Oral administration of irinotecan in patients with solid tumors: an open-label, phase I, dose escalating study evaluating safety, tolerability and pharmacokinetics.

BACKGROUND: Oral drug formulations have several advantages compared to intravenous formulation. Apart from patient convenience and favorable pharmacoeconomics, they offer the possibility of frequent drug administration at home. In this study, we present a new oral irinotecan formulation designed as an enteric coated immediate release tablet which in pre-clinical studies has shown good exposure with low variability. METHODS: A phase I, dose escalating study to assess safety, tolerability, pharmacokinetics and efficacy of an oral irinotecan formulation and to establish the maximum tolerated dose (MTD). Each treatment cycle was once-daily irinotecan for 14 days followed by 1 week rest. RESULTS: 25 patients were included across four cohorts; 3 patients were included in cohort 1 (20 mg/m2), 7 patients were included in cohort 2 (30 mg/m2), 3 patients were included in cohort 3 (25 mg/m2) and 12 patients were included in cohort 4 (21 mg/m2). Median age was 67 years, 52% were performance status (PS) 0 while 48% were PS 1. Median number of prior therapies was 3 (range 1-6). MTD was established at 21 mg/m2. No responses were observed. Nine patients (36%) had stable disease (SD), lasting median 19 weeks (range 7-45 weeks). Among these five patients had previously received irinotecan. No grade 3/4 hematologic toxicities were reported. Totally six patients experienced grade 1/2 anemia, three patients had grade 1/2 leucopenia and 1 patient had grade 1 thrombocytopenia. Most common non-hematological grade 1 and 2 adverse events were nausea, fatigue, diarrhea, vomiting and cholinergic syndrome. Grade 3 toxicities included diarrhea, fatigue, nausea and vomiting, no grade 4 events were reported. PK data showed consistent daily exposures during treatment at days 1 and 14 and no drug accumulation. SN-38 interpatient variability was in the same range as after infusion. CONCLUSIONS: Oral irinotecan was generally well tolerated; side effects were manageable and similar in type to those observed with intravenous irinotecan. Hematological toxicities were few and only grade 1/2. In this heavily pre-treated patient population, oral irinotecan demonstrated activity even among patients previously treated with irinotecan.

The polymorphism IL-1beta T-31C is associated with a longer overall survival in patients with multiple myeloma undergoing auto-SCT.

Proinflammatory cytokines are suspected to play a role in the pathogenesis of multiple myeloma (MM). Therefore, it is possible that inborn genetic variations leading to a modified expression of these cytokines will influence the outcome for these patients. We investigated 348 MM patients undergoing high-dose melphalan treatment followed by Auto-SCT and examined the influence of single nucleotide polymorphisms (SNPs) in genes involved in the inflammatory response. We found that the polymorphism IL-1beta T-31C significantly influenced overall survival (OS; P=0.02) and that carriers of the variant C-allele had a significantly longer survival than homozygous wild-type allele TT-carriers (relative risk 0.6 (95% CI=0.5-0.9); P=0.008). The polymorphisms IL-6 G-174C, IL-10 C592A, PPARgamma2 Pro(12)Ala, COX-2 A-1195G, COX-2 T8473C and NFKB1 ins/del did not influence the OS in this group of patients. Furthermore, homozygous carriers of the variant allele of IL-1beta T-31C were at 1.37-fold (CI=1.05-1.80) increased risk of MM as compared with population-based controls (P=0.02). Our results indicate that IL-1beta is involved in the pathogenesis of MM.

[Comparison of efficacy, safety and cost-effectiveness of intravenous versus oral propafenone in paroxysmal atrial fibrillation]. / Porównanie skutecznosci, bezpieczenstwa i kosztów leczenia dozylna i doustna postacia propafenonu u chorych z napadowym migotaniem przedsionków.

The purpose of this study was to investigate the efficacy, safety and cost-effectiveness of intravenous and oral propafenone in the conversion of paroxysmal atrial fibrillation propafenone to sinus rhythm. We analysed two groups of 100 consecutive patients (pts) treated because of propafenone with duration < 48 h. The first group was treated with intravenous PFN (bolus of 70 to 140 mg) and the second group was treated with oral PFN (300 to 600 mg). These 2 groups were comparable in age, sex, evidence of CAD, hypertension, mitral valve disease, history of hyperthyroidism and the level of K+ at admittance. Conversion to sinus rhythm was achieved in 64 (64%) pts who received i.v. propafenone and in 77 (77%) who received oral propafenone (p < 0.05). We conclude that oral and intravenous propafenone is safe in the termination of propafenone. Oral route of administration appears to be superior to intravenous because of greater efficacy and cost-effectiveness.

[Treatment of cardiogenic shock in myocardial infarction with intraaortic counterpulsation]. / Leczenie wstrzasu kardiogennego w zawale serca kontrapulsacja wewnatrzaortalna.

The purpose of this study was to analyse the effects of intraaortic balloon counterpulsation (IABP) in treatment of patients with acute myocardial infarction (MI) complicated by cardiogenic shock. The study group consists of 20 consecutive patients (13 males and 7 females, aged 38-82 years) with cardiogenic shock developed in the course of MI. Catecholamines were administrated in all patients before intraaortic balloon pumping was instituted. IABP was performed using Datascope device. Efficacy of the procedure was determined with invasive measurements of arterial blood pressure and the level of diuresis. Of 20 patients with cardiogenic shock, 7 were successfully treated with IABP and they were discharged from the hospital.

[Value of Doppler echocardiography in evaluating pulmonary arterial pressure in patients with mitral valve defect]. / Wartosc badania echokardiograficznego metoda Dopplera w ocenie cisnienia w tetnicy plucnej u chorych z wada mitralna.

In 40 patients aged 25-52 years (mean 36 years) with mitral valve disease but without overt circulatory failure haemodynamic studies and echocardiographic examinations were carried out recording the blood flow in the pulmonary artery and the blood flow through the tricuspid valve by pulsating and continuous-wave methods. From the obtained curves the time was calculated from the beginning of the flow to its maximum (TPV), the pre-ejection time (RPEP) and the right-ventricular ejection time (RVET), and the indices TPV/RVET and RPEP/RVET. Moreover, in 14 patients with coexistent insufficiency of the tricuspid valve the systolic pressure in the pulmonary artery was calculated by determining the systolic gradient across the tricuspid valve. On the basis of the results of haemodynamic examination the patients were divided into two groups: with normal (24 patients) and with raised (16 patients) pressure in the pulmonary artery. In the group of mitral valve disease and pulmonary hypertension a significantly shorter TPV, lower values of the TPV/RVET index and greater values of the RPEP/RVET index were found as compared with the patients with mitral disease and normal value of the systolic arterial pressure in the pulmonary artery. The systolic arterial pressure in the pulmonary artery determined on the basis of Doppler echocardiography with measurement of the regurgitation wave in tricuspid valve insufficiency showed a high agreement (r = 0.94) with the pressure recorded during cardiac catheterization.

[Comparative investigation of cardiac output using impedance rheography and invasive methods]. / Badania porównawcze rzutu minutowego serca metoda reografii impedancyjnej i metodami inwazyjnymi.

Authors performed comparative measurements of cardiac output using the impedance rheography and Fick's method in healthy men (6) reaching the value of correlation coefficient 0.88 and in patients with acquired cardiac defects (n = 21; r = 0.68). Authors also compared cardiac output values measured at rest and during exercise by means of thermodilution and rheographic methods in patients with heart failure (n = 9). Correlation coefficient was respectively 0.92 and 0.81.