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Biomedical subjects

R Calvo

Publications and source records attributed to R Calvo.

At least 91 records · Page 5Linked to original sources
PubMed1993

Netilmicin kinetics in urology.

Plasma kinetics of netilmicin, an aminoglycoside antibiotic was studied in 62 patients undergoing urologic surgery. Despite the use of a standard 100 mg-dose, no toxic levels were achieved except in one patient. A poor correlation was found between netilmicin plasma elimination constant and creatinine clearance (r = 0.34, p = NS). We can conclude that the prediction of netilmicin plasma concentrations is not possible using only demographic patient's data. The monitoring of netilmicin levels should be performed in long-term treatments but not in 4-dose regimes such as in urologic prophylaxis.

Adult↗
PubMed1993

Unchanged protein binding of penbutolol in renal insufficiency: a possible role of carbamylation.

The effect of in vitro carbamylation of serum protein with potassium cyanate on protein binding of penbutolol, a basic agent exclusively bound to alpha 1 acid glycoprotein (AAG), was investigated. Carbamylation of serum resulted in a weak increase on free fraction of penbutolol (4.45 +/- 0.54% before carbamylation vs 5.66 +/- 0.40% after; p < 0.025). Parallelly, potassium cyanate added to pure AAG and incubated for 90 min induced carbamylation of this protein (38 mumoles of 14C cyanate incorporated per gram of protein). A study in serum from patients with chronic renal disease (pre and postdialysis) showed no changes in protein binding of penbutolol, although AAG levels were significantly higher. However, Scatchard [1949] plot for penbutolol binding to serum from renal patients (both pre and postdialysis) showed a decrease in affinity constant (nKa = 11.13 x 10(5) M-1 in healthy volunteers, vs 5.56 x 10(5) M-1 in patients before dialysis and 4.57 x 10(5) M-1 after dialysis). We concluded that carbamylation of serum AAG in uremic patients could explain, in part, the absence of changes in protein binding of any basic drugs in this pathological condition. It appears that a decreased affinity constant could balance the effect of increased AAG levels.

Adult↗
PubMed1992

Investigation of conformational specificity at GPIIb/IIIa: evaluation of conformationally constrained RGD peptides.

RGD-containing proteins and peptides are known to bind to the platelet GPIIb/IIIa receptor and inhibit platelet aggregation. That a conformational component to the specificity exists is suggested by significantly lower activity of linear RGD analogs relative to closely related cyclic peptides and small proteins containing the RGD sequence. Recently, conformations for a suite of RGD containing cyclic peptides have been defined by NMR-based methods and, for one molecule, by X-ray diffraction. We report here the NMR-based conformational analysis of an additional cyclic peptide, cyclo(Pro-Arg-Gly-Asp-D-Pro-Gly), and compare the conformational variations in the suite of peptides and related analogs. Biological activity data for these peptides shows a preference of the platelet GPIIb/IIIa receptor for one conformation of the RGD sequence, but suggests its ability to bind a second, distinct conformation.

Amino Acid Sequence↗
PubMed1992

In vivo potentiation of atracurium neuromuscular blockade by nimodipine in rabbits.

The interaction between nimodipine, a calcium channel blocker, used for the treatment of subarachnoid haemorrhage, and atracurium, was studied in rabbits. An intravenous dose of 0.1 mg.kg-1 of nimodipine given over 3 min caused a potentiation of the neuromuscular blocking action of atracurium (administered at an infusion rate of 7.5 micrograms.kg-1.min-1), measured on the indirectly stimulated tibialis-anterior muscle of the animal. (ED50)inf and (ED95)inf were significantly reduced (30.7% and 23.3%) in nimodipine-treated animals (P less than 0.05 and P less than 0.02, respectively). No changes were observed in recovery rate.

Animals↗
PubMed1992

Influence of changes in protein binding on the central activity of antidepressants.

The central effect (expressed as analgesic response), protein binding and brain uptake of mianserin were measured in mice receiving drug intraperitoneally. A significant decrease of the central effect of mianserin (30 mg kg-1) was seen in mice with experimental inflammation when compared with control animals (reaction time (s) = 12.12 +/- 1.22 vs 25.56 +/- 2.92; P less than 0.001) and the dose-analgesia response curve (10-60 mg kg-1) was significantly shifted to the right in mice with inflammation. In serum of mice with inflammation, unbound concentration of mianserin was decreased from 19.37 +/- 0.73 to 17.83 +/- 0.30% (P less than 0.05) and seromucoid levels were significantly increased (P less than 0.001). Following the intraperitoneal administration of 30 mg kg-1 of mianserin, brain uptake decreased in diseased mice when compared with control animals (P less than 0.02), suggesting that the decrease in analgesia was secondary to a decrease in drug delivery to the brain because of increased protein binding.

Animals↗
PubMed1992

Thyroid hormones and 5'-deiodinase activity in neonatal undernourished rats.

Undernutrition was induced in rats submitted to food restriction from the fetal stage, and malnutrition was continued after birth until 70 days of life. Body weight was decreased to less than 50%. Plasma T4 and T3 and pituitary TSH content were determined between 8-70 days of life. In control rats, plasma T4 and T3 reached a maximum at 14 and 35 days of life, respectively, and TSH pituitary content at 45 days of life. In undernourished rats, after 8 days of life, plasma T4 and T3 and pituitary TSH content were decreased to about 50% or less, and the pattern of sequential changes observed in control rats was absent or modified. T4 and T3 concentrations were measured in heart, liver, and brain in the fetus (22 days old) and 8, 14, and 23 days after birth, as well as liver and brain 5'-deiodinases (5'D). Hepatic 5'D type I was always decreased in undernourished rats from 8-70 days after birth. Liver and heart T4 and T3 concentrations were decreased in 14-day-old undernourished rats as well as brain T3. Brain 5'D type II was decreased at 8 and 14 days, and total brain 5'D activities at 8 days. These changes occurred during the critical period for brain development (7th to 20th day) during which most processes of myelination take place and T3 brain normal levels are required.

Aging↗
PubMed1992

L-thyroxine and 3,5,3'-triiodothyronine concentrations in the chicken egg and in the embryo before and after the onset of thyroid function.

The concentrations of T4 and T3 were measured by specific RIAs in chicken embryonated eggs and embryonic tissues before (at 4 and 6 days of incubation) and after the onset of thyroid function (at 10-20 days). All samples were submitted to extensive delipidation and purification. T4 and T3 were found in the yolk, as described by others, and also in the egg white, although at lower concentrations. The initial total maternal supplies per egg are 67 ng T4 and 30 ng T3 in the yolk, and 2.4 ng T4 and 1.9 ng T3 in the egg albumen. Whole 4-day-old embryos contained a total of 2.48 pg T4 and 0.65 pg T3. The head (mostly brain) of 6-day old embryos contained 4.1 pg T4 and 4.6 pg T3; T4 (but not T3) was also measurable in the carcass. The concentrations of T4 increased progressively between 10 and 20 days in the brain, eyes, liver, and heart; they were especially high in the eyes (4.8 ng/g) and liver (8.2 ng/g) at 20 days. T3 levels increased markedly in the brain (to 5.1 ng/g at 20 days) and less markedly in the eyes (to 1.3 ng/g) and heart (to 1.6 ng/g), but were low and stable in liver up to 18 days (0.3 ng/g), after which there was a sudden increase to 1.4 ng/g at 20 days. Iodothyronines are, therefore, available to the chick embryo throughout development both before and after the onset of thyroid function. T3 concentrations, especially in the brain, reach much higher levels than previously inferred from the low plasma T3 levels. These findings show similarities with those described for the fetal rat.

Analysis of Variance↗
PubMed1992

The rat placenta and the transfer of thyroid hormones from the mother to the fetus. Effects of maternal thyroid status.

We have studied the effects of maternal thyroid status on the effectiveness of the rat placenta near term as a barrier for the transfer of T4 and T3 to the fetus. Dams were given methimazole to minimize the fetal contribution to the T4 and T3 pools, so that the iodothyronines found in the conceptus are ultimately of maternal origin. The dams were infused with saline, or with T4 or T3 at doses ranging from 2.3-27.8 nmol T4 and from 0.77-20.7 nmol T3/100 g BW per day. A group of normal pregnant dams (C) was included. At 21 days of gestation T4, T3, and rT3 were measured by RIA in maternal and fetal plasma, and in maternal and fetal sides of the placenta. The total fetal extrathyroidal T4 and T3 pools were also determined. The dose-related changes in T4, T3, and rT3 levels in the placenta confirm the presence of both inner and outer ring iodothyronine deiodinase activities, and suggest increasing accumulation of the iodothyronines. Despite this, fetal extrathyroidal T4 and T3 increase progressively in T4-infused groups as a function of maternal circulating T4 levels. Fetal extrathyroidal T3 increases progressively in T3-infused groups as a function of maternal plasma T3. There was no evidence that the net maternal contribution of T4 or T3 would be proportionally less when the maternal pools became very high. It was concluded that the rat placenta is only a limited barrier for the transfer of T4 and T3 to the fetus.

Animals↗
PubMed1992

The influence of renal failure on the kinetics of intravenous midazolam: an "in vitro" and "in vivo" study.

The effect of renal failure upon the "in vitro" binding of midazolam, a new water-soluble short-acting benzodiazepine, has been studied in man. An increase of its free fraction (ranging from 2.52 to 5.17%) in serum from uremic patients was observed. A similar situation was originated in rabbits by administering uranyl nitrate (2 mg/Kg i.v.) and posterior hypnosis with midazolam. Uremic rabbits showed a marked increase in the free concentration of midazolam in serum (ranging from 8.9 to 13.7 micrograms/ml) and in midazolam brain levels (156.2 micrograms/g in cortex vs 84.5 micrograms/g in control animals). A positive correlation between brain and serum free concentration of midazolam was also observed. It is concluded that in renal patients more unbound drug is available to produce central nervous system effects, and a decrease in intravenous dose of midazolam could be recommended in this clinical situation.

Adolescent↗
PubMed1992

Homeostasis of brain T3 in rat fetuses and their mothers: effects of thyroid status and iodine deficiency.

Faced with large variations in iodine, T4 or T3 supply, the fetal brain is able to maintain T3 homeostasis to a greater degree than apparent from changes in plasma and other tissues, such as the liver. Changes in the activity of 5'D-II play an important role in this homeostasis, although this does not exclude other regulatory mechanism(s), such as changes in type III (5D) activity, in uptake of the iodothyronines by the brain, or in cerebral iodothyronine turnover rates. T3 generated locally from T4 is more important than plasma derived T3 as determinant of the total T3 available to the brain throughout the life cycle of the rat. It is especially important during the fetal and neonatal phases of brain development, when the brain depends almost exclusively on the supply of T4. Fetal brain T3 homeostasis is maintained despite large fluctuations in the supply of T4. An excess of T3 also affects brain T3 to a lesser degree than it does other tissues. If present results are relevant to man, they suggest that overtreatment of mother of a congenital hypothyroid fetus with T4 is not likely to be harmful for the fetal brain. Treatment with T3 should be avoided, as it deprives the fetal brain of the main regulatory mechanism involved in homeostasis of brain T3, namely generation of T3 from T4.

Animals↗
PubMed1991

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↗
PubMed1991

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↗
PubMed1991

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↗
PubMed1991

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↗
PubMed1990

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↗