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Subduction zones generate the largest earthquakes on Earth, yet their detailed structure, and its influence on seismic and aseismic slip, remains poorly understood. Geological studies of fossil subduction zones characterize the seismogenic interface as a 100 m–1 km thick zone1–3 in which deformation occurs mostly on metres-thick faults1,3–6. Conversely, seismological studies, with their larger spatial coverage and temporal resolution but lower spatial resolution, often image the seismogenic interface as a kilometres-wide band of seismicity7. Thus, how and when these metre-scale structures are active at the seismic-cycle timescale, and what influence they have on deformation is not known. Here we detect these metres-thick faults with seismicity and show their influence on afterslip propagation. Using a local three-dimensional velocity model and dense observations of more than 1,500 double-difference relocated earthquakes in Ecuador, we obtain an exceptionally detailed image of seismicity, showing that earthquakes occur sometimes on a single plane and sometimes on several metres-thick simultaneously active subparallel planes within the plate interface zone. This geometrical complexity affects afterslip propagation, demonstrating the influence of fault continuity and structure on slip at the seismogenic interface. Our findings can therefore help to create more realistic models of earthquake rupture, aseismic slip and earthquake hazard in subduction zones.Using observations of double-difference relocated earthquakes in a local three-dimensional velocity model for Ecuador, a detailed image of seismicity is created, forming the base for more realistic models of earthquake rupture, slip and hazard in subduction zones. [ABSTRACT FROM AUTHOR]

In the frame of the DAMAST (Dams and Seismicity) project, we deployed a dense high-fidelity seismological real-time network to investigate in detail the spatio-temporal seismicity distribution around the Enguri high dam, situated in the greater Caucasus in western Georgia. We aim at recording the weak seismicity in a 10 km distance around the dam structure. To lower the detection threshold by reducing the ambient background noise, we installed four seismic stations in shallow (ca. 20 m) and deep boreholes. From these stations, KIT1 with a depth of ca. 250 m is the deepest seismological station in Georgia. In this paper, we characterize the seismicity recorded by the local seismic network from October 2020 to July 2022. To have a better historical picture of the seismic activity, especially since the dam construction and initial operations, re-processing of the old seismological catalogs was carried out. This required digitizing the paper-only catalog copies prior to relocation. We finally obtain a uniform catalog for the Enguri region to characterize the seismicity and start investigating its possible relationship with the exploitation of the dam reservoirs. [ABSTRACT FROM AUTHOR]

Estimates of the onset times of P phases from active source experiments can effectively be used in developing wavespeed models, and the large number of recordings typical of such experiments incentivizes the development of automated approaches to generate these estimates. The simplicity and repeatability of an airgun source such as that used in the 2016 Pisagua/Iquique Crustal Tomography to Understand the Region of the Earthquake Source (PICTURES) project in northern Chile suggested that a straightforward application of waveform cross-correlation would suffice for arrivals recorded by a network of inland seismic stations, but did not work well due to significant variations in waveform morphology. For similar reasons, the machine learning application PhaseNet also did not work well. Application of an alternative algorithm typically used in passive source investigations that is indifferent to waveform morphology, the Regressive ESTimator (REST) autopicking package, also proved unsatisfactory, largely because the limited spectral bandwidth of the airgun source and the frequent occurrence of local seismicity led to numerous false picks. This motivated the development of a new approach, named CORREL, that is a hybrid of REST and cross-correlation, with the addition of a constraint in the form of a polynomial function based on the REST picks that provides a reasonable prediction of an onset time. Compared to the results obtained originally from REST and simple waveform correlation, the application of CORREL to the PICTURES data both significantly increased the number of arrivals estimated and greatly reduced the number of outliers. The combination of techniques retains the precision afforded by cross correlation while taking advantage of the accuracy afforded by absolute time picking. The predictive polynomial also provides CORREL a better means to discriminate true shots from the abundant natural seismicity. [ABSTRACT FROM AUTHOR]

We describe a new harmonic tidal analysis method, which constrains the solution to be near a reference model. This regularization stabilizes the linear regression, allowing us to infer model parameters for each tidal harmonic. This overcomes the need to create a priori groupings of harmonics. The inversion is done iteratively by adjusting the reference model to reduce the data misfit. The frequency dependence of the solution is thus data-driven. We find models for the different spherical degrees independently. Our procedure allows narrow-band variations of the tidal admittance. We test the hypothesis that some of the temporal variations of tidal parameters found in previous studies were caused by inappropriate body tide models in combination with a priori wave grouping. We determine a local response model from 11.5 years of data recorded by the superconducting gravimeter SG056 at Black Forest Observatory (BFO, Schiltach). Using this as an a priori model in a non-regularized moving window analysis of wave groups composed from summed harmonics, we find that periodic variations of groups M1, K1, μ 2, N2, L2, and S2 are reduced by up to a factor of 7 compared to earlier studies. Some variations previously seen in the M2 group are captured as well. [ABSTRACT FROM AUTHOR]

Monitoring small magnitude induced seismicity requires a dense network of seismic stations and high-quality recordings in order to precisely determine events' hypocentral parameters and mechanisms. However, microseismicity (e.g. swarm activity) can also occur in an area where a dense network is unavailable and recordings are limited to a few seismic stations at the surface. In this case, using advanced event detection techniques such as template matching can help to detect small magnitude shallow seismic events and give insights about the ongoing process at the subsurface giving rise to microseismicity. In this paper, we study shallow microseismic events caused by hydrofracking of the PNR-2 well near Blackpool, UK, in 2019 using recordings of a seismic network which was not designed to detect and locate such small events. By utilizing a sparse network of surface stations, small seismic events are detected using template matching technique. In addition, we apply a full-waveform moment tensor inversion to study the focal mechanisms of larger events (ML > 1) and used the double-difference location technique for events with high-quality and similar waveforms to obtain accurate relative locations. During the stimulation period, temporal changes in event detection rate were in agreement with injection times. Focal mechanisms of the events with high-quality recordings at multiple stations indicate a strike-slip mechanism, while a cross-section of 34 relocated events matches the dip angle of the active fault. [ABSTRACT FROM AUTHOR]

The margins of the Caribbean and associated hazards and resources have been shaped by a poorly understood history of subduction. Using new data, we improve teleseismic P-wave imaging of the eastern Caribbean upper mantle and compare identified subducted-plate fragments with trench locations predicted from plate reconstruction. This shows that material at 700–1200 km depth below South America derives from 90–115 Myr old westward subduction, initiated prior to Caribbean Large-Igneous-Province volcanism. At shallower depths, an accumulation of subducted material is attributed to Great Arc of the Caribbean subduction as it evolved over the past 70 Ma. We interpret gaps in these subducted-plate anomalies as: a plate window and tear along the subducted Proto-Caribbean ridge; tearing along subducted fracture zones, and subduction of a volatile-rich boundary between Proto-Caribbean and Atlantic domains. Phases of back-arc spreading and arc jumps correlate with changes in age, and hence buoyancy, of the subducting plate. Seismic imaging of subducted plates offers a way to improve plate tectonic reconstructions. Here, Braszus et al. use new ocean-bottom seismometer data from the Lesser Antilles to locate subducted spreading centres and faults thus providing a new understanding of the evolution of the Caribbean plate. [ABSTRACT FROM AUTHOR]

Following the Mw 8.8 Maule megathrust earthquake that occurred on February 27, 2010, in central Chile, a sequence of normal faulting crustal earthquakes occurred close to the city of Pichilemu. This activity lasted several months and included two large events (Mw = 6.9 and Mw = 7.0) on March 11, 2010. An initial investigation of this activity analyzed a data set of about 630 earthquakes recorded locally by 8 short-period seismic stations and attributed this seismicity to the activation of the "Pichilemu fault system." While there is no visible surface faulting associated with this system, it is inferred from discontinuities in lithofacies in the metamorphic complex of Pichilemu and from morphological breaks attributed to post-Pliocene neotectonic activity. There are no recorded shallow crustal earthquakes in the Pichilemu area prior to the 2010 events. In this study, we combine locally recorded earthquake data from the 2010 seismic deployment and data from 20 seismic stations (short period, three components, continuous recording) deployed in 2017 around Pichilemu, Chile, to create a more detailed characterization of the Pichilemu fault system through local earthquake tomography (LET). The combined data set composed of P- and S-wave arrival times from 3691 events was inverted to generate a 3D elastic wave speed model from the surface to about 50-km depth. One hundred twenty-two focal mechanisms for relocated earthquakes with M ≥ 1 were also generated. Relocated hypocenters show that most of the recorded seismicity is associated with the Pichilemu fault system; its main structure is oriented N145°E, and it is seismically active along about 50 km long. Normal faulting mechanisms predominate for events with M≥2, being similar to the mechanisms of the Mw 7.0 March 11, 2010, Pichilemu earthquakes. Low-velocity anomalies correlate with fracture zones associated with the Pichilemu fault, and a high contrast in Vp/Vs coincides with known structures of Paleozoic to Mesozoic age. A high Vp/Vs ratio is observed where a projection of the fault reaches the interplate contact, suggesting that this zone of the forearc crust is likely weakened by the presence of fluids from the slab. A high Vp anomaly is contiguous with the fault system and appears to be related to the presence of granitic rocks which belong to the Coastal Batholith within the Cordillera de la Costa. We suggest that the location of the Pichilemu fault system is governed by rheological contrasts inherited from the evolution of the subduction complex represented by the current Cordillera de la Costa, and we infer that the orientations of those structures, the possible hydration of them from the interplate contact and associated crustal blocks, play a key role in fault activation following the stressing by a great subduction earthquake. [ABSTRACT FROM AUTHOR]

Oceanic lithosphere carries volatiles, notably water, into the mantle through subduction at convergent plate boundaries. This subducted water exercises control on the production of magma, earthquakes, formation of continental crust and mineral resources. Identifying different potential fluid sources (sediments, crust and mantle lithosphere) and tracing fluids from their release to the surface has proved challenging1. Atlantic subduction zones are a valuable endmember when studying this deep water cycle because hydration in Atlantic lithosphere, produced by slow spreading, is expected to be highly non-uniform2. Here, as part of a multi-disciplinary project in the Lesser Antilles volcanic arc3, we studied boron trace element and isotopic fingerprints of melt inclusions. These reveal that serpentine—that is, hydrated mantle rather than crust or sediments—is a dominant supplier of subducted water to the central arc. This serpentine is most likely to reside in a set of major fracture zones subducted beneath the central arc over approximately the past ten million years. The current dehydration of these fracture zones coincides with the current locations of the highest rates of earthquakes and prominent low shear velocities, whereas the preceding history of dehydration is consistent with the locations of higher volcanic productivity and thicker arc crust. These combined geochemical and geophysical data indicate that the structure and hydration of the subducted plate are directly connected to the evolution of the arc and its associated seismic and volcanic hazards. Serpentine subducted below the Lesser Antilles volcanic arc supplies water to the arc, controlling the location of seismicity, volcanic productivity and thickness of crust. [ABSTRACT FROM AUTHOR]

Stress variation and fluid migration occur in deformation zones, which are expected to affect seismic waves reflected off or propagating across such structures. We developed a basic experimental approach to monitor the mechanical coupling with respect to seismic coupling across a single discontinuity between a granite sample in contact with a steel platen. Piezoceramics located on the platen were used to both generate and record the P and S wave fields reflected off the discontinuity at normal incidence. This way, normal ( B) and tangential ( B) compliances were calculated using Schoenberg's linear slip theory (Schoenberg, J Acoust Soc Am 68:1516-1521, ) when the roughness, the effective pressure ( P, up to 200 MPa), and the nature of the filling (gas or water) vary. We observe that increasing the effective pressure decreases B and B, which is interpreted as the effect of the closure of the voids at the interface, permitting more seismic energy to be transmitted across the interface. Values of B are significantly higher than those of B at low P (<60-80 MPa) in dry conditions, and significantly drop under water-saturated conditions. The water filling the voids therefore helps to transmit the seismic energy of compressional waves across the interface. These results show that the assumption B ≈ B commonly found in some theoretical approaches does not always stand. The ratio B/ B actually reflects the type of saturating fluids and the effective pressure, in agreement with other experimental studies. However, we illustrate that only the relative variations of this ratio seem to be relevant, not its absolute value as suggested in previous studies. Consequently, the use of B against B plots may allow effective pressure variation and the nature of the pore fluid to be inferred. In this respect, this experimental approach at sample scale helps to pave the way for remotely monitoring in the field the hydro-mechanical state of deformation zones, such as seismogenic faults, fractured reservoirs, or lava conduits. [ABSTRACT FROM AUTHOR]

Constraints on the potential size and recurrence time of strong subduction-zone earthquakes come from the degree of locking between the down-going and overriding plates, in the period between large earthquakes. In many cases, this interseismic locking degree correlates with slip during large earthquakes or is attributed to variations in fluid content at the plate interface. Here we use geodetic and seismological data to explore the links between pore-fluid pressure and locking patterns at the subduction interface ruptured during the magnitude 8.8 Chile earthquake in 2010. High-resolution three-dimensional seismic tomography reveals variations in the ratio of seismic P- to S-wave velocities (Vp/Vs) along the length of the subduction-zone interface. High Vp/Vs domains, interpreted as zones of elevated pore-fluid pressure, correlate spatially with parts of the plate interface that are poorly locked and slip aseismically. In contrast, low Vp/Vs domains, interpreted as zones of lower pore-fluid pressure, correlate with locked parts of the plate interface, where unstable slip and earthquakes occur. Variations in pore-fluid pressure are caused by the subduction and dehydration of a hydrothermally altered oceanic fracture zone. We conclude that variations in pore-fluid pressure at the plate interface control the degree of interseismic locking and therefore the slip distribution of large earthquake ruptures. [ABSTRACT FROM AUTHOR]

Cracks play a very important role in many geotechnical issues and in a number of processes in the Earth's crust. Elastic waves can be used as a remote sensing tool for determining crack density. The effect of varying crack density in crystalline rock on the P- and S-wave velocity and dynamic elastic properties under confining pressure has been quantified. The evolution of P- and S-wave velocity were monitored as a suite of dry Westerly granite samples were taken to 60, 70, 80 and 90 % of the unconfined uniaxial strength of the sample. The damaged samples were then subjected to hydrostatic confining pressure from 2 MPa to 200 MPa to quantify the effect of varying crack density on the P- and S-wave velocity and elastic properties under confining pressure. The opening and propagation of microcracks predominantly parallel to the loading direction during uniaxial loading caused a 0.5 and 6.3 % decrease in the P- and S-wave velocity, respectively. During hydrostatic loading, microcracks are closed at 130 MPa confining pressure. At lower pressures the amount of crack damage in the samples has a small but measureable effect. We observed a systematic 6 and 4 % reduction in P- and S-wave velocity, respectively, due to an increase in the fracture density at 2 MPa confining pressure. The overall reduction in the P- and S-wave velocity decreased to 2 and 1 %, respectively, at 50 MPa. The elastic wave velocities of samples that have a greater amount of microcrack damage are more sensitive to pressure. Effective medium modelling was used to invert elastic wave velocities and infer crack density evolution. Comparing the crack density results with experimental data on Westerly granite samples shows that the effective medium modelling used gave interpretable and reasonable results. Changes in crack density can be interpreted as closure or opening of cracks and crack growth. [ABSTRACT FROM AUTHOR]

Acoustic emission (AE) monitoring is a non-invasive method of monitoring fracturing both in situ, and in experimental rock deformation studies. Until recently, the major impediment for imaging brittle failure within a rock mass is the accuracy at which the hypocenters may be located. However, recent advances in the location of regional scale earthquakes have successfully reduced hypocentral uncertainties by an order of magnitude. The least-squares Geiger, master event relocation, and double difference methods have been considered in a series of synthetic experiments which investigate their ability to resolve AE hypocentral locations. The effect of AE hypocenter location accuracy due to seismic velocity perturbations, uncertainty in the first arrival pick, array geometry and the inversion of a seismically anisotropic structure with an isotropic velocity model were tested. Hypocenters determined using the Geiger procedure for a homogeneous, isotropic sample with a known velocity model gave a RMS error for the hypocenter locations of 2.6 mm; in contrast the double difference method is capable of reducing the location error of these hypocenters by an order of magnitude. We test uncertainties in velocity model of up to ±10% and show that the double difference method can attain the same RMS error as using the standard Geiger procedure with a known velocity model. The double difference method is also capable of precise locations even in a 40% anisotropic velocity structure using an isotropic model for location and attains a RMS mislocation error of 2.6 mm that is comparable to a RMS mislocation error produced with an isotropic known velocity model using the Geiger approach. We test the effect of sensor geometry on location accuracy and find that, even when sensors are missing, the double difference method is capable of a 1.43 mm total RMS mislocation compared to 4.58 mm for the Geiger method. The accuracy of automatic picking algorithms used for AE studies is ±0.5 µs (1 time sample when the sampling rate is 0.2 µs). We investigate how AE locations are effected by the accuracy of first arrival picking by randomly delaying the actual first arrival by up to 5 time samples. We find that even when noise levels are set to 5 time samples the double difference method successfully relocates the synthetic AE. [ABSTRACT FROM AUTHOR]

Background and Objective: The BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone) chemotherapy regimen for the treatment of advanced Hodgkin's lymphoma has a superior outcome, but its toxicity (mainly haematotoxicity) is pronounced and highly variable. The present study was conducted to address the role of pharmacokinetics in individual toxicity.Study Design: Three plasma samples and a 24-hour urine collection for day 1 of the first three cycles of chemotherapy were analysed in 30 patients, and the pharmacokinetic parameters of the respective drugs were estimated by population pharmacokinetic methods (nonlinear mixed-effects model [NONMEM] software). Demographic data, doses and durations of infusion were also recorded. The effect of these parameters on platelet counts was estimated by analysis of covariance using a general linear model.Results: The pharmacokinetic parameters and respective covariates were similar to the published data. The body surface area, peak concentrations of etoposide, urinary recovery of dechloroethylcyclophosphamide (formed by cytochrome P450 [CYP] 3A4) relative to the cyclophosphamide dose and number of cycles had a significant effect on toxicity. These factors explained 37% of the interindividual variability in the change in platelet counts from day 1 to day 8 of each cycle.Conclusion: The results show that the individual pharmacokinetics of BEACOPP drugs are an important link between dosage and toxicity. Accordingly, individualisation of treatment based on pharmacokinetics may result in more uniform toxicity. Individualisation may also allow escalation of the mean dose, which is probably related to better efficacy. As a consequence of the present study, infusion rates should be standardised, and the potential of a dose reduction in the first cycle and of CYP3A4 phenotyping should be addressed in clinical studies. [ABSTRACT FROM AUTHOR]

Two seismic wave attenuation factors, scatteringattenuation Qs -1 and intrinsicabsorption Qi -1 are measured using theMultiple Lapse Time Window (MLTW) analysis method forthree different frequency bands, 1–2, 2–4, and 4–8 Hz.Data from 54 temporally deployed seismic stationslocated in northern Chile are used. This methodcompares time integrated seismic wave energies withsynthetic coda wave envelopes for a multiple isotropicscattering model. In the present analysis, the waveenergy is assumed to decay with distance in proportionto1/ GSF·exp(- ( Qs -1+ Qi -1)·ω r/ v), where r, ω and v are the propagationdistance, angular frequency and S wave velocity,respectively, and GSF is the geometricalspreading factor. When spatial uniformity of Qs -1, Qi -1 and v isassumed, i.e. GSF = 4π r2, theestimates of the reciprocal of the extinction length, Le -1 (= ( Qs -1+ Qi -1)·ω/ v), are 0.017,0.012 and 0.010 km-1, and those of the seismicalbedo, B0 (= Qs -1/ ( Qs -1+ Qi -1)), are 0.48, 0.40and 0.34 for 1–2, 2–4 and 4–8 Hz, respectively, whichindicates that scattering attenuation is comparable toor smaller than intrinsic absorption. When we assumea depth dependent velocity structure, we also findthat scattering attenuation is comparable to orsmaller than intrinsic absorption. However, since thequantitative estimates of scattering attenuationdepend on the assumed velocity structure (strength ofvelocity discontinuity and/or Moho depth), it isimportant to consider differences in velocitystructure models when comparing attenuation estimates. [ABSTRACT FROM AUTHOR]

Presents a study that uses compressional-to-shear converted teleseismic waves observed on several temporary networks in the Central Andes to image the deep structure associated with the region's tectonic processes. Indication from a relatively thin crust below that thinning of the lithospheric mantle may have contributed to the uplift of the Puna plateau; Evidence for the presence of kinetically delayed metamorphic reactions in subducting plates; Observation of an intracrustal low-velocity zone below the Altiplano and Puna plateaux.

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A novel slow release preparation containing 24 mg molsidomine has been investigated in 6 healthy subjects. Individual concentration/time-profiles after the tablet showed two separate concentration peaks at 2.2 h and 15.0 h. The relative bioavailability of the slow release preparation in comparison to an aqueous solution of molsidomine was 0.67. The in vivo dissolution profile revealed either a progressive decrease in dissolution velocity caused by altered physico-chemical conditions in the ileum and the colon or a progressive reduction in the absorption constant. In all subjects deconvolution revealed a punctual increase in absorption about 15 h post-dose, coinciding with the second peak of the concentration/time-profile. Therapeutic plasma levels of molsidomine (> 5 ng · ml were not maintained over 24 h by this slow release formulation. [ABSTRACT FROM AUTHOR]

Sera from 17 patients with Type I diabetes and 19 healthy volunteers have been examined to evaluate whether the kinetics of the binding of drugs to Site II of serum albumin is altered in diabetes. Stopped-flow measurements showed that the association velocity and the affinity constants of the fluorescent marker dansylsarcosine were significantly lower in diabetics (160 s and 2.0 × 10 l·mol) than in non-diabetics (196s and 4.0 × 10 l·mol). The dissociation velocity was not different [20.3 s vs. 19.4 s]. Although patients with a reduced albumin concentration were excluded the diabetics had significantly lower concentrations than the healthy volunteers. There was a significant correlation between decreased glycosylation of albumin and increased association velocity. The dissociation velocity constants were correlated with the molar concentration ratio of free fatty acids/human serum albumin. Thus, the extent of glycosylation and the amount of fatty acids bound per mole albumin can both affect the kinetics of drug binding to Site II. The lower affinity in patients with Type I diabetes is due to the increased in the glycoalbumin concentration. [ABSTRACT FROM AUTHOR]

The pharmaceutical market in the FRG offers about 11,000 different preparations and formulations. A restricted list (pharmacopoeia) containing approximately 1,000 drugs has been proved to cover the routine requirements of a university clinic and most of the additional drugs demanded by the physicians as 'exceptis excipiendis'. Restrictive control of requests for drugs not included in the internal pharmacopoeia by clinical pharmacologists has reduced the absolute number of requests by half, and about 60% of the remaining requests could be replaced by drugs listed in the pharmacopoeia. The majority of the special requests arose from the continuation of drugs presented to out-patients by the resident physicians after admission of the patient to the hospital. The supervision may lead to more critical revision of out-patient medication, but a substantial reduction of drug expenditure was not attained, as the drugs requested amounted only to a minor fraction of the overall drug expenditure by the hospital. [ABSTRACT FROM AUTHOR]

Ten patients with essential hypertension (WHO grade I-II) were treated in an open dose-adjustment study with the standard regimen of slow-release nifedipine 20 mg b. d. for 2 weeks and with an individualized dose for 6 weeks. The optimum dose, defined as that producing a pre-dose diastolic blood pressure (dBP) of 90 mm Hg at steady state, was determined from the individual concentration-effect relationship after a test-dose of 20 mg. On standard therapy, the reduction in pre-dose dBP was inadequate in 4 patients and it was excessive in 1 patient. After 2 weeks of individualized treatment, the required pre-dose antihypertensive effect was obtained in all patients. The individual doses required were 10 mg b. d., 10 mg t. d. s. 20 mg b. d., 20 mg t. d. s. and 20 mg q. d. s. One patient dropped out of the study because of side effects. Loss of the antihypertensive effect was observed in one patient after 6 weeks of treatment. On the optimized dose, the average value of the pre-and 2 h post-dose steady state nifedipine concentrations (27.6 μg/l) compared well with model-derived optimum concentrations (28.6 μl/l) (r=0.9210). The results show that the dose of nifedipine can be accurately predicted using the individual concentration-effect relationship after a single dose. [ABSTRACT FROM AUTHOR]

The pharmacokinetics of pengitoxin has been studied in 28 healthy subjects after intravenous and oral administration. The mean plasma concentration 24 h after 0.5 mg i.v. was 5.2 ng · ml. Following an open two-compartment model a mean elimination half-life of 60.5 h (24.9 to 103.5 h) and a mean volume of distribution (V) of 66.91 (31.8 to 109.61) were calculated. Absorption calculated by comparison of the AUC-values amounted to 99%. Within 4 days, 16.7% (11.7 to 21.1%) or 27.8% (18.4 to 33.7%) (0.5 mg i.v. or 1.2 mg p.o.) was excreted in urine. After pengitoxin 0.5 mg i.v. total body clearance and renal clearance were 13.3 ml · min (7.0 to 18.6 ml · min) and 3.0 ml · min (1.9 to 3.9 ml · min) respectively. The elimination half-life of pengitoxin is longer than that of digoxin and distinctly shorter than that of digitoxin, whilst its distribution volume and clearance are closer to those of digitoxin than of digoxin. [ABSTRACT FROM AUTHOR]

The correlation between the daily dose of digoxin, its plasma level and clinical characteristics of 213 patients receiving β-acetyldigoxin treatment has been evaluated. After logarithmic transformation of lognormally distributed variables multiple linear regression analysis was performed. Eight predictor variables were chosen: sex, age, height, weight, glycoside dose, creatinine and potassium level in serum and dose of spironolactone. The resulting correlation coefficient was 0.46, i. e. only 100×r=21.4% of the variance of the steady state digoxin plasma level could be interpreted with the aid of these variables. For only 4 of the 8 variables (age, glycoside dose, serum level of creatinine, and spironolactone dose) were partial coefficients of regression and of correlation significantly different from zero. Almost 80% of the variance could not be accounted for. This finding is in accordance with conclusions in the literature. [ABSTRACT FROM AUTHOR]

Five healthy volunteers received digoxin 0.4 mg or β-methyldigoxin 0.4 mg i. v., daily for 14 days, in a randomized cross-over arrangement. By monitoring minimal plasma concentrations during multiple dosing, it was found that the steady state pharmacokinetics of digoxin and β-methyldigoxin could be estimated even better by a one-compartment than by a two-compartment model. The following mean parameters were calculated: the half life of digoxin of 1.54±0.31 days was significantly shorter than the half life of 2.29±0.34 days for β-methyldigoxin. The distribution volume of 807±187 liters for digoxin was not significantly larger than the 735±227 liters for β-methyldigoxin. Renal digoxin clearance of 191±25 ml/min was significantly higher than both the renal clearance of β-methyldigoxin of 111±23 ml/min and also the creatinine clearance, which indicates tubular secretion of digoxin. There was a 2.8-fold accumulation of β-methyldigoxin injected once a day, which was significantly higher than the 1.8-fold accumulation of digoxin. [ABSTRACT FROM AUTHOR]

To obtain true half lives, glycoside elimination from six healthy subjects was studied for 14 days after multiple intravenous doses or oral administration of a daily maintenance dose of β-methyldigoxin 0.3 mg. After oral or intravenous administration of β-methyldigoxin ceased, the plasma concentrations declined from the 14th to the 16th days with a half life of 1.7 days. From the 16th to the 20th day a change from a shorter to a longer half life of 2.8 and 2.9 days was observed. Similar half lives were found in urine: after the last dose the initial slope from the 14th to the 16th day had a half life of 1.8 days, and the terminal slope had one of 3.2 days. The results indicate release of the glycoside from slowly equilibrating tissues. [ABSTRACT FROM AUTHOR]

The time course of radioactivity in plasma and the excretion in urine and faeces over 7 days were determined in 12 healthy subjects after single oral and intravenous doses of a solution ofH-β-methyldigoxin. 62.2±2.1 and 29.0±5.2 per cent of the dose were excreted in urine and faeces, respectively, within 7 days of intravenous administration, compared with 55.2±2.8 and 28.6±5.7 per cent after oral administration. This indicates almost complete absorption of the glycoside when given in solution. 12 hours after its administration a pseudo-distribution equilibrium was reached and the average half life of tritiated compounds was 1.3 days. By 48 - 96 hours after treatment the average half life was 2.8 days. O-demethylation was revealed as the main metabolic degradation step in man. The rate of Demethylation was higher after oral than i.v. administration. Thus, only 31% of the radioactivity excreted in the urine consisted of unchanged β-methyldigoxin after oral administration compared to 51% after i.v. dosing. Only traces of bis- and monoglycosides were excreted in urine, but there were considerable amounts in faeces, where they accounted for more than 35% of the total excretion. Up to 40% of the radioactivity in plasma and urine consisted of polar conjugates during the first 12 hours after administration of β-methyldigoxin. The mono- and bisglycosides were identified as the main products of conjugation. During the 7 days approximately 15% of the administered dose was metabolized by splitting off glycosidic bonds and conjugation to polar compounds. [ABSTRACT FROM AUTHOR]

Four patients with a biliary fistula received 0.5 mgH-methylproscillaridin as a single oral dose. 55% of the dose was excreted in bile, 16% in urine and 3% in faeces. More than 60% of the radioactivity excreted in bile and urine appeared within the first 24 hours. 78% of the radioactivity in bile consisted of CHCl-insoluble metabolites of methylproscillaridin, incubation of which with β-glucuronidase led to splitting off glucuronic acid from almost 80%. Methylproscillaridin can be regarded as the principal conjugated compound. TLC-separation of CHCl-soluble compounds from bile showed identical running of radioactivity with methylproscillaridin, proscillaridin and scillarenin and three unknown metabolites P, P, and P. In urine the CHCl-soluble fraction averaged 16% to 34% of the total amount and was identified as methylproscillaridin, proscillaridin, scillarenin, P and P. The relative composition of the total radioactivity in faeces amounted to 77% methyl-proscillardidin, 4% scillarenin and 12% polar metabolites. [ABSTRACT FROM AUTHOR]

0.5 mgH-proscillaridin-4-methylether was administered orally to 5 healthy males. Maximum plasma levels of total radioactivity were reached after one to two hours. In two subjects a second peak was observed between 6 and 12 hours. The plasma half life of total radioactivity was 51 hours. 20% and 56% respectively of the dose were eliminated in urine and faeces during the following 7 days. 55% of the total radioactivity in plasma, 80% in urine and 20% in faeces consisted of CHCl-insoluble compounds. 50 - 60% of the latter in plasma and urine could be hydrolysed by β-glucuronidase. More than 90% of the split products were identified as conjugates of methylproscillaridin. TLC-separation of the CHCl-soluble fractions of plasma and urine yielded two unidentified metabolites, P and P, as the main compounds, besides methylproscillaridin, proscillaridin and scillarenin. In faeces more than 90% of the non-polar fraction was identified as methylproscillaridin. Shortly after administration ofH-methylproscillaridin, the radioactivity in plasma consisted mainly of CHCl-in-soluble conjugates and of the metabolite P. [ABSTRACT FROM AUTHOR]

The metabolites of tritiated 4‴-methyldigoxin (MD) has been studied in bile, urine and faeces from 3 patients 24 h after cholecystectomy and T-tube drainage. 5.6-15.6% of the doses were eliminated in bile and 28.5-57.8% in urine within 48 h. In bile after 6 h, approximately 5% of the excreted products were bisglycosides (B) and only traces were monoglycosides (M), whereas 55.3±4.5% were CHCl-insoluble metabolites. At the same time urine contained 15.5±1.3% CHCl-insoluble compounds. Anaerobic incubation of bile with a stool suspension (SS) decreased the polar fraction by 64.8±4.5% (n=6); incubation with a previously autoclaved SS decreased it only by 12.7±2.7%. Preincubation of SS with carbenicillin, cephalotin and ampicillin to depress bacterial growth largely suppressed the metabolic activity. TLC-analysis revealed that the decrease in the polar fraction corresponded to an increase of M, whilst MD, digoxin and B were almost unaltered. The results imply that B and M were formed in the liver, B was preferentially eliminated unchanged in bile and M was conjugated to CHCl-insoluble compounds prior to excretion. The polar conjugates were split by bacterial enzymes in the colon to yield M, which could be detected in faeces. [ABSTRACT FROM AUTHOR]

H-digoxigenin-mono-digitoxoside 1 mg was swallowed by 6 healthy subjects. Maximum plasma levels of radioactivity were reached within 1-2 h; in two subjects there was a second peak at 8-12 h. No definite half lives could be determined because the falls in plasma activity were not exponential. 3.9-39% and 34.5-76.6% of the dose were eliminated in urine and faeces, respectively. 75-90% of the total radioactivity in plasma was CHCl-insoluble, there was less of this fraction in urine, and the major portion in faceces was CHCl-soluble. The CHCl-insoluble fraction in urine was separated into 3 components by chromatography on an AlO-column and consisted mainly of conjugates of the monoglycoside and 3-epidigoxigenin. TLC-separation of the lipophilic fraction in urine also revealed unchanged monoglycoside and 3-epidigoxigenin, as well as traces of digoxigenin, 3-ketodigoxigenin and 2 unidentified, more polar metabolites. In faeces, the main excretion product was the unchanged compound, and traces of digoxigenin, 3-epidigoxigenin, 3-ketodigoxigenin and one of the more polar metabolites detected in urine. Two patients with surgical T-tube bile-duct drainage showed significantly greater biliary excretion after oral administration of the digoxigenin-mono-digitoxoside than after digoxin. Almost all the radioactivity excreted in bile was CHCl-insoluble and the monoglycoside was shown to be the only conjugation partner present by incubation with arylsulfatase and β-glucuronidase. The results show that digoxigenin-mono-digitoxoside has such a rapid metabolic inactivation and biliary clearance in man that it is unlikely to be of any therapeutic value. [ABSTRACT FROM AUTHOR]

Studies investigating the antiischemic action of converting enzyme inhibitors (CEIs) in patients with coronary artery disease (CAD) have, after single dosing, provided evidence for mechanisms of action such as coronary vasodilation and reduction of myocardial oxygen-consumption due to pre- and afterload reduction. Measurements of exercise-induced ST-segment depression and exercise duration as criteria for clinical efficacy have revealed contradictory findings. Patient characteristics, which may be important for a satisfactory response to CEI treatment, have yet to be identified. Patients with ischemic left ventricular dysfunction may benefit from CEI therapy. Neurohumoral factors, e.g., plasma renin activity and atrial natriuretic peptide, may also be relevant. The antiischemic efficacy of CEls given as monotherapy has not yet been convincingly demonstrated. The protective effect of CEI treatment with regard to ventricular enlargement after myocardial infarction seems to be established; however, data on mortality are still outstanding. [ABSTRACT FROM AUTHOR]

The lowering of blood pressure with beta-blocking drugs has had a low impact on coronary heart disease (CHD) mortality and the question has been raised whether adverse changes in plasma lipoproteins offset the benefits of blood pressure reduction. Comparison of plasma lipoprotein concentrations in hypertensive patients treated with commonly used beta-blockers with lipoprotein concentrations in patients with coronary heart disease shows that these drugs cause clinically important shifts in the cholesterol ratio [total cholesterol (TC): high-density lipoprotein cholesterol (HDLC)] and reductions in the atheroprotective lipoprotein HDLC. The magnitude of these changes is sufficient to increase the risk of heart attack two- to four-fold depending on the initial cholesterol ratio and the duration of treatment. Only beta-blockers with marked intrinsic sympathomimetic agonist activity (pindolol) or combined alpha-beta-blocking properties (Labetalol) appear free of adverse effects on plasma lipoproteins and triglycerides. Chronic treatment with other betablockers should be accompanied by cholesterol and HDLC measurements at the beginning of therapy. Plasma lipoprotein measurements at 3-6 month intervals seem mandatory in patients with cholesterol values greater than 6 mmol/l (230 mg/dl) and (TC):HDLC ratios above 5 at the start of treatment. The risk of a coronary event must be regarded as unacceptable when the cholesterol ratio exceeds a critical value of about 6. Further controlled studies are needed to evaluate the effects of beta-blockers in hypertension when administered for periods of up to a year or more. More information is required on the behaviour of lipoprotein subspecies and apoproteins. Since the changes in lipoproteins reported in studies referred to in this review may have been submaximal the risks and the benefits from beta-blocker therapy must be carefully considered. [ABSTRACT FROM AUTHOR]

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Copyright of Klinische Wochenschrift is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The metabolism and tissue distribution of intravenously administered C-canrenoate-potassium (CR-K) was studied at various time intervals in 10 dogs. After a rapid decline of total radioactivity immediately after injection, the elimination in plasma occurred in two distinct phases with half-lives of 6.8 and 23.6 h. Canrenoate was rapidly converted to lipid- and water-soluble metabolites which were separated by thinlayer chromatography. Most tissues showed similar concentrations of total radioactivity as plasma. An accumulation of radioactivity per g wet weight was detected in the adrenal glands and fat tissue as well as in the metabolic and excretory organs but not in the heart. Taking into consideration that skeletal muscle, fat tissue and liver constitute about 64% of the body weight, it is obvious that the main part of total radioactivity was present in these tissues. In contrast to plasma, urine and feces, where various metabolites could be analysed, the bulk of radioactivity in tissues is represented by canrenone. Thus, the estimation of the parent compound and its metabolites in plasma, urine and feces does not allow final conclusions about the active substance in various tissues. Within 72 h 47% of the dose was recovered in urine and 49% in feces. [ABSTRACT FROM AUTHOR]

26 mongrel dogs were given a single dose of 0.03 mg/kg tritium-labelled digoxin, β-methyldigoxin, digitoxin or ouabain 2 hrs or 95 hrs following experimental coronary occlusion. Examination of the epicardial ECG was performed by moving from intact to ischemic or necrotic zones. 60 min after glycoside administration the animals were sacrificed and tissue samples from the marked heart muscles areas and from the skeletal muscle were analysed for glycoside content. The early glycoside uptake in acute ischemic or necrotic myocardium was diminished independently of the physicochemical properties of the glycoside. Significantly higher glycoside concentrations (ng/g wet weight) were measured in the injured myocardium 3 hrs after coronary occlusion than 96 hrs afterward ( p<0.005). The values in acute ischemic myocardium varied considerably. This non-homogeneity of glycoside uptake in the acute ischemic heart muscle may partly explain the increased sensitivity to glycosides in myocardial infarction. The decline of glycoside concentration correlates with the alterations in the epicardial ECG. The cardiac effects of cardenolides 60 min after intravenous administration was caused by the unchanged glycoside. In contrast to the myocardium, glycoside accumulation could not be found in the skeletal muscle. The concentrations of digoxin, β-methyldigoxin and digitoxin in the skeletal muscle were significantly higher than the concentration of ouabain, which was rapidly eliminated via the urine. [ABSTRACT FROM AUTHOR]

The influence of pretreatment with spironolactone (84 mg/kg at 3 days, twice per day) on the tritium levels in plasma, urine and feces of female SD-rats ( n=9) was investigated at various time periods after oral administration of 25 μg/kg H-digitoxin. In plasma, the concentrations of total radioactivity are reduced in pretreated animals to about 20% of tritium levels in control rats, while the half-life of radioactivity in both groups is almost identical, 2.9 days in pretreated rats and 2.8 days in controls. The lower plasma levels of tritium in pretreated rats coincide with a six-fold decrease in the urinary H-elimination and a corresponding increase in the fecal excretion. This is due to a higher biliary clearance of tritiated products in the early phase of elimination. The separation of the excretion products by TLC shows that spironolactone pretreatment enhances the splitting of the glycosidic bonds of digitoxin. The amount of digitoxigenin-bis-digitoxoside and of digitoxigenin-mono-digitoxoside excreted in urine and feces within 96 hrs is four and ten times greater than that recovered in control animals, respectively. The formation of the hydroxylation products digoxin and digoxigenin-bis-digitoxoside is decreased from 50% of the total excreted radioactivity in control to 15% in pretreated rats. The conjugation reactions with glucuronic and sulfuric acid are increased after pretreatment with spironolactone. Thus, the effect of spironolactone on digitoxin kinetics is apparently related to an enhancement of the hepatic excretory mechanism as well as to an enhanced metabolism. [ABSTRACT FROM AUTHOR]

The metabolic conversion of spironolactone (I) to canrenone (II) was investigated using a chemical model reaction by treatment of spironolactone in aqueous medium at pH 13. The dethioacetylation proceeds in two steps, i.e., a fast hydrolysis to the 7α-thiol function present in congeners VI and VI ( K=0.42 min), and a rate limiting step by elimination of HS yielding the 4,6-dien-3-one function present in canrenone (II) and canrenoate (III) ( K=0.13 h). The metabolic conversion of I to II was evaluated by intravenously injecting equimolar amounts of I, the 7α-thiol VI, II and III. Following injection of I, the only fluorigenic metabolites detectable were II, III, and an intermediate polar metabolite, which was identified by tlc and mass spectrometry as the 7α-thiol-17β-hydroxycarboxylic acid VI. The plasma t of I was 4 and 5 min, respectively, in two rats. The t of VI amounted to 8 and 12 min, respectively, and roughly corresponded to the formation rate canrenone (II). Injection of the 7α-thiol VI resulted in plasma concentrations of VI, II and III similar to those obtained from injection of I. It can be concluded that hydrolysis of the 7α-thioacetyl I to the 7α-thiol VI is a very rapid metabolic step, that the γ-lactone ring is in a rapid enzymatic equilibrium with the corresponding γ-hydroxylic acids, and that elimination of HS from VI yielding II is the overall rate limiting step in the metabolic conversion of I to II. The elimination of intravenous doses of H-I and H-III occurred predominantly by biliary excretion of polar conjugated metabolites (80 and 95%, respectively, of the dose over 12 h) followed by extensive enterohepatic cycling. Urinary excretion remained below 3% of the dose over 12 h in bile fistula rats. [ABSTRACT FROM AUTHOR]

In 1063 patients (≥60 years, 531 men, 532 women) the plasma concentration during digitalis maintenance therapy (metildigoxin, n=356, beta-acetyldigoxin, n=359, and digitoxin, n=348) was determined and related to sex, age, body weight, serum potassium, renal function and the prescribed daily maintenance dose. Classification of treatment groups according to renal function (Crea ≤1.3 mg/dl//> 1.3 mg/dl) did not show any difference of the mean maintenance doses. In multiple linear regression analyses only a weak relationship between plasma digitalis concentration and the studied variables was found, which could be equally attributed to dose, creatinine and serum potassium in the digoxin derivative groups, whereas for digitoxin only body weight had a significant effect on the plasma concentration. During a maintenance dose of 0.07 or 0.1 mg/die which was given to 87% of patients in the digitoxin group, 70% were found to have plasma levels within the therapeutic range. [ABSTRACT FROM AUTHOR]

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The efficacy of an antacid or synthetic secretin in elevating the intragastric pH above 4 was tested in a controlled, prospective study. Twenty-one high-risk surgical patients received an antacid and 17 secretin. Antacid prophylaxis resulted in a significantly higher intragastric pH than with secretin. This was especially true in patients with several risk factors. The percent of secretin patients with a pH below 4 was higher. An increase in dosage was necessary in 4 of the 17 patients receiving secretin and in none of those receiving antacids. One stress ulcer hemorrhage occurred during secretin prophylaxis. [ABSTRACT FROM AUTHOR]

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The importance of smoking as a possible factor in coronary heart disease (CHD) may be related to the effect of carbon monoxide (CO) on oxygen exchange at the hemoglobin molecule (Hb). We examined the kinetics of this process in vitro and ex vivo using a fast-reaction technique (stopped-flow) whereby the dissociation-rate constant of oxygen was determined in the blood of smokers and non-smokers and at fixed HbCO-concentrations in non-smokers blood. In non-smokers, carbon monoxide saturated blood was obtained by gassing with carbon monoxide and mixing the samples with appropriate carbon monoxide free blood to achieve HbCO-concentration in the range of 10-60%. The reaction time course for the oxygen-dissociation was divided into a non-linear-initial phase (loss of the first oxygen molecule) and a subsequent linear phase. The oxygen-dissociation velocity decreased from 96.5 × 10 ms to 42.7 × 103 ms in the linear phase at pH 7.4 and decreased from 29.2 × 103 ms to 20.9 × 103 ms at pH 9.2 when the HbCO-concentration was increased to 63%. For the initial phase at pH 7.4, the dissociation velocity decreased depending on the HbCO-concentration. In non-smokers 50% of the bound oxygen was released in 17.5±2.3 ms ( n = 13) whereas in smokers 19.4±1.8 ms ( n = 14) ( p<0.05) was required. For non-smokers the initial reaction proceeded with a dissociation-rate constant of k = 50.4±11.9 × 10 ms ( n = 13), in smokers this process was slower (k = 42.7±5.9 × 10 ms ( n = 14) ( p<0.05). In the latter phase the reaction (occuring over 14-30 ms) the rate of oxygen-release in smokerswas also reduced (k = 77.1±7.3 × 10 ms versus k = 85.1±13.7 × 10 ms; p = 0.05). These differences were presumably due to the presence of 8.9±2.3% ( n = 14) HbCO in smokers. In non-smokers theHbCO-concentration was 0.81±0.11% ( n = 13). These results support the view that increased HbCO-levels are responsible for a decreased oxygen capacity and a slower oxygen dissociation-rate from hemoglobin in smokers. This phenomenon can impair oxygen availability in CHD patients who smoke. [ABSTRACT FROM AUTHOR]

The inhibition of dansylsarcosine (DS) binding at the benzodiazepine binding site of human serum albumin has been studied in the presence of saturated and unsaturated free fatty acids (FFA) of various chain lengths (C6-C20, C18:1, C18:2). In order to determine the mechanism of displacement, velocity constants for association ( k) and dissociation ( k) and binding constants ( K and K′) have been measured using the stopped-flow method. The inhibitory effect of FFA on DS binding kinetics at site II is dependent of their structure. With increasing amounts of FFA the association velocity constant of DS binding decreases from 520 s (fatty acid free albumin) by a factor of 3-10 and affinity decreases according to FFA chain length. Inhibition is strongest in the presence of caprylic, capric and lauric acid (C8-C12) i.e. with more than one mole FFA per mole albumin, DS association could no longer be measured. Short chain caproic and the long chain FFA C14-C20 showed only a less inhibitory effect since in the presence of a twofold excess k ranged between 100 and 200 s Dissociation velocity of DS from the benzodiazepine binding site could be measured in relationship to FFA chain length using ibuprofene, another drug binding at site II. Dissociation velocity constants k remained constant up to 2 moles FFA per mole albumin ( k = 16-18 s). A rise in k to 70 s was seen, however, when 2-4 moles capric, lauric, myristic and palmitic (C10-C16) acid were bound, whereas no change was observed when increasing concentrations of caproic, caprylic, stearic and arachic acid. The more compact unsaturated FFA oleic and linoleic acids did not inhibit DS binding to the same extent as their saturated homologue stearic acid. k and k values resembled those when comparable amounts of myristic acid were bound indicating that chain length is the relevant parameter. It can be concluded that two different types of FFA inhibition of binding at the benzodiazepine binding site exist. Short-chain FFA (C6-C8) may be specifically bound at binding site II thereby competitively displacing DS. Longchain FFA (C12-C20), however, occupy their binding sites far from the benzodiazepine binding site. Inhibition occurs via an allosteric mechanism. Capric acid is unique in showing as well as competitive as well as allosteric inhibition characteristics. [ABSTRACT FROM AUTHOR]

Binding curves obtained by the stopped-flow method for the association of warfarin and human serum albumin (HSA) at pH 6.0 and 9.0 have been analysed with digital- and analog computers. The first association product (WHSA') at pH 6-9 does not contribute to the observed fluorescence enhancement during warfarin-HSA complex formation. A similar consecutive relaxation process leads to a more stable warfarin-HSA complex, with HSA in the neutral (N)-form (pH 6) and base (B)-form (pH 9). This rearrangement can be measured by stopped-flow ( k=31 s at pH 6; k′=63 s at pH 9). At pH 6 a further concentration dependent relaxation process has been observed indicating that the complex of warfarin with the N-form of HSA gets partially converted into its B-form with a half-time for this N→B transition in the range of 0.2-0.4 s. A drug such as warfarin can act as effector molecule for conformational changes of the HSA tertiary and quaternary structure during the formation of a high affinity complex. [ABSTRACT FROM AUTHOR]

We have studied the binding of warfarin to human serum albumin (HSA) with the stopped-flow method. At 37°C the rate constant for the velocity of dissociation of the stable warfarin-HSA complex is 10s ( t=0.07 s). Concentration and temperature dependent association constants for warfarin binding to HSA have been measured (2.5·10 M s at 6°C, 9.8·10 M s at 22°C and 15.3·10 M s at 37°C). Our experimentally obtained relaxation constants are best explained by the existence of 5 equivalent low affinity binding sites for warfarin on the HSA molecule, each capable of conversion into a high affinity site. The measured energy of activation for this conversion is 57.5 kJ M. [ABSTRACT FROM AUTHOR]

The tissue distribution after repeated intravenous administration of tritium-labelled digoxin, β-methyldigoxin and ouabain was examined in heart and brain of 6 beagle dogs. In addition, the (Na+K)-ATPase activity was measured in various heart and brain areas, and its affinity to the cardiac glycosides was determined. The glycoside concentrations in the atria are lower than in the ventricles, and the left heart areas show higher concentrations than the right areas. Significant differences in the (Na+K)-ATPase activity or its binding capacity in the various heart areas, which could be responsible for this characteristic distribution pattern, were not found. In agreement with its greater lipid-solubility, β-methyldigoxin shows a higher accumulation in the brain than digoxin and ouabain. However, while β-methyldigoxin is evenly distributed throughout all brain areas, concentration differences are found for digoxin and ouabain in the telencephalon, cerebellum and brain stem. This characteristic distribution of the more polar glycosides may be partly determined by the different structure of the capillaries in the central nervous system. In addition, the binding affinities for digoxin and ouabain also differ in the various crude brain preparations. In the diencephalon, pons, cerebellum and medulla the dissociation constants as a reciprocal measure of the binding affinity were lower for digoxin with 7.5 to 9.9×10 than in the telencephalon, mesencephalon and spinal cord with dissociation constants of 1.1 to 1.45×10 M. Since, in these brain areas higher glycoside concentrations per g wet weight were also measured, the glycoside accumulation in the various brain areas could be dependent on the higher receptor affinity of these brain areas. On the other hand, the binding affinities for β-methyldigoxin were the same in all brain areas, with a mean dissociation constant of 1.45×10 M. [ABSTRACT FROM AUTHOR]

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