Exchange interactions and magnetic dimension in Cu(L-alanine)2.
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Journal Article↗
Biomedical subjects
R Calvo
Publications and source records attributed to R Calvo.
Maternal thyroid hormones during pregnancy: effects on the fetus in congenital hypothyroidism and in iodine deficiency.
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Animals↗
Development of a small RGD peptide fibrinogen receptor antagonist with potent antiaggregatory activity in vitro.
The development of potent antithrombotic agents from the fibrinogen platelet receptor binding sequences Fg-alpha 572-575 -Arg-Gly-Asp-Ser- and Fg-gamma 400-411 -HHLGGAKQAGDV, believed to be a cryptic RGD-type sequence, is described. The tetrapeptide Ac-RGDS-NH2 itself is capable of inhibiting platelet aggregation in vitro at high concentrations, IC50 91.3 +/- 0.1 microM [in vitro antiaggregatory activity employing dog platelet rich plasma (PRP)/ADP], due to low platelet fibrinogen receptor affinity, Ki 2.9 +/- 1.9 microM (purified, reconstituted human platelet GPIIb/IIIa), relative to fibrinogen, Ki 38.0 +/- 6.0 nM. The peptide is also unstable to plasma, suffering total loss of in vitro activity upon incubation in PRP for 3 h (T1/2 90 min). Only modest improvements in potency were achieved with linear analogues of Ac-RGDS-NH2, while dramatic results were achieved with cyclic analogues, culminating in the cyclic disulfide Ac-cyclo-S,S-[Cys-(N alpha-Me)Arg-Gly-Asp-Pen]-NH2 (SK&F 106760) with improved plasma stability (100% activity after 3 h), affinity (Ki 58 +/- 20 nM purified human receptor), and potency (IC50 0.36 +/- 0.4 microM dog PRP/ADP). The affinity of this peptide is 2 orders of magnitude greater than that of Ac-RGDS-NH2. The affinity of the analogue is also comparable to fibrinogen. This peptide constitutes a first potent small peptide entry into the class of novel antithrombotic agents called fibrinogen receptor antagonists.
Amino Acid Sequence↗
Thyroid hormones and 5'-deiodinase in the rat fetus late in gestation: effects of maternal hypothyroidism.
Having previously observed that T4 and T3 levels in fetal rat brain and brown adipose tissue are clearly higher than expected from their low circulating levels, we have now studied thyroid hormone concentrations and 5'-deiodinase activities (5'D) in several other rat fetal tissues during the last 6 days of gestation (dg), namely 17-22 dg. This period comprises the onset of fetal thyroid activity. Total thyroidal T4 and T3 contents increased 100- and 400-fold, respectively; T4 concentrations increased 8- to 10-fold in plasma, carcass, lung, and liver, and T3 increased 4.5- to 9-fold, except in plasma and liver, where T3 levels increased less than 2-fold in plasma and 3-fold in liver. During this developmental period 5'D activity increased 5- and 10-fold in fetal liver and lung, respectively. In fetuses from hypothyroid [thyroidectomized (T)] dams, body weight was lower than in fetuses from normal dams. Total thyroidal T4 and T3 contents were initially the same, but decreased markedly in fetuses from T dams by the end of gestation. At the earliest fetal ages studied (17-18 dg) T4 and T3 concentrations were lower in carcass, liver, lung, and brain, although near term there were no consistent differences between the fetal tissues from T and control dams, probably because of compensatory stimulation of thyroidal secretion. Liver 5'D was decreased by 50% throughout gestation, and lung 5'D activities were lower by the end of gestation. Thyroid hormones in placentas from T dams were very low, but increased by the end of gestation because of the contribution by the fetal thyroid. Present results describe the ontogenic profiles for thyroid hormone concentrations and 5'D activities during late fetal development; active regulatory mechanisms are already present at this age. It has been frequently stated that rat fetuses near term are deficient in thyroid hormones, and that their thyroid hormone economy is independent of maternal thyroid status, but present results show that near term, T4 and T3 concentrations in several tissues reach levels that are 50% or more of those described for adult animals, and that fetal thyroid function is influenced by maternal hypothyroidism.
Animals↗
Outer ring iodothyronine deiodinases and thyroid hormone economy: responses to iodine deficiency in the rat fetus and neonate.
Female rats were fed a low iodine diet (LID) or the same diet supplemented with KI (IOD) and mated. Plasma TSH, T4 and T3 in thyroid, plasma, and tissues, and 5'-deiodinase activities (5'D) were measured in maternal, fetal, and neonatal samples. Plasma T4 was markedly reduced in LID dams, TSH was increased, and T3 was normal. Placental T4 was decreased to 10%, and placental T3 to 50%. In LID fetuses there was a complete depletion of both extrathyroidal and intrathyroidal stores of T4 and T3. The thyroid responded with increased synthesis and secretion of T3 over T4, as assessed from the T3 to T4 ratios. Near birth, brain T4 and T3 concentrations were only 6.7% and 12% of those in IOD fetuses, despite a marked increase in brain 5'D-II and a T4-sparing decrease in liver and lung 5'D-I. Brown adipose tissue 5'D-II increased 7-fold, and brown adipose tissue T4 and T3 concentrations were only decreased by 50%. After birth, the availability of iodine improved somewhat through maternal milk, and the thyroidal and extrathyroidal pools of T4 and T3 increased, although they remained much lower than those in IOD pups. Brain 5'D-II markedly increased in LID pups, and this together with an increase in plasma and brain T4 ensured almost normal brain T3 during the suckling period. The thyroidal secretion of T3 over T4 continued to be increased in LID pups during the suckling period and appeared to be related to their high circulating TSH levels. Both LID fetuses and newborns can respond to iodine deficiency as adults rats, but the fetus is more sensitive to LID because of its dependence on maternal T4. The success of the adaptative mechanisms in protecting the brain from severe T3 deficiency depends on the supply of iodine, the limiting factor for the synthesis of T4.
Animals↗
Effect of halothane anesthesia and trifluoroacetic acid on protein binding of benzodiazepines.
The in vitro effect of the halothane metabolite, trifluoroacetic acid, on the protein binding of three different benzodiazepines (diazepam, lorazepam and midazolam) has been investigated. Furthermore, protein binding of these drugs was studied in serum from patients under the effect of halothane anesthesia (1-2.5%; 2.5 h). Trifluoroacetic acid, 4 mmol/l, displaced diazepam and midazolam from serum and produced a marked increase in the free percentage, but did not influence lorazepam binding. Moreover, 48 h after the end of halothane anesthesia, there were changes in protein binding of diazepam (3.9 +/- 0.3% at 48 h vs. 3.3 +/- 0.3% before halothane anesthesia; p less than 0.05). It can be concluded that halothane anesthesia (1-2.5%; 2.5 h) may temporarily potentiate the pharmacological effect of diazepam in the postoperative period following anesthetic procedures.
Adult↗
Effects of cefotaxime on the serum protein binding of sulfisoxazole.
The possible acylating effects of cefotaxime on sulfisoxazole binding to serum proteins were evaluated in vitro in samples of human sera incubated with 50-1000 micrograms ml-1 cefotaxime at 37 degrees for 1 h and then dialyzed against saline. This incubation resulted in concentration-related increases in the free fraction of sulfisoxazole (+25 per cent, +30 per cent, and +45 per cent, with 250, 500, and 1000 micrograms ml-1 cefotaxime, respectively). Sulfisoxazole binding was also studied in samples of sera from patients given prophylactic cefotaxime (3 g d-1, IV) following elective surgery. Sulfisoxazole free fraction increased from 7.6 +/- 0.7 per cent in samples obtained before starting treatment to 9.2 +/- 0.8 per cent 24 h thereafter, and to 10.4 +/- 1.0 per cent after 5 days of treatment, but this difference was not statistically significant. A Scatchard plot of pooled samples showed a reduction in overall affinity (from 2.38 X 10(-4) M to 1.77 X 10(-4) M) without changes in the number of binding sites. The effects of cefotaxime on sulfisoxazole binding and kinetics were also studied experimentally in the rabbit. Treatment with 30 mg kg-1 cefotaxime t.i.d. for 2 days increased the unbound fraction of sulfisoxazole in vivo, from 17.2 +/- 2.9 per cent to 27.3 +/- 3.6 per cent (p less than 0.02). Treatment with high doses of cefotaxime, and perhaps other 3-acetoxymethylcephalosporins, may result in changes in the serum protein binding of some acidic drugs.
Animals↗
Long term evaluation of high tibial valgus osteotomy.
We present a long term evaluation of 100 high valgus tibial osteotomies with a mean follow up of 11 years. Knees with slight or moderate osteoarthritis had the best results. Slight overcorrection was beneficial, but gross overcorrection was not. There were few complications and the overall long term results were good.
Activities of Daily Living↗
Electron paramagnetic resonance investigation of photosynthetic reaction centers from Rhodobacter sphaeroides R-26 in which Fe2+ was replaced by Cu2+. Determination of hyperfine interactions and exchange and dipole-dipole interactions between Cu2+ and QA-.
We report electron paramagnetic resonance (EPR) experiments in frozen solutions of unreduced and reduced photosynthetic reaction centers (RCs) from Rhodobacter sphaeroides R-26 in which Fe2+ has been chemically replaced by the isotope 65Cu2+. Samples in which the primary quinone acceptor QA is unreduced (Cu2+QA:RCs) give a powder EPR spectrum typical for Cu2+ having axial symmetry, corresponding to a d(x2 - y2) ground state orbital, with g values g parallel = 2.314 +/- 0.001 and g perpendicular = 2.060 +/- 0.003. The spectrum shows a hyperfine structure for the nuclear spin of copper (65I = 3/2) with A parallel = (-167 +/- 1) x 10(-4) cm-1 and /A perpendicular/ = (16 +/- 2) x 10(-4) cm-1, and hyperfine couplings with three nitrogen ligands. This has been verified in samples containing the naturally occurring 14N isotope (l = 1), and in samples where the nitrogen ligands to copper were replaced by the isotope 15N (l = 1/2). We introduce a model for the electronic structure at the position of the metal ion which reflects the recently determined three-dimensional structure of the RCs of Rb. sphaeroides (Allen, J. P., G. Feher, T. O. Yeates, H. Komiya, and D. C. Rees. 1987. Proc. Natl. Acad. Sci. USA. 84:5730: Allen, J. P., G. Feher, T. O. Yeates, H. Komiya, and D. C. Rees. 1988. Proc. Natl. Acad. Sci. USA, 85:8487) as well as our EPR results. In this model the copper ion is octahedrally coordinated to three nitrogens from histidine residues and to one carboxylate oxygen from a glutamic acid, forming a distorted square in the plane of the d(x2 = y2) ground state orbital. It is also bound to a nitrogen of another histidine and to the other carboxylate oxygen of the same glutamic acid residue, in a direction approximately normal to this plane. The EPR spectrum changes drastically when the quinone acceptor QA is chemically reduced (Cu2+QA-:RCs); the change is due to the exchange and dipole-dipole interactions between the Cu2+ and QA- spins. A model spin Hamiltonian proposed for this exchange coupled cooper-quinone spin dimer accounts well for the observed spectra. From a comparison of the EPR spectra of the Cu2+QA:RC and CU2+QA-:RC complexes we obtain the values /J0/ = (0.30 +/- 0.02) K for the isotropic exchange coupling, and /d/ = (0.010 +/- 0.002) K for the projection of the dipole-dipole interaction tensor on the symmetry axis of the copper spin. From the EPR experiments only the relative signs of J0 and d can be deduced; it was determined that they have the same sign. The magnitude of the exchange coupling calculated for Cu2+QA-:RC is similar to that observed for the Fe2+QA-:RC complex (J0 = -0.43K). The exchange coupling is discussed in terms of the superexchange paths connecting the Cu2+ ion and the quinone radical using the structural data for the RCs of Rb. sphaeroides. From the value of the dipole-dipole interaction, d, we determined R approximately 8.4 A for the weighted distance between the metal ion and the quinone in reduced RCs, which is to be compared with 10 A obtained from x-ray analysis of unreduced RCs. This points to a shortening of the Cu2+ -QA- distance upon reduction of the quinone, as has been proposed by Allen et al. (1988).
Amino Acid Sequence↗
Decrease in penbutolol central response as a cause of changes in its serum protein binding.
Penbutolol is a beta-adrenoceptor antagonist that is extensively bound to alpha 1-acid glycoprotein (alpha 1-AGP), a protein that increases in inflammatory diseases thereby binding more drug in such conditions. Changes in serum binding can lead to modifications in the pharmacokinetics and pharmacodynamics of a drug, therefore, the central effect (as the anticonvulsant response) and brain uptake of penbutolol given intravenously to mice with experimental inflammation have been measured. A significant decrease of the central effect of penbutolol and its brain uptake was seen in diseased when compared with control animals (P less than 0.01). A parallel decrease in free fraction of penbutolol in diseased vs normal animals was detected. These results suggest that there is an increase in serum binding of basic drugs related to increments in alpha 1-AGP concentration, which reduces their central pharmacological effect.
Animals↗
Congenital hypothyroidism, as studied in rats. Crucial role of maternal thyroxine but not of 3,5,3'-triiodothyronine in the protection of the fetal brain.
To study the protective effects of maternal thyroxine (T4) and 3,5,3'-triiodothyronine (T3) in congenital hypothyroidism, we gave pregnant rats methimazole (MMI), an antithyroid drug that crosses the placenta, and infused them with three different doses of T4 or T3. The concentrations of both T4 and T3 were determined in maternal and fetal plasma and tissues (obtained near term) by specific RIAs. Several thyroid hormone-dependent biological end-points were also measured. MMI treatment resulted in marked fetal T4 and T3 deficiency. Infusion of T4 into the mothers increased both these pools in a dose-dependent fashion. There was a preferential increase of T3 in the fetal brain. Thus, with a T4 dose maintaining maternal euthyroidism, fetal brain T3 reached normal values, although fetal plasma T4 was 40% of normal and plasma TSH was high. The infusion of T3 pool into the mothers increased the total fetal extrathyroidal T3 pool in a dose-dependent fashion. The fetal T4 pools were not increased, however, and this deprived the fetal brain (and possibly the pituitary) of local generation of T3 from T4. As a consequence, fetal brain T3 deficiency was not mitigated even when dams were infused with a toxic dose of T3. The results show that (a) there is a preferential protection of the brain of the hypothyroid fetus from T3 deficiency; (b) maternal T4, but not T3, plays a crucial role in this protection, and (c) any condition which lowers maternal T4 (including treatment with T3) is potentially harmful for the brain of a hypothyroid fetus. Recent confirmation of transplacental passage of T4 in women at term suggests that present results are relevant for human fetuses with impairment of thyroid function. Finding signs of hypothyroidism at birth does not necessarily mean that the brain was unprotected in utero, provided maternal T4 is normal. It is crucial to realize that maintainance of maternal "euthyroidism" is not sufficient, as despite hypothyroxinemia, the mothers may be clinically euthyroid if their T3 levels are normal.
Animals↗
Contribution of maternal thyroxine to fetal thyroxine pools in normal rats near term.
Normal dams were equilibrated isotopically with [125I]T4 infused from 11 to 21 days of gestation, at which time maternal and fetal extrathyroidal tissues were obtained to determine their [125I]T4 and T4 contents. The specific activity of the [125I]T4 in the fetal tissues was lower than in maternal T4 pools. The extent of this change allows evaluation of the net contribution of maternal T4 to the fetal extrathyroidal T4 pools. At 21 days of gestation, near term, this represents 17.5 +/- 0.9% of the T4 in fetal tissues, a value considerably higher than previously calculated. The methodological approach was validated in dams given a goitrogen to block fetal thyroid function. The specific activities of the [125I]T4 in maternal and fetal T4 pools were then similar, confirming that in cases of fetal thyroid impairment the T4 in fetal tissues is determined by the maternal contribution. Thus, previous statements that in normal conditions fetal thyroid economy near term is totally independent of maternal thyroid status ought to be reconsidered.
Analysis of Variance↗
Thyroid hormone economy in pregnant rats near term: a "physiological" animal model of nonthyroidal illness?
We have studied the changes in thyroid hormone economy that occur in normal pregnant rats between 17-22 days of gestation. T4 and T3 decreased in all extrathyroidal tissues studied, namely plasma, liver, kidney, lung, heart, and skeletal muscle. The exception is the concentration of T3 in cerebral cortex, which remains unchanged, possibly as a consequence of an increase in type II 5'-iodothyronine deiodinase activity. The marked decrease observed in most T4 and T3 pools was not accompanied by a commensurate increase in circulating TSH levels, which at 21 days gestation were either unchanged or actually decreased. The TSH response to TRH appeared to be prolonged. alpha-Glycerophosphate dehydrogenase activity was decreased in the liver, in accordance with its thyroid hormone deficiency. Hepatic type I 5'-iodothyronine deiodinase activity, however, did not decrease, but was slightly increased. Thus, thyroid hormone economy in the pregnant rat near term shows striking similarities with several (but not all) of the changes described in patients with nonthyroidal illness and in several animal models used to study this condition. It is suggested that attenuation of the negative feedback response to the decrease in thyroid hormone pools, leading to low levels of thyroid hormones in most tissues, is the normal physiological response to situations where preservation of energy (and protein) represents a distinct adaptive advantage, as in the case of the pregnant rat and her conceptus.
Animals↗
Serum binding of ketoconazole in health and disease.
The plasma protein binding of ketoconazole, an oral antifungal agent of a weak basic nature, was measured after the addition of the drug (10 micrograms.ml-1) to serum from 35 healthy individuals, ten patients with chronic renal disease and seven patients with hepatic cirrhosis. The percentage of free ketoconazole was markedly increased in patients with chronic renal disease and in patients with hepatic cirrhosis, when it was compared with the group of healthy volunteers (7.33 +/- 0.11 in renal patients; 6.12 +/- 1.43 in hepatic patients compared with 2.93 +/- 0.12 in healthy individuals). The binding ratio of ketoconazole in health and disease was significantly related to plasma albumin concentration, but not to plasma alpha 1-acid glycoprotein (AAG) concentration. Moreover, ketoconazole binds to isolated human serum albumin in a greater proportion but does not bind to isolated AAG indicating that human serum albumin is the major binding protein for this drug in plasma.
Adult↗
Displacement of warfarin from human serum proteins by halothane anaesthesia.
The in vitro effects of the halothane metabolite, trifluoroacetic acid, on the binding of warfarin to human serum proteins have been investigated. An increase in the percentage of free warfarin following incubation with different concentrations of trifluoroacetic acid (1 and 4 mmol/l) was observed. In addition, protein binding of warfarin was studied in serum from patients undergoing halothane anaesthesia (1-2.5%; 2.5 h). After 24 h from the end of the halothane anaesthesia, an increase in the percentage of free warfarin was also detected (0.92 +/- 0.06% at 24 h vs 0.60 +/- 0.02% before halothane administration; P less than 0.005). We conclude that halothane anaesthesia may temporarily potentiate the pharmacological effect of warfarin in the postoperative period following anaesthetic procedures.
Adult↗
Thyroid hormones and 5'-deiodinase in rat brown adipose tissue during fetal life.
Brown adipose tissue (BAT) iodothyronine 5'-deiodinase (5'D) activities are very high during fetal life but decrease 10-fold a few hours before birth. Accordingly, BAT 3,5,3'-triiodothyronine (T3) concentrations are also very high. The temporal patterns of changes in BAT 5'-D and fetal plasma insulin are similar (and differ from the pattern for catecholamines) but are not superimposable. A causal role for insulin in the activation of fetal BAT 5'-D is therefore not supported by the data. Maternal thyroidectomy leads to a decrease in the total and relative weight of fetal BAT and to a 30-50% increase in BAT 5'-D activities; BAT thyroid hormone concentrations are essentially unchanged. Fetal hypothyroidism was induced by giving methimazole and resulted in a marked decrease of BAT thyroxine (T4) and T3 concentrations. This treatment increased BAT 5'-D activity only on day 21 of gestation, but no effect was observed on day 20. The fetal 5'-D response to thyroid hormones infused into the methimazole-treated dams was studied at 21 days of gestation. The increase in BAT 5'-D induced by methimazole treatment was prevented by T4 infused into control dams but not by T3. In fetuses from thyroidectomized dams, the pattern of 5'-D regulation by thyroid hormones was impaired. It is suggested that the high concentrations of thyroid hormones present in fetal BAT might participate in the general maturation and development of fetal BAT.
Adipose Tissue, Brown↗
Effect of heparin administration on flunitrazepam protein binding.
Non-esterified fatty acids have been shown to displace diazepam from its plasma binding sites both in vitro and in vivo. However, the binding of other benzodiazepines such as lorazepam is not affected in similar situations. Flunitrazepam exhibits a substantial degree of binding to plasma proteins, therefore it was deemed interesting to investigate the role of free fatty acids on flunitrazepam binding to human plasma proteins. Incubation of plasma with sodium oleate (1.5 and 3.0 microEq per ml) produced a decrease in the binding of flunitrazepam. The free fraction increased from 4.20 +/- 0.34 to 6.30 +/- 0.53 and to 22.18 +/- 1.28% respectively). Sodium heparin administration (10IU/kg, intravenously) increased free fatty acids levels and produced similar changes in the binding of flunitrazepam. After ten minutes of heparin administration free fatty acids increased from 0.16 +/- 0.03 mEq/l to 0.34 +/- 0.01 mEq/l and the free fraction of flunitrazepam in plasma increased from 3.70 +/- 0.22% to 6.20 +/- 1.24%. These binding data further support a relationship between increases in the concentrations of free fatty acids and decreases in the fraction of flunitrazepam bound to plasma proteins.
Adult↗
[Computerized program for rapid evaluation of the critical surgical patient with multiple trauma].
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Critical Care↗