicine 02/1995; 46(2):62-72. · 2.07 Impact Factor
-
Gastroenterology 05/1994; 106(4):1131-2. · 11.68 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Patients with severe congestive heart failure (New York Heart Association [NYHA] functional classes III-IV) often can tolerate only low doses of angiotensin-converting enzyme (ACE) inhibitors because pronounced hypotension caused by additional ACE inhibitor increments may decrease renal perfusion. The use of high-dose loop diuretics is currently advised to overcome diuretic resistance in refractory congestive heart failure (CHF). In a baseline controlled study, we evaluated 21 patients with diuretic resistance and evident fluid retention for the responses to 5 days of double drug therapy consisting of high-dose loop diuretic (10 mg oral bumetanide) in combination with the maximum tolerable dose of an ACE inhibitor (individualized to blood pressure and kidney function). Five patients (24%) showed a gross natriuresis and reduction in excess weight > 25% in response to this therapy. The remaining 16 patients (76%) with insufficient responses (i.e., < 25% reduction in excess weight) subsequently received 100 mg spironolactone once a day for 7 days in addition to the double therapy. Spironolactone coadministration was highly effective in 13 of 16 patients (81%). Marked natriuresis and diuresis were achieved within the next week of treatment, and CHF symptoms regressed or disappeared. The clinical course was similar in the bumetanide-ACE inhibitor and the bumetanide-ACE inhibitor-spironolactone treatment (triple therapy) groups. Plasma aldosterone was significantly higher (p < 0.05) in the patients who needed spironolactone. The 3 patients who were considered refractory to triple therapy exhibited the highest baseline plasma aldosterone concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)
The American Journal of Cardiology 01/1993; 71(3):21A-28A. · 3.37 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The renin-angiotensin-aldosterone system is activated by diuretics and involved in the diuretic resistance of cirrhotic patients with ascites and oedema. In previous studies relatively high doses of captopril (25-400 mg daily) were unsuccessful in promoting diuresis and natriuresis in these patients. We analyzed the efficacy of a low dose of captopril in eight patients with massive ascites resistant to therapy of salt/fluid restriction and increasing doses of spironolactone and furosemide. Mean duration of diuretic use was 73 days (range 7-240 days). After at least 3 days of observation on 80 mg furosemide and 100 mg spironolactone only, captopril was added. Four out of eight patients responded with an increase in natriuresis and diuresis; daily dose of captopril was 20.6 mg in responders and 26.5 mg in non-responders. After the addition of captopril the mean weight change was -7.5 kg in responders and +0.25 kg in non-responders. Mean urinary sodium output in responders increased from 72.8 (S.D. = 35.2) to 128.5 (63.5) mmol within 10 days. Increased diuresis in responders made diuretic reduction necessary: mean furosemide from 80 to 53.3 mg, and mean spironolactone from 100 to 68.1 mg. Creatinine clearances remained stable. High levels of plasma renin activity, plasma aldosterone and angiotensin-II were found in all patients. Non-responders showed more severe hyponatremia and higher vasopressin levels. Natriuretic atrial factor (NAF) was in the upper-normal range or slightly elevated in both groups. In non-responders we noticed low levels of cGMP in 24-h urine, compared with responders.(ABSTRACT TRUNCATED AT 250 WORDS)
Journal of Hepatology 06/1992; 15(1-2):40-7. · 9.26 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Corneal pathology in Crohn's disease is relatively rare. We had the opportunity to take a biopsy of a bullous mass in the cornea of a man with Crohn's disease. Analysis of electronic pictures shows an aberrant structure of the nucleus, a very dense nuclear membrane and fragmented nucleoles. The cytoplasm contains many patches without membrane; the basal membrane is composed of filaments, and the stroma possesses figures of fingerprint-type. This unclassified description of the cornea might be typical for Crohn's disease.
Ophthalmologica 02/1985; 190(2):72-6. · 1.42 Impact Factor
-
Nederlands tijdschrift voor geneeskunde 07/1982; 126(24):1092-6.
-
[show abstract]
[hide abstract]
ABSTRACT: Corneal pathology in Crohn’s disease is relatively rare. We had the opportunity to take a biopsy of a bullous mass in the cornea of a man with Crohn’s disease. Analysis of electronic pictures shows an aberrant structure of the nucleus, a very dense nuclear membrane and fragmented nucleoles. The cytoplasm contains many patches without membrane; the basal membrane is composed of filaments, and the stroma possesses figures of fingerprint-type. This unclassified description of the cornea might be typical for Crohn’s disease.
Ophthalmologica 08/1970; 190(2):72-76. · 1.42 Impact Factor
