The aim of this study was to investigate whether multiple doses of the oral and highly selective dipeptidyl peptidase-4 inhibitor linagliptin affect the steady-state pharmacokinetics of the ...P-glycoprotein substrate digoxin. This single-center, open-label, two-period cross-over study involved healthy subjects (
n
= 20), randomized to treatment sequence AB or BA, where A comprised 0.25 mg digoxin qd for 5 days, then 0.25 mg digoxin qd plus 5 mg linagliptin qd for 6 days, and B comprised 0.25 mg digoxin qd for 11 days. A treatment-free period (≥35 days for AB and 14 days for BA) separated each treatment in both sequences. There were no clinically significant changes in steady-state pharmacokinetic parameters of digoxin when it was co-administered with linagliptin. The ratio of the adjusted-by-treatment geometric mean ratios and associated 90% confidence intervals for the AUC
τ,ss
,
C
max,ss
and renal clearance (CL
R
,0
–
24,ss
) of digoxin were all within the bioequivalence range 80–125%, which is important as digoxin has a narrow therapeutic range. There was a low incidence of adverse events, which were randomly distributed between treatment groups. In conclusion, linagliptin did not alter the pharmacokinetics of digoxin in this study, indicating that linagliptin does not inhibit P-glycoprotein or other transporters relevant for digoxin pharmacokinetics. These results suggest that linagliptin and digoxin can be co-administered without dose adjustment. Administration of digoxin alone and with linagliptin was well tolerated.
The effects of the proton pump inhibitor lansoprazole on the bioavailability of a low‐dose oral contraceptive (OC), containing 0.03 mg ethinyloestradiol (EE) and 0.15 mg levonorgestrel (LNG), were ...investigated. Twenty‐four healthy females (aged 19‐35 years; weight 60.6 +/‐ 7.1 kg) participated in a multiple‐dose, placebo‐controlled, randomized two‐way cross‐over study. All subjects received the OC over 2 full menstrual cycles from day 1 to day 21 separated by a drug‐free interval of 7 days. Lansoprazole (60 mg day‐1) or placebo was coadministered for 3 weeks each. Plasma concentrations of EE and LNG were determined by GC‐MS. The 90% confidence intervals for ratios of Cmax and AUC after log transformation of both EE and LNG ranged between 91 and 111%, indicating that lansoprazole did not affect the bioavailability of EE and LNG.
The aim of this series of studies was to determine the potential for pharmacokinetic interaction between candesartan (administered orally as the prodrug candesartan cilexetil) and hydrochlorothiazide ...(HCTZ), nifedipine, glibenclamide, warfarin, digoxin or the components of an oral contraceptive formulation. All studies were performed in healthy volunteers using randomised, crossover or add-on study designs. Candesartan cilexetil was administered orally at doses of 8, 12 or 16 mg. The pharmacokinetic parameters were determined for comparator agents and candesartan following administration of each agent alone or in combination. There were no changes in the drug plasma concentrations of nifedipine, glibenclamide, digoxin or oral contraceptives when co-administered with candesartan cilexetil. Co-administration of candesartan cilexetil caused a slight but significant decrease in the AUC of HCTZ. However, the 90% confidence intervals (CI) for AUC ratios for HCTZ when co-administered with candesartan cilexetil were within the defined limits of bioequivalence. Candesartan cilexetil produced a 7% decrease in trough plasma warfarin concentration but this had no effect on prothrombin time. Co-administration of candesartan cilexetil with HCTZ produced a statistically significant increase in the bioavailability and Cmax values for candesartan (18% and 25%, respectively). However, this increase is not considered to be clinically relevant. No other co-administered drug (nifedipine, glibenclamide, digoxin, oral contraceptive) affected the pharmacokinetic parameters of candesartan. Candesartan cilexetil was well tolerated both alone and in combination with the other agents.
An oral solution available as ethanol-free droplets of the fixed drug combination tilidine-HCl 50 mg/naloxone-HCl 4 mg (CAS 27107-79-5 and CAS 465-65-6, respectively; Tilidin-ratiopharm plus Tropfen) ...was investigated in 12 healthy volunteers together with an ethanol-containing reference preparation for comparable bioavailability. The study was conducted in an open, randomized, two-way cross-over design applying single doses of 20 droplets (equivalent to 50 mg tilidine-HCl/4 mg naloxone-HCl) of either formulation in the fasting state. The drug plasma profiles were monitored for a period of 48 h by means of LC-MS/MS for tilidine and its active metabolite nortilidine, whereas GC-MS was employed in order to determine naloxone and its phase I metabolite, 6-beta-naloxole. Maximum concentrations (Cmax) achieved were 22.28 ng/ml (tilidine) and 92.78 ng/ml (nortilidine) for the test preparation. Corresponding values for the reference preparation were 24.95 ng/ml (tilidine) and 100.73 ng/ml (nortilidine). The extent of drug absorption (AUC0-infinity) amounted to 38.83 ng h/ml and 467.63 ng h/ml for the prodrug tilidine and the metabolite nortilidine of the test preparation and corresponded well to 43.81 ng h/ml and 493.85 ng h/ml of the reference. Regarding the rate of drug absorption, essentially identical tmax and Rabs values for both tilidine and nortilidine of either preparation in addition pointed to well comparable liquid formulations and equipotent analgesia may be inferred from opioid pharmakokinetic profiles. Pharmacokinetics of the opioid antagonist naloxone and 6-beta-naloxole were also determined and resulted in well coinciding profiles for both preparations. Thus despite the fact that only minimum oral naloxone bioavailabilities were observed, plasma level monitoring of naloxone and 6-beta-naloxole allowed for demonstration of systemic exposure of opioid antagonistic compounds throughout a period of 2-3 h after oral drug administration. Due to the limited number of subjects involved, the primary aim of the study did not consist in demonstration of drug bioequivalence. Rather a comparable bioavailability between preparations was assumed if AUC and Cmax point estimators of 90% confidence intervals would be contained within a 0.80-1.20 range. The study outcome revealed that all four investigated analytes met this requirement, whilst nortilidine pharmacokinetic parameters even fulfilled commonly accepted bioequivalence criteria, i.e. inclusion of 90% confidence intervals of AUC- and Cmax-ratios within acceptance limits of 80% and 125%. Increased data variation observed with bioavailability parameters of tilidine, naloxone and 6-beta-naloxole prevented their bioequivalence demonstration based on only 12 study participants. In conclusion, single doses of two different tilidine/naloxone 50 mg/4 mg liquid formulations revealed well comparable bioavailability for all 4 analytes investigated. Both treatments were fairly well tolerated. Most frequently reported adverse events were dizziness, headache and nausea, which all recovered without sequelae and necessity of concomitant treatment.
Two cases of priapism occurring during heparin therapy for sudden hearing loss are reported. The association of anticoagulants and priapism is increasingly recognized. Literature studying possible ...mechanisms of the role of heparin in priapism is reviewed.
Citalopram (CAS 59729-33-8) belongs to the so-called 'second generation' antidepressant drugs and is used for the treatment of patients with major depression or other depressive disorders. In the ...present study, two different oral citalopram formulations (Citalopram-ratiopharm film-coated tablets as test preparation and tablets of a reference preparation distributed in Germany) were investigated in 20 healthy volunteers in order to prove bioequivalence between both preparations. A single 40 mg oral dose was administered according to an open, randomised, two-period cross-over design in the fasted state. Blood samples for determination of citalopram plasma concentrations were collected at pre-defined time points up to 168 h following drug administration. A wash-out period of 21 days separated both treatment periods. Citalopram plasma concentrations were determined by means of a validated HPLC method with fluorescence detection. Maximum plasma concentrations (Cmax), of 34.77 ng/ml (test) and 34.42 ng/ml (reference) were achieved. Areas under the plasma concentration-time curve (AUC0-infinity) of 1,719.69 ng*h/ml (test) and 1,725.71 ng*h/ml (reference) were determined. The results showed nearly identical rate and extent of drug absorption. Also further pharmacokinetic parameters were well comparable with each other. Thus, tmax showed values of 3.29 h (test) and 3.77 h (reference). The plasma elimination half-life (t1/2) was 42.50 h (test) und 44.46 h (reference). Both primary target parameters Cmax and AUC0-infinity were tested parametrically by analysis of variance (ANOVA). Bioequivalence between test and reference preparation was demonstrated since for both parameters AUC and Cmax the 90 % confidence intervals of the T/R-ratios of logarithmically transformed data were in the generally accepted range of 80 %-125 %.
In this paper, a constructively and technologically modified leno loom is introduced, which enables for the first time the low-damage processing of coarse high-performance fibers such as heavy tows ...with a non-crimped warp and weft yarn system to scrims. The modified leno loom requires just a single shedding element to achieve the vertical and horizontal offset motion of the weft yarn system for pattern generation. These modifications allow the low-damage processing of coarse high-performance fibers in the warp (straight yarn) and the weft yarn systems to create leno fabrics. These leno fabrics produced with the modified loom are investigated experimentally. By means of a three-factorial analysis of variance, the influence of tensile forces operating during processing and weft density on the crimp and the tensile strength of the straight yarn is examined. It is revealed that the property degradation (tensile/breaking strength) of the straight yarn caused by the weaving process is drastically reduced to 4.2% compared to an unprocessed roving. The determined crimp of the straight yarn affected by process-inherent tensile forces is 0.1% at its maximum. Thus, the presented leno-woven fabrics offer an enormous application potential for the reinforcement of brittle matrices, such as ceramic or concrete.
Measurement of relative renal function in azotemic patients can be misleading due to elevated background activity and delayed renal concentration of radiotracer. When there is delayed excretion of ...the tracer and obvious splenic or hepatic activity superimposed over one of the kidneys, it often is advantageous to delay the differential uptake measurement to allow renal activity to increase and background activity to decrease rather than use the standard 1- to 2- or 2- to 3-minute interval after radiopharmaceutical injection. The accompanying case illustrates the use of delayed images to obtain a more accurate assessment of relative renal function. The measurement must be made before the excretion of tracer into the ureter or bladder.
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