Netilmicin or tobramycin was administered to 197 patients in a prospective randomized double-blind trial. Of these patients, 140 recipients of nine or more doses of netilmicin or tobramycin could be evaluated for nephrotoxicity. Fifty-five patients were able to cooperate in the administration of serial audiograms. Nephrotoxicity of similar severity developed in 7 of 73 (9.6%) recipients of tobramycin and in 7 of 67 (10.4%) recipients of netilmicin (P > 0.05). Mild or slight auditory toxicity developed in 5 of 28 (17.8%) recipients of tobramycin and in 2 of 27 (7.4%) recipients of netilmicin (P > 0.05).Toxicity is the major limiting factor in the clinical usefulness of aminoglycosides (16,26). In experimental animals the nephrotoxicity and ototoxicity of netilmicin are lower than those of the other aminoglycosides (3,6,9,11,18,20,22,25, 36 Florence, Italy, 1981), and in a large prospective randomized trial (15) the ototoxicity of netilmicin was lower than that of tobramycin (P = 0.037). In four prospective randomized studies reported so far, however, the rates of toxicity of netilmicin, gentamicin, and amikacin have been similar (2,4,10,17).Adult patients with possible or documented sepsis, urinary or biliary tract infection, or pneumonia and for whom an aminoglycoside was considered indicated by a doctor other than one of the investigators were candidates for entry into the trial. Informed consent was obtained in each case. Patients allergic to aminoglycosides or infected with an organism known to be resistant to tobramycin or netilmicin or who had received an aminoglycoside in the previous 30 days were not entered into the study. The trial was prospective and controlled. Drug assignments were random (a computer-generated table was used), and a double-blind evaluation of toxicity was performed. Serum aminoglycoside measurements and appropriate dosage changes were supervised by an nonblinded member of the investigative group. The patient and the clinical investigator (J.M.G.) responsible for the evaluation of each case did not know which aminoglycoside had been given. Antibiotic therapy other than aminoglycosides and nonantibiotic therapy were not controlled in trial protocol. The loading dose of tobramycin and netilmicin was 1.7 mg per kg of total body weight given intravenously over 20 or 30 min. Maintenance doses were initially adjusted for renal function according to a nomogram * Corresponding author.
Background The management of anaemia and secondary hyperparathyroidism (SHPT) in haemodialysis patients with chronic kidney disease means a significant consumption of drugs with high economic and health consequences. Purpose To evaluate the potential economic impact of the different erythropoiesis stimulating agents (ESA) and active vitamin D analogues in haemodialysis patients in terms of cost minimisation. Materials and methods Retrospective observational study, in adult haemodialysis patients treated with ESA and active vitamin D analogues between January 2011 and February 2012. The sources of drug use data included drug acquisition costs and the prescribed monthly dose (PMD) defined as the average maintenance dose. Therapeutic equivalence was assumed in compliance with KDOQI and KDIGO quality criteria guidelines (haemoglobin, parathyroid hormone, calcium-phosphorus product). Statistical analysis was done using SPSS. The comparisons of averages were done using Student’s T test with a CI95% p < 0.05. Results 473 patients were included, 59% of them men. The total cost of the medicines dispensed was 1,207,225 €. For anaemia 328 patients were treated with epoetin: average PMD of 58,427 ± 38,989 IU and a total cost of 535,907 €; 145 patients were treated with darbepoetin: average PMD of 272 ± 213 mcg and a total cost of 222.214 €. The conversion ratio epoetin/darbepoetin was 214 IU:mcg, the PMDs cost 169 ± 113 € and 192 ± 150 €, respectively, and no significant differences were found (p = 0.07). To manage SHPT, 220 patients were treated with alfacalcidol: average PMD of 12.6 mcg and a cost of 16.965 €; 130 patients were treated with paricalcitol: average PMD of 24.3 mcg and a cost of 71.739 €. The conversion ratio alfacalcidol/paricalcitol was 1:2 mcg, and the PMDs cost 12.4 ± 6.8 € and 81.5 ± 33.8 €, respectively, reaching statistical significance (p < 0.001). Using alfacalcidol instead of paricalcitol could save 61,711 €. Conclusions Alfacalcidol seems to be the best cost alternative, even with a conversion ratio higher than the one recommended by the manufacturer (1:3 mcg). Epoetin and darbepoetin generate similar costs. This data supports the therapeutic positioning of these medicines in our field. No conflict of interest.
the patients were still on MMF and 70% on steroids. In the four arms, the mean GFR change over the 2nd and 3rd year was between +1 and -3 ml/min. At 3 years, the low-dose tacrolimus arm still had the highest GFR, although the difference was not signifi cant (68 vs 62-65 ml/min, p = 0.10). Over the 2nd and 3rd years all arms had low rates of biopsy-proven acute rejection (BPAR; 1-3%) and graft loss (3-6%). Non-fatal cardiovascular events were rare (42 cases in total until month 36): 5.2% in the standard-dose CsA, 5.5% in the low-dose CsA 2.4% in the low-dose tacrolimus, and 4.6% in the low-dose sirolimus group. Conclusions: Observational follow-up results based on approximately half of the core Symphony population indicate that during the 2nd and 3rd years renal function was stable, BPAR and graft loss rates were low, and many patients changed treatment regimen. The ITT arm with 2 g MMF + low-dose tacrolimus + daclizumab + steroids still resulted in highest renal function and lowest graft loss at 3 years, but these differences were not statistically signifi cant.
BackgroundA triple regimen with tacrolimus constitutes the basis of immunosuppressive protocols after orthotopic liver transplantation (OLT).PurposeThe aim was to analyse the efficacy and safety of once daily tacrolimus (TAC-OD) (Advagraf) individualised dosing through a Bayesian approach in de novo OLT patients.Material and methodsThis was a retrospective study (September 2012–April 2016). Inclusion criteria: adult OLT patients with a minimum follow-up of 7 days. Immunosuppressive protocol: TAC-OD (first dose: 0.15 mg/kg/day), mycophenolate mofetil (1 g/24 hours orally) and steroids within the first 24 hours after OLT. Patients with renal dysfunction were treated with interleukin-2 receptor antagonists and tacrolimus was delayed. Blood trough levels of tacrolimus were monitored every 24 hours during hospitalisation and every outpatient visit. Dose adjustments were performed with every blood withdrawn through calculation of the empirical Bayesian estimates of the pharmacokinetic parameters. Population pharmacokinetics models were implemented in NONMEM V.7.3. Tacrolimus target trough levels were 8–10 ng/mL during the first month, reducing progressively to 5–8 ng/mL. Efficacy variables: tacrolimus trough levels, hospital stay and survival. Safety variables: serum creatinine (SCr).Results2515 concentrations were collected from 99 patients (83 men/16 women). Mean age was 57.0 years (95% CI 53.9–60.14), IMC 16.07±4.7 kg/m2 and MELD 15 (95% CI 12–18). Median (p25–p75) trough concentrations (ng/mL) of tacrolimus were 8.9 (5.3–11.6), 7.5 (5.4–9.7), 8.78 (6.9–10.65) and 9.7 (8.17–11.9) at 2, 7, 15 and 30 days, and 8.43 (7.38–10.02), 7.9 (6.45–9.04), 7.53 (6–9.17), 7.22 (6–8.7), 6.37 (5–7.25), 6.1 (5.2–7.48), 4.4 (3.8–6.35) and 4.5 (4–5.3) at 2, 3, 6, 12, 18, 24, 36 and 42 months after transplantation (statistically significant decrease after the second month, p<0.05). Basal mean SCr was 1.11 mg/dL (95% CI 1.17–1.45) and it remained stable after 7 days of OLT (SCr 0.98 mg/dL; 95% CI 0.8–1.36) until 4 years (1.11 mg/dL; 95% CI 0.99–1.24) (p>0.05). Median hospital stay after transplantation was 4 days (p25–p75: 3–6). Patient survival at 1, 3 and 4 years was 85%, 83.4% and 79.6%, respectively. Mean time of survival was 41 months (95% CI 37.6–44.4).ConclusionOur dosing protocol of TAC-OD based on Bayesian methodology was feasible in routine clinical practice, the target concentration was achieved at 48 hours in 75% of patients and it showed favourable outcomes in terms of survival and safety.No conflict of interest
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