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PubMed1989

Bioaccumulation of cadmium by the freshwater isopod Asellus aquaticus (L.) from aqueous and dietary sources.

Experiments were conducted to determine the kinetics and relative importance of aqueous and dietary uptake of cadmium by the freshwater isopod Asellus aquaticus (L.). Test animals were exposed during 30 days to aqueous Cd in a continuous flow system (exposure levels: 0.2 - 10 microg litre(-1)) and kept on a diet of previously contaminated Elodea sp. (range of Cd concentrations: 2-350 microg g(-1), dry weight). Preceding semi-static experiments on dosage-control of the dietary factor revealed a rapid uptake of Cd by Elodea, with relatively high concentration factors (CF), which ranged from 4.8 to 5.5 (dry weight log (CF) after 16 days). For Asellus uptake from water appeared to be the predominant route. Highly significant bioconcentration of cadmium from water was observed in the animals, even at exposure levels below 1.0 microg litre(-1). In the various treatments, direct uptake from water accounted for 50-98% of the body burdens after 30 days exposure. The experimental results were described with a first order one-compartment bioaccumulation model. Model parameter estimates (mean +/- standard error) were obtained for rate constant of uptake (560 +/- 110 day(-1)), rate constant of elimination (0.032 +/- 0.017 day(-1)) and assimilation efficiency of Cd uptake from food (1.1 +/- 0.7%). The (dry weight) bioconcentration factor (BCF) and bioaccumulation factor (BAF) for extrapolated steady state conditions were estimated at 18 000 (BCF) and 0.08 (BAF). Experiments conducted at two different pH levels (5.9 versus 7.6) revealed no significant effects of pH on the uptake of aqueous Cd by the isopods. The results are discussed in relation to their potential significance to the field situation.

Journal Article↗

PubMed2006

Seasonal variation in heavy metal accumulation in subtropical population of the terrestrial isopod, Porcellio laevis.

The aim of the present study is to evaluate the seasonal fluctuation of heavy metals in the isopod Porcellio laevis at four uncontaminated subtropical locations. This study was carried out at four different field sites in Assiut, Egypt. The concentrations of cadmium, lead, copper, and zinc in animal, soil, and litter (mug/g dry weight) were monthly recorded during the period from June 2002 till May 2003. There was little difference in metal accumulation trends between the sites. In general, the isopod showed significant increased Pb and Zn concentration during summer and spring months, whereas this was not the case for Cd and Cu. The bioaccumulation (BAF) and bioconcentration factors (BCF) of the metals revealed marked seasonal changes throughout the year. Generally, BAF of metals were higher during summer and spring, and BCF were higher during summer and autumn. Comparing the metal accumulation with climatic fluctuations (measured) it was speculated that temperature was the main factor causing seasonal fluctuations of the internal metal concentration in the isopod.

Animals↗

PubMed2005

A reproducible method for studying three-dimensional knee kinematics.

The methods used in movement analysis often rely on the definition of joint coordinate systems permitting three-dimensional (3D) kinematics. The first aim of this research project was to present a functional and postural method (FP method) to define a bone-embedded anatomical frame (BAF) on the femur and tibia, and, subsequently, a knee joint coordinate system. The repeatability of the proposed method was also assessed. Using FP method to define the BAFs, 4 kinematic parameters (flexion/extension, abduction/adduction, tibial internal/external rotation, and antero-posterior translation) were computed for 15 subjects walking on a treadmill. The repeatability for all four kinematic parameters was then assessed, using intra- and inter-observer settings. After pooling the results for all observers, the mean repeatability value ranged between 0.4 degrees and 0.8 degrees for rotation angles and between 0.8 and 2.2 mm for translation.

Adolescent↗

PubMed2006

H+-ATPase activity in selective disruption of H+-K+-ATPase alpha 1 gene of mice under normal and K-depleted conditions.

The outer medullary collecting duct (OMCD) plays an important role in acid-base homeostasis by two luminal proton ATPases, H(+)-ATPase and H(+)-K(+)-ATPase (HKA), both of which are in the intercalated cells (ICs) of OMCD. We showed previously that HKAalpha1 (gastric H(+)-K(+)-ATPase) activity is the essential H(+)-K(+)-ATPase activity under normal conditions, and that HKAalpha2 (colonic H(+)-K(+)-ATPase) is induced and mediates increased proton-secretion under K-depleted conditions. To better understand the role of H(+)-ATPase (potassium-independent) in acid secretion and the relationship between H(+)-ATPase and a specific HKA isoform, we examined H(+)-ATPase activity in the H(+)-K(+)-ATPasealpha1 knockout (KO) mice under normal and K-depleted conditions. Mice were fed a potassium-free diet and studied after 7 days. Segments of the OMCD were perfused in vitro, and intracellular pH (pH(i)) was measured by ratiometric fluorescence microscopy using the pH-sensitive indicator BCECF-AM. The isolated OMCD tubules obtained from mice fed a potassium-free diet were examined by fluorescent immunocytochemistry with an antibody to the 31-kDa subunit of H(+)-ATPase (E-11) and were compared with those obtained from a normal diet. In the absence of Na(+) and K(+), the H(+)-ATPase-mediate pH(i) recovery rates were 6.7 +/- 1.1 x 10(-4) units/s (n = 7 ICs) in wild-type (WT) mice and increased to 8.7 +/- 1.8 x 10(-4) (P < 0.05; n = 6) in HKAalpha1 KO mice. K-independent proton transport activity was significantly inhibited by the H(+)-ATPase inhibitor bafilomycin A(1) (BAF, 10 nM) with luminal applied in both WT and KO mice. Comparison of the results indicated upregulation of BAF-sensitive H(+)-ATPase activity in KO mice. To determine the intracellular localization of H(+)-ATPase in the intercalated cells of OMCD, we dissected the OMCD and performed fluorescent immunocytochemistry with the H(+)-ATPase antibody in the WT and KO mice. In the WT mice, on normal diet, H(+)-ATPase staining distributed diffusely throughout the intercalated cells and was slightly polarized to the apical plasma membrane in the KO mice, consistent with increase in the H(+)-ATPase-mediate pH(i) recovery in the KO mice. One week of a potassium-free diet resulted in a significant increase in the degree of H(+)-ATPase polarization at the apical plasma membrane in both WT and KO mice. Hypokalemia stimulates H(+)-ATPase in the intercalated cells of OMCD of both WT and KO mice. The enhanced activity of H(+)-ATPase plays an important role in compensatory proton secretion in the HKAalpha1 KO mice under normal conditions.

Animals↗

PubMed2005

Metal contamination of soils and crops affected by the Chenzhou lead/zinc mine spill (Hunan, China).

In 1985, the collapse of the tailing dam in Chenzhou lead/zinc mine (Hunan, southern China) led to the spread of mining waste spills on the farmland along the Dong River. After the accident, an urgent soil cleaning up was carried out in some places. Seventeen years later, cereal (rice, maize, and sorghum), pulses (soybean, Adzuki bean, mung bean and peanut), vegetables (ipomoea, capsicum, taro and string bean) and the rooted soils were sampled at four sites: (1) the mining area (SZY), (2) the area still covered with the mining tailing spills (GYB), (3) the cleaned area from mining tailing spills (JTC), and (4) a background site (REF). Metal concentrations in the crops and soils were analyzed to evaluate the long-term effects of the spilled waste on the soil and the potential human exposure through food chains. The results showed that the physical-chemical properties of the soils obviously changed due to the different farming styles used by each individual farmer. Leaching effects and plant extraction of metals from some soils were quite weak. Certain soils were still heavily polluted with As, Cd, Zn, Pb and Cu. The contamination levels were in the order of GYB>SZY>JTC showing that the clean-up treatment was effective. The maximum allowable concentration (MAC) levels for Chinese agricultural soils were still highly exceeded, particularly for As and Cd (followed by Zn, Pb and Cu), with mean concentrations of 709 and 7.6 mg kg(-1), respectively. These concentrations exceed the MAC levels by 24 times for As and 13 times for Cd at GYB. Generally, the edible leaves or stems of crops were more heavily contaminated than seeds or fruits. Ipomoea was the most severely contaminated crop. The concentrations of Cd and Pb were 3.30 and 76.9 mg kg(-1) in ipomoea leaves at GYB, which exceeded the maximum permit levels (0.5 mg kg(-1) for Cd and 9 mg kg(-1) for Pb) by 6.6 and 8.5 times, respectively. Taro (+skin) could accumulate high concentrations of Zn and Cd in the edible stem, and rice and capsicum had high Cd concentration in the edible parts. However, the toxic element concentrations in maize, sorghum, Adzuki bean, soybean and mung bean remained lower than the threshold levels. The bio-accumulation factors (BAFs) of crops were in the order: Cd>Zn>Cu>Pb>As. BAF was typically lower in the edible seeds or fruits than in stems and leaves. The accumulation effect strongly depends on the crop's physiological properties, the mobility, of the metals, and the availability of metals in soils but not entirely on the total element concentrations in the soils. Even so, the estimated daily intake amount of Cu, Zn, Cd, and Pb from the crops grown in the affected three sites and arsenic at SZY and GYB exceeded the RDA (Recommended dietary allowance) levels. Subsequently, the crops grown in Chenzhou Pb/Zn mine waste affected area might have a hazardous effect on the consumer's health. This area still needs effective measures to cure the As, Cd, Pb, Zn and Cu contamination.

Accidents, Occupational↗

PubMed2006

Cellular co-factors of HIV-1 integration.

To achieve productive infection, the reverse transcribed cDNA of human immunodeficiency virus type 1 (HIV-1) is inserted in the host cell genome. The main protein responsible for this reaction is the viral integrase. However, studies indicate that the virus is assisted by cellular proteins, or co-factors, to achieve integration into the infected cell. The barrier-to-autointegration factor (BAF) might prevent autointegration. Its ability to bridge DNA and the finding that the nuclear lamina-associated polypeptide-2alpha interacts with BAF suggest a role in nuclear structure organization. Integrase interactor 1 was found to directly interact with HIV-1 integrase and to activate its DNA-joining activity, and the high mobility group chromosomal protein A1 might approximate both long terminal repeat (LTR) ends and facilitate integrase binding by unwinding the LTR termini. Furthermore, the lens-epithelium-derived growth factor (LEDGF; also known as p75) seems to tether HIV-1 integrase to the chromosomes. Although a direct role in integration has only been demonstrated for LEDGF/p75, to date, each validated cellular co-factor for HIV-1 integration could constitute a promising new target for antiviral therapy.

Animals↗

PubMedDate not supplied

Ingested bovine amniotic fluid enhances morphine antinociception in rats.

Ingestion by rats of rat placenta or amniotic fluid enhances opioid-mediated, or partly opioid-mediated, antinociception produced by morphine injection, vaginal or cervical stimulation, late pregnancy, and foot shock. This phenomenon is believed to be produced by a placental opioid-enhancing factor (POEF). Ingestion by rats of human or dolphin placenta has also been shown to enhance opioid antinociception, suggesting that POEF may be common to many mammalian species. We tested bovine amniotic fluid (BAF) for its capacity to enhance morphine antinociception in female Long-Evans rats, as determined by percentage change from baseline tail-flick latency in response to radiant heat, and we report that 0.50 mL BAF effectively enhanced morphine antinociception but did not by itself produce antinociception. The efficacy of POEF across species suggests that POEF may have been functionally (and structurally) conserved during evolution. Furthermore, the availability of POEF at parturition, as well as its ability to enhance pregnancy-mediated antinociception without disrupting maternal behavior, offers a tenable explanation for the long-debated ultimate causality of placentophagia.

Amniotic Fluid↗

PubMed2000

Degradation pathway of persistent branched fatty acids in natural anaerobic ecosystem.

Branched fatty acids (BAFs) in industrial effluents are often persistent in biological wastewater treatment systems and end up as organic contaminants in the water environment. In this study, degradation of eight characteristic BAFs in a natural anaerobic ecosystem of an eutrophic river sediment was studied in vitro by enrichment culture techniques. The anaerobic consortium, comprising of BFA-degrading and methane-producing genera, degraded BFAs with a tertiary carbon through beta-oxidation followed by methanogenesis mechanisms. The consortium could not degrade BFAs with a quaternary carbon. The degree of branching at the alpha or beta position along the carbon chain interfered with the beta-oxidation mechanisms, and hence affected the degradability of the compound.

Bacteria, Anaerobic↗

PubMed1998

Bioaccumulation and retention of lead in the mussel Mytilus galloprovincialis following uptake from seawater.

Bioaccumulation of lead in the mussel Mytilus galloprovincialis from 210Pb-labeled bulk seawater (dissolved and particulate pathways combined) was examined over 21 days. The lead bioaccumulation factor (BAF) at equilibrium was estimated to be 211 +/- 10 ml g-1. This value was two orders of magnitude lower than BAFs reported in the literature for other trace metals in this bivalve indicating that lead is not efficiently accumulated by mussels from bulk seawater. The resultant lead distribution in mussels was 49 +/- 10% in soft tissues and 46 +/- 16% in the shell suggesting similar uptake rates (Bq day-1) in both compartments throughout the exposure. Total elimination for lead in mussels was adequately described by a short-term compartment with a biological half-life for loss of 1.4 +/- 0.3 days and a long-term compartment which released lead only very slowly (Tb1/2 = 2.5 +/- 0.7 months). No difference was noted for lead elimination rates in shell and in soft parts. When experimentally exposed to lead under conditions representative of natural environmental lead levels in water, including both that in the dissolved phase and in the food, the shell compartment was shown to contain the major fraction of the total lead accumulated by mussels. Therefore mussels may be considered as good bioindicators of lead contamination accumulated from the dissolved rather than from the particulate source. Furthermore, the relatively slow uptake and the long depuration half-life of lead will limit the ability of mussels to accurately record short-term variations in lead concentrations in the surrounding waters, a fact which should be taken into consideration in order to define the appropriate sampling frequency for mussels used in biomonitoring programs involving lead.

Animals↗

PubMed2006

Deriving site-specific 2,2-bis(chlorophenyl)-1,1-dichloroethylene quality criteria of water and sediment for protection of common tern populations in Bohai Bay, North China.

In this paper we first present a method of deriving site-specific water and sediment quality criteria of chemicals for protecting wildlife populations. The method has two steps: (1) identification of the threshold concentration in specific tissue corresponding to a population benchmark response and (2) extrapolating quality criteria on the basis of the bioaccumulation in tissue from the water or sediment (e.g., the bioaccumulation factor (BAF) and biota/ sediment accumulation factor (BSAF)). The method was applied to derive 2,2-bis(chlorophenyl)-1,1-dichloroethylene (p,p'-DDE) quality criteria of water and sediment of Bohai Bay, China, for common tern populations. The benchmark concentration in eggs of the common tern was determined to be 663 ng/g wet weight from the relationship curve between concentration (biotic burden in eggs) and the intrinsic rate of population increase (r) calculated by an age-structured matrix approach. The p,p'-DDE concentrations (mean 58.79 and ranging from 13.14 to 326.60 ng/g wet weight) measured in common tern eggs (n = 35), collected from the Beidagang wetland on the coast of Bohai Bay in China, and those in surface water or sediment from literature values were combined to estimate the probability distribution of BAF and BSAF using the Monte Carlo method. Finally, the marine water and sediment quality criteria of p,p'-DDE in Bohai Bay were estimated to be 4 ng/L and 1.9 ng/g dry weight, respectively.

Animals↗

PubMed2006

Environmental monitoring of hydrophobic organic contaminants: the case of mussels versus semipermeable membrane devices.

Concentrations of hydrophobic chemicals in mussels and semipermeable membrane devices (SPMDs) from nine studies published over the past decade, amended with new data obtained in the Scheldt-North Sea area, were assessed to understand the similarities and differences between these sampling matrixes. A model was developed to describe the concentration ratios, using literature values of elimination rate constants and steady-state accumulation factors of both samplers as key parameters. The model could successfully describe the results of seven studies. Differences in concentration ratios among these studies were related to the variability of mussel bioaccumulation factors (BAFs) and water sampling rates of SPMDs. For two studies, the model could only describe the data by adopting unrealistically high water sampling rates, and for one study there were not enough data to test the model. We argue that SPMDs will generally yield more reliable estimates of exposure concentrations than mussels, because in situ BAF values are difficult to estimate, whereas the in situ exchange kinetics of SPMDs can be quantified by measuring the dissipation rates of performance reference compounds. The implications of the results for future and existing monitoring programs are discussed.

Animals↗

PubMed2006

Partitioning and bioaccumulation of PBDEs and PCBs in Lake Michigan.

Water from Lake Michigan and fish from all five Great Lakes have been sampled and analyzed for a suite of six polybrominated diphenyl ether (PBDE) congeners and 110 polychlorinated biphenyl congeners (PCBs). The Lake Michigan dissolved phase PBDE congener concentrations (0.2 to 10 pg/L) are similar to dissolved phase PCB congener concentrations (nondetected to 13 pg/L). Partitioning of PBDEs between the particulate and dissolved phases exhibits behavior similar to that of PCBs. Organic-carbon-normalized water-particle partition coefficients (log K(OC)s) ranged from 6.2 to 6.5. Lake trout are depleted in BDE-99 relative to dissolved phase concentrations, and in contrast to what is expected from the PCB congener patterns. This reflects suspected debromination of BDE-99 in the food web of Lake Michigan. A regression of the log of the bioaccumulation factor (BAF) and the log of the octanol-water partition coefficent (K(OW)) indicated a positive relationship for both PCB congeners and PBDE congeners. BDE-99 does not appear to followthe same trend, a further indication that it is subject to biotransformation. Using the PBDE BAFs for Lake Michigan and the PBDE fish concentrations from the other Great Lakes it is expected that the dissolved phase concentrations of congeners in the other lakes would range from 0.04 to approximately 3 pg/L.

Animals↗

PubMed2000

Caspase-dependent and independent cell death in rat hepatoma 5123tc cells.

The objective of this study was to establish whether apoptosis in 5123tc rat hepatoma cells required the caspase-3 dependent pathway. Apoptosis was induced by either growth factor deprivation or treatment with a topoisomerase II inhibitor, VM26, in the absence or presence of caspase inhibitors (DEVD-fmk, z-VAD-fmk and BAF). The results indicated that, although these inhibitors at 10 microM concentration completely blocked caspase-3 activity, they had no effect on either the rate of cell death or on any other apoptotic features, e.g., chromatin condensation, DNA fragmentation, protein cleavage, suggesting that caspase-3 was not required to mediate nuclear destruction in these hepatoma cells. At higher concentrations, up to 100 microM, z-VAD-fmk and BAF, but not DEVD-fmk, did block apoptosis, however, they also caused cell swelling and membrane permeabilization, which are the hallmarks of necrotic cell death. Clearly, high concentrations of these inhibitors must have interfered non-specifically with other metabolic pathways, e.g., z-VAD-fmk at a high concentration blocked protein phosphorylation, and caused cell death by a different mechanism.

Amino Acid Chloromethyl Ketones↗

PubMed2002

Inhibition of protein phosphatase-1 is linked to phosphorylation of p53 and apoptosis.

p53 is a multifunctional protein and its activity can be modulated by phosphorylation and dephosphorylation. In this study, we sought to examine the notion that serine/threonine phosphatases (PP-1 and PP-2A) are active modulators of the p53-dependent apoptotic pathway. Exposure of neonatal rat cardiomyocytes to the established apoptotic agents, bafilomycin A1 (BAF) or staurosporine (STAU) induced apoptosis and caused a decrease in PP-1 activity of 35%. This response was restricted to apoptotic stimuli as treatment with phenylephrine neither decreased PP-1 and PP-2A activity nor induced DNA fragmentation in cardiomyocytes. The level of phosphorylated p53 was increased as a result of BAF or STAU-treatment. We further examined the effect of PP-1 inhibition on cardiomyocytes by the use of the phosphatase inhibitor, okadaic acid, and an antisense strategy. Okadaic acid (100 nM) resulted in a decrease in PP-1 activity of 45%, enhanced phosphorylation of p53, and stimulated apoptosis. Furthermore, overexpression of the antisense PP-1 catalytic subunit transcript caused a 44% decrease in expression of PP-1, with no change in the levels of the PP-2A catalytic subunit, and also evoked DNA fragmentation. Our data support the view that decreased activity of PP-1 is an important signaling event in the apoptotic process.

Animals↗

PubMed1997

Interleukin-2 induces tyrosine phosphorylation of SHP-2 through IL-2 receptor beta chain.

Coupling of interleukin-2 (IL-2) to the IL-2 receptor (IL-2R) induces rapid increase in tyrosine phosphorylation of cellular substrates through activation of non-receptor protein tyrosine kinases. Here, we report that stimulation through the IL-2R induced tyrosine phosphorylation of the SH2-containing protein-tyrosine phosphatase SHP-2 in F7, a hematopoietic BAF-B03 transfectant clone expressing the IL-2Rbeta chain. The tyrosine phosphorylation of SHP-2 was specific since another protein-tyrosine phosphatase SHP-1, which is structurally homologous to SHP-2, was not tyrosine phosphorylated. The IL-2-induced tyrosine phosphorylation of SHP-2 required the acidic region within the IL-2Rbeta chain where Src-family PTKs interact. Though the serine-rich region within IL-2Rbeta chain was also required for the phosphorylation of SHP-2, Jak3 activation was dispensable. In COS-7 cells, co-expression of SHP-2 with Lyn resulted in increased tyrosine phosphorylation levels of SHP-2, whereas co-expression of SHP-2 with Fyn failed to alter the levels significantly. Considering that Lyn and Fyn are major Src-family PTKs expressed in BAF-B03 cells, our data suggest that Lyn may be principally responsible for the tyrosine phosphorylation of SHP-2 in F7 cells. Furthermore, the IL-2 stimulation also induced tyrosine phosphorylation of SHP-2 in the human IL-2-dependent T-cell line ILT-Mat. Taken together, these studies demonstrate an involvement of SHP-2 in the IL-2-mediated signaling events through the activation of specific PTKs.

Animals↗

PubMed1998

Bcl-X is the major pleiotropic anti-apoptotic gene activated by retroviral insertion mutagenesis in an IL-3 dependent bone marrow derived cell line.

In order to identify genes capable of inhibiting apoptosis induced by different pathways, without inducing proliferation we have performed retroviral insertion mutagenesis in the IL-3 dependent bone marrow derived Baf-3 cell line. Out of 200 mutants obtained in three separate mutagenesis experiments, four mutants were resistant to multiple apoptosis inducing pathways (including growth factor starvation, staurosporine, etoposide and cyclosporin A) and did not proliferate in the absence of IL-3. These four mutants overexpress the bcl-X gene following a retroviral insertion 5' of the translation initiation site. These results indicate that the bcl-X gene is a major pleiotropic anti-apoptotic gene in Baf-3 cells. They also suggest that the Bcl-2 family of genes might be the only one capable of inhibiting apoptosis induced by multiple pathways without inducing cell proliferation.

Alleles↗

PubMed2002

Multivariate analysis of the bioaccumulation of polychlorinated biphenyls (PCBs) in the marine pelagic food web from the southern part of the Baltic Sea, Poland.

The concentration, pattern, bioaccumulation and biomagnification features of many chlorobiphenyl congeners including non- and mono-ortho chlorine substituted members have been determined in a pelagic food chain including mixed phyto- and zooplankton, herring (Clupea harengus), harbour porpoise (Phocoena phocoena) and black cormorants (Phalacrocorax carbo sinensis) collected from the southern part of the Baltic Proper. TCDD (tetrachlorodibenzo-p-dioxin) toxic equivalents (TEQs) in plankton, herring, harbour porpoise and cormorants were 0.42, 5.3, 79 and 2,700 pg g(-1) lipid weight, respectively. Concentrations of total polychlorinated biphenyls (PCBs) in plankton, herring, harbour porpoise and cormorants were 1.9, 120, 8700 and 2,100 ng g(-1) wet weight (210, 1,300, 10,000 and 42,000 ng g(-1) lipid weight) respectively. Herring, harbour porpoise and black cormorant apparently bioaccumulate many PCBs found in their food, and the values of the bioaccumulation factors (BAFs) for PCBs were approximately 10 in herring, 35 in harbour porpoise and up to 300 in breast muscle of cormorants. Harbour porpoise clearly is able to metabolize the most toxic non-ortho PCBs (no. 77, 126 and 169) and a few mono-ortho PCBs (no. 114, 123 and 156), while all non- and mono-ortho PCBs are bioaccumulated by herring. Penta-, hexa- and hepta-CBs were the dominatant homologue classes both in the muscle tissue and liver. PCB congeners nos. 201, 209, 172/192, 194 and 195 were characterized by the largest BAFs (between 100 and 300). Principal component analysis has been used to analyse the interdependences and differences in the CB congener accumulation patterns between the components of the investigated pelagic food web.

Animals↗

PubMed1999

Pharmacokinetic-pharmacodynamic model for fantofarone cardiac and brachial haemodynamic effects in healthy volunteers.

AIMS: To investigate the pharmacokinetics of SR 33671, the main active metabolite of the calcium antagonist fantofarone, and the relationships between its concentrations and pharmacodynamic effects after a single oral administration of two doses (100 and 300 mg) of fantofarone. METHODS: A placebo-controlled, randomized, double-blind and crossover study was performed in six healthy volunteers. SR 33671 plasma concentrations (C, ng ml-1 ) and effects (E) on heart rate (HR, beats min-1 ), PR interval duration (ms), brachial artery flow (BAF, ml min-1 ) and brachial vascular resistance (BVR, mmHg s ml-1 ) were determined repeatedly after drug intake. Haemodynamic effects were expressed as percent changes from initial values. Bi-exponential (pharmacokinetics), and linear [E=S.C+E0, for cardiac effects] or sigmoid [E=Emax.Cgamma/(CEgamma50+Cgamma ), for haemodynamic effects] models were fitted to individual data. RESULTS: Peak plasma concentrations and areas under the curve up to 24 h were (mean+/-s.d.) 16+/-10 ng ml-1 and 157.50+/-89.13 ng ml-1 h, and 63+/-11 ng ml-1 and 535.50+/-135.11 ng ml-1 h, after 100 and 300 mg, respectively. Terminal half-life was approximately 4 h. For pharmacodynamics, we obtained: S=-0.201+/-0.057 beats min-1/ng ml-1 for HR, S=0.526+/-0.114 ms/ng ml-1 for PR interval duration, Emax=42+/-6%, CE50=8.8+/-7.2 ng ml-1 and gamma=2.2+/-1.5 for BAF, and Emax=-28+/-4%, CE50=5.8+/-5.1 ng ml-1 and gamma=3.4+/-1.8 for BVR. At a SR 33671 concentration of 15 ng ml-1, BVR is decreased by 27% whereas HR is reduced by less than 3 beats min-1 and PR interval duration is increased by less than 8 ms. CONCLUSIONS: Fantofarone is able to induce submaximal peripheral vasodilating effects at doses that are devoid of any clinically significant cardiac effect.

Adult↗