Pharmacokinetics and safety of teneligliptin in subjects with hepatic impairment.

The pharmacokinetics of teneligliptin was compared in 3 groups of 8 subjects assigned according to their degree of hepatic impairment (mild, moderate, or matched healthy subjects). Hepatic impairment was associated with an increase in maximal plasma concentration (Cmax ) and overall exposure (AUC0-∞ ) to teneligliptin. Geometric least square mean ratios for Cmax in subjects with mild and moderate hepatic impairment were 25% and 38% higher than in healthy subjects, and those for AUC0-∞ were 46% and 59% higher than in healthy subjects, respectively. For both parameters, the upper limit of the 90% confidence intervals was outside the 80%-125% "no effect" limit, but below the FDA-recommended "dose-adjustment" boundary of 200%. The lower mean total clearance in subjects with mild (9.79 L/h) or moderate (8.57 L/h) hepatic impairment resulted in longer mean half-lives (27.9 and 30.9 hours, respectively) than in healthy subjects (clearance: 13.11 L/h, half life: 24.8 hours). Protein binding ranged between 36.9% and 47.5% in subjects with hepatic impairment and between 32.5% and 34.5% in healthy subjects. Overall, teneligliptin was well tolerated by subjects with hepatic impairment. These results may indicate that caution will be needed when administering teneligliptin to subjects with hepatic impairment.

Pharmacokinetics of Teneligliptin in Subjects With Renal Impairment.

The pharmacokinetics of teneligliptin was compared in renally impaired and healthy subjects. Subjects were assigned to one of four groups of eight subjects, according to the stage of disease [mild, moderate, severe or end stage renal disease (ESRD)], while matched healthy subjects were allocated to one of two reference groups. Mild, moderate and severe renal impairment had no effect on maximum plasma concentration (Cmax ) following a single oral dose of 20 mg teneligliptin, as defined in the FDA guideline. AUC0-∞ was increased in all groups relative to the reference group but this was unrelated to the degree of renal impairment. Mean plasma protein binding was <80% in all groups. Overall, teneligliptin was well tolerated by subjects with renal impairment or ESRD. Dialysis is not expected to affect the efficacy or safety of teneligliptin. These results indicate that dose adjustment may not be needed when teneligliptin is administered to subjects with mild, moderate or severe renal impairment or ESRD.

Pharmacokinetic and pharmacodynamic profile of new biosimilar filgrastim XM02 equivalent to marketed filgrastim Neupogen: single-blind, randomized, crossover trial.

OBJECTIVE: Filgrastim XM02 is a biosimilar non-glycosylated recombinant methionyl form of human granulocyte colony-stimulating factor (r-MetHuG-CSF) expressed in Escherichia coli for subcutaneous and intravenous administration in the treatment of different forms of neutropenia and stem cell mobilization. This study was conducted to compare the pharmacokinetic and pharmacodynamic characteristics of the new biosimilar filgrastim XM02 with the marketed filgrastim (Neupogen). METHODS: Two filgrastim doses (5 and 10 microg/kg) of the new biosimilar filgrastim XM02 and the marketed filgrastim were administered either as intravenous infusion or subcutaneous injection in four single-dose, crossover, randomized substudies, conducted in 36 subjects each. Serum concentrations of filgrastim were determined using an enzyme-linked immunosorbent assay test kit on samples taken at intervals up to 48 hours after administration. The CD34+ stem cell count up to 15 days after administration was determined by flow cytometry using a validated CD34+ cell enumeration kit, and the absolute neutrophil count (ANC) up to 96 hours after dosing was determined by the Beckman Coulter AcT differential automated hematology analyzer. The primary pharmacokinetic endpoint was the AUC (48 h) (area under the serum concentration-time curve) of filgrastim serum concentration determined by the linear trapezoidal rule. Equivalence (biosimilarity) between the two filgrastim products was assessed by 90% confidence limits obtained from analyses of variance of log-transformed pharmacokinetic and pharmacodynamic endpoints, applying 80-125% equivalence intervals. RESULTS: The mean serum concentration profiles of filgrastim, ANC and CD34+ cells over time were similar for the two filgrastims. The 90% confidence intervals for all test/reference ratios for pharmacokinetic and pharmacodynamic endpoints lay within the accepted bioequivalence range of 80-125%. Both filgrastims showed similar safety profiles and were well tolerated. CONCLUSIONS: Equivalence of the two filgrastims was clearly demonstrated for all four dose/route of administration groups. Equivalence could be demonstrated for the serum concentration profile, for the ANC profile and, even more importantly, for the CD34+ cell count, which is a marker for the ability of the granulocyte colony-stimulating factor to mobilize stem cells.

Risk factors for symptomatic stone recurrence after transpapillary laser lithotripsy for difficult bile duct stones using a laser with a stone recognition system.

BACKGROUND: Laser-induced shock-wave lithotripsy (LISL) is successfully used for the treatment of difficult bile duct stones. The aim of this study was to assess the long-term risk for a symptomatic bile duct stone recurrence after LISL and to detect risk factors predicting recurrence. METHODS: Between 1993 and 2001, 80 patients with difficult bile duct stones were successfully treated by intracorporeal LISL through the papilla of Vater. Seventy-one of these patients [median age, 65.8 years; 51 women (71.8%)] were followed for a median (range) period of 58 (1-114) months. RESULTS: Eleven patients (15.5%) had a symptomatic stone recurrence. The median (range) period between laser lithotripsy and recurrence was 40 (5-85) months. The presence of a bile duct stenosis (P=0.032) and a body-mass index below 25 (P=0.025) were significantly associated with an increased risk for stone recurrence. A gallbladder in situ, the presence of gallbladder stones, dilation of the bile duct, or a peripapillary diverticulum was not associated with stone recurrence. CONCLUSIONS: The presence of a bile duct stenosis is significantly related to bile duct stone recurrence after treatment with LISL. The impact of the body mass index on stone recurrence is interesting. The gallbladder status did not predict stone recurrence in our study.

What is the "optimal" follow-up schedule for ICD patients?

BACKGROUND: In the absence of comparative studies, recommended routine follow-up (FU) intervals for implantable cardioverter defibrillator (ICD) patients range from 1 to 6 months; most patients are followed at 3 month intervals. METHODS: Six hundred and eighteen ICD patients were routinely seen 4 weeks after implant and then every 3 months. Unplanned visits (UPV) were either patient initiated or due to manufacturer recalls. FU visits included patient history/examination, ICD interrogation, pacing/sensing threshold and pacing/shock impedance. Chest X-rays were performed every 6 months. To validate FU interval recommendations, a comparative analysis on the detection of complications was performed, relying either on the information of every, or of every other FU visit, i.e., on 3 or 6 month intervals. RESULTS: During 3.3+/-2.8 years, 137 complications occurred in 110 patients (17%). However, identification of only 34% was dependent on the FU schedule, since the mode of detection was ICD interrogation in 38 and history/physical examination in nine patients. The remainder was diagnosed by UPV in 47, manufacturer recall in seven, accidental discovery during device replacement in two, and routine X-ray in 34 patients. Complication free survival at 2 years was 86.4% for patients implanted before 1999, and 89.2% thereafter (P=0.003). Regarding 6 rather than 3 month FU intervals, a theoretical maximum delay of 3 months in the detection of potentially life-threatening complications would have occurred in 1.7% of all patients. For those implanted after 1999, this related to only 0.9%. CONCLUSIONS: ICD-related complications detected during routine FU visits are relatively rare, particularly with newer generation ICD systems. Thus, 6 month FU intervals appear to be safe. With new developments such as patient alert features and telemedical data transmission, FU intervals in ICD clinics might even be further extended.

[Eptifibatide in patients with percutaneous coronary intervention in clinical practice. Results of a prospective registry]. / Einsatz von Eptifibatid bei der perkutanen koronaren Intervention im klinischen Alltag. Ergebnisse eines prospektiven Registers.

BACKGROUND AND PURPOSE: The use of potent platelet inhibitors has been shown to reduce the rate of ischemic complications in patients with percutaneous coronary intervention (PCI) in randomized clinical trials. Eptifibatide is a small-molecule glycoprotein (GP) IIb/IIIa receptor inhibitor. Eptifibatide given with a double bolus of 180 microg/kg 10 min apart followed by an infusion of 2.0 microg/kg/h achieves a high grade of platelet inhibition, which was associated with a highly significant clinical benefit in the randomized ESPRIT Study. The aim of the present prospective registry was to evaluate the efficacy and safety of eptifibatide in clinical practice. METHODS: A total of 673 patients who received eptifibatide during PCI were prospectively enrolled in the registry between January 2001 and November 2002 in 31 clinical centers. RESULTS: The intervention was performed for stable angina in 283 patients (42.1%), for unstable angina in 70 patients (10.4%), for non-ST elevation myocardial infarction in 120 patients (17.8%), and for acute ST elevation myocardial infarction in 200 patients (29.7%). Therapy with eptifibatide was predominantly initiated in the catheter laboratory before or during the intervention and maintained for a mean of 20 h. Major bleeding complications, in 50% of the patients at the catheter insertion site, were observed in 1.2% of the patients. A thrombocytopenia < 100,000/microl was not reported. The total mortality rate was < 1%, a myocardial infarction or reinfarction was observed in up to 3%, depending on the clinical indication for PCI. CONCLUSION: These data are comparable to the results reported in randomized clinical trials with eptifibatide and document the safety and efficacy of this small-molecule GP IIb/IIIa inhibitor in clinical practice in a wide range of patients undergoing PCI.

The impact of intensive serial plasmapheresis and iron supplementation on iron metabolism and Hb concentration in menstruating women: a prospective randomized placebo-controlled double-blind study.

BACKGROUND: Iron (Fe) depletion is common among regular whole-blood donors, but can be prevented through regular oral Fe supplementation. Little is known, however, about the Fe metabolism of donors undergoing intensive plasmapheresis. These donors lose considerable amounts of blood drawn for laboratory analyses and remaining in the disposable plastic sets. STUDY DESIGN AND METHODS: Menstruating women were enrolled in a prospective placebo- controlled double-blind study. One hundred women were randomly allocated to receive either 100 mg of elemental Fe per day or placebo over 24 weeks and asked to donate plasma at 1-week intervals. Hb was determined before each plasmapheresis. Ferritin, transferrin, and Fe concentration and reticulocyte count were measured every 4 weeks. RESULTS: Thirty donors in the placebo group and 29 receiving Fe completed the study. The total mean blood loss was 526 mL in the placebo group and 546 mL in the Fe arm (p=0.271). The number of donations with Hb values lower than 12.5 g per dL requiring prolongation of the time interval until the next plasmapheresis was significantly greater in the placebo arm. In the placebo group (n=30), ferritin levels began to decline significantly 4 weeks after entry. When the study was completed, Hb concentration and reticulocyte count also were found to be significantly lower in the placebo group than in the Fe study arm (p=0.028 and p=0.036, respectively). Hb, ferritin, and transferrin levels and reticulocyte counts did not change significantly in the Fe group during the observation period. CONCLUSION: Menstruating women undergoing regular plasmapheresis at short intervals are prone to develop Fe depletion. This can be prevented by regular Fe intake. Laboratory analyses in product plasma instead of serum gained from whole-blood samples could be an alternative to reduce blood loss.

Variability of Holter electrocardiographic findings in patients fulfilling the noninvasive MADIT criteria. Multicenter Automatic Defibrillator Implantation Trial.

In the MADIT study, a selected group of postinfarction patients with asymptomatic nonsustained ventricular tachycardia (NSVT) has been shown to benefit from prophylactic ICD treatment. The present study analyzed the variability of NSVT in a patient population fulfilling the non-invasive MADIT criteria. Three consecutive Holter ECGs were performed in weekly intervals in 68 postinfarction patients with an LVEF < or = 0.35. Patients with NSVT underwent programmed ventricular stimulation (PVS); patients were implanted with an ICD if sustained VT or VF was inducible. If NSVT was found in at least two recordings, the arrhythmia was defined as reproducible. In 28 (41%) of the 68 patients, NSVT was found in at least one recording. Seventeen patients revealed NSVT in the first, the remaining 11 in the second registration; no patient had NSVT only in the third Holter. Of the patients with NSVT, 50% had only one, 39% had two, and 11% had three positive recordings. Thus, reproducible NSVT was found in only 50% of the patients with NSVT. Predictors for reproducibility were LVEF > 0.27, NYHA Class I, absence of digitalis therapy, and > 2 NSVT per 24-hour period. Reproducible NSVT was not associated with risk factors such as elevated mean heart rate, reduced heart rate variability, late potentials, or inducibility of sustained VT during PVS. During 17 +/- 9 months of follow-up, seven (10%) patients experienced arrhythmic events: two without and five with previously documented NSVT. In the latter patients, first occurrence of NSVT was consistently in the first Holter; only two of them had reproducible NSVT. In postinfarction patients, the risk factor NSVT exhibits marked spontaneous variability, especially in those with a low number of NSVT per 24-hour period, LVEF < 0.27 or NYHA III, which limits its clinical value as a selection criterion for PVS. Reproducibility of NSVT itself does not seem to be an independent risk factor.