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Biomedical subjects

R Calvo

Publications and source records attributed to R Calvo.

At least 55 records · Page 3Linked to original sources
PubMed1997

Low-grade, malt-type, primary B-cell lymphoma of the conjunctiva.

Although primary ocular lymphomas may be found in the conjunctiva, eye lids and lacrimal glands, the majority nevertheless occur in the orbit. Only a few cases of primary conjunctival lymphoma have been described in the literature. A 68-year-old man presented with a painless swelling of the epibulbar conjunctiva of the right eye. A diffuse lymphoid infiltrate consisting of small-sized lymphoid cells with the morphology and distribution characteristics of mucosa-associated lymphoid tissue was observed. Immunohistological study demonstrated the B lymphocyte lineage of tumor cells and Bcl-1 and bcl-2 rearrangements were negative. After clinical staging including thoracic, abdominal, brain and orbital CT scans, fiberoptic gastroscopy and bone marrow biopsy, no other foci of this lymphoma were found. Radiation therapy was given and the patient currently remains free of lymphoma 30 months after diagnosis.

Aged↗
PubMed1996

Effects of thyroid hormone on the androgenic expression of KAP gene in mouse kidney.

The kidney androgen-regulated protein (KAP) gene exhibits a cell-specific hormonal regulation of its expression in the epithelial cells of proximal tubules of mouse kidney, where T3 is required for constitutive expression in the straight segments and androgens for expression in the convoluted ones. By using different models of hypothyroidism, we demonstrate that maximal androgen-mediated induction of the gene depends on thyroid hormone as well. This constitutes a specific event, since vitamin D3 cannot mimic the effects of T3, albeit their remarkable functional relationship. It is also shown that while congenital hypothyroid hyt/hyt male mice, exposed to maternal T3 in the gestational period, exhibit diminished but existent androgen-dependent cortical responses, mice exposed to goitrogens during gestation and postnatally are unable to express the gene even at postnatal day ninety. Impairment of KAP cortical expression in hypothyroid animals does not correlate with lower levels of androgens or androgen receptor expression.

Animals↗
PubMed1996

The effect of changes in gastric pH induced by omeprazole on the absorption and respiratory depression of methadone.

The effect of omeprazole (2 mg kg-1 i.v.) on respiratory depression induced in rats by acute oral methadone administration (5 mg kg-1) was examined and compared with control animals that only received methadone. Quantitative assessments of arterial Pco2,Po2, pH, and respiratory rate were employed as criteria for evaluation. Intragastric pH was measured in each rat immediately before and 2 h after methadone. Plasma concentration of methadone was measured for 3 h. The relationship between drug effect and the systemic bioavailability of methadone, measured as the area under the plasma concentration-time curve (AUC0-180), was also evaluated. The intensity of the methadone-induced respiratory depression was significantly greater in the omeprazole group than in control rats. A significant variation (p < 0.01) in all respiratory parameters was detected from 30 to 120 min after methadone. Omeprazole caused a significant increase in methadone levels (Cmax = 156 +/- 6.5 ng mL-1 against 51 +/- 5.8 ng mL-1 in control; p < 0.05). AUC0-180 was higher (p < 0.05) after omeprazole treatment (18.6 +/- 1.4 micrograms mL-1 min) than in control (6.8 +/- 0.6 microgram mL-1 min). Two hours after treatment with omeprazole, intragastric pH values were significantly elevated (4.7 +/- 0.1 against 2.2 +/- 0.04) and continued increasing, being 6.4 +/- 0.1 at the end of the experiment. Correlation was observed between intragastric pH and the area under the effect- (respiratory depression-) time curve (r = 0.74; p < 0.001). A relationship between plasma methadone levels at 120 min and gastric pH (r = 0.92; p < 0.001) was detected. A significant correlation between the area under the effect-time curve (0-120 min) and AUC0-180 has been also observed (r = 0.90; p < 0.01). These pharmacokinetic and pharmacodynamic changes could be gastric pH dependent because they were mimicked when gastric pH was experimentally modified by bicarbonate whereas opposite results were obtained with acidic pH2 solution.

Administration, Oral↗
PubMed1996

Serum protein binding of propofol in patients with renal failure or hepatic cirrhosis.

BACKGROUND: Serum protein binding is a limiting factor in the access of drugs to the central nervous system. Disease-induced modifications of the degree of binding may influence the effect of anesthetic drugs. METHODS: The protein binding of propofol, an intravenous anaesthetic agent which is highly bound to serum albumin, has been investigated in serum samples from healthy volunteers, from patients with chronic renal failure not undergoing hemodialysis, from patients with chronic renal failure included in a regular hemodialysis program, and from patients with hepatic cirrhosis. Protein binding was determined by the ultrafiltration technique using an Amicon Micropartition System, MPS-1. RESULTS: The percentage of unbound propofol (mean(SD)) in healthy volunteers (n = 16) was 0.98 (0.48) % showing a high interindividual variability. Chronic renal failure did not significantly modify serum protein binding of propofol. In the chronic renal failure group not undergoing regular hemodialysis (n = 9), unbound propofol was 0.92 (0.34) %. In addition, patients in periodic dialysis did not show changes in propofol binding either compared before (1.11 (0.33) %; n = 13) or after hemodialysis (0.87 (0.38) %; n = 12). A slight decrease in albumin concentration was found in all renal patients (P < 0.05) in comparison to healthy volunteers. Creatinine and urea concentrations were higher in these patients (P < 0.01) but in the postdialysis group, the differences in urea levels were not significant when compared with those of volunteers. No changes in the degree of propofol binding were observed in patients with hepatic cirrhosis (0.97 (0.30) %; n = 14) when compared with the group of healthy volunteers. Significant differences were observed in albumin (P < 0.01) and bilirubin (P < 0.05) concentrations. Considering all subjects, the degree of binding did not correlate with biomedical data. CONCLUSION: Due to the absence of significant changes in the protein binding it is unlikely that there will be an exaggerated pharmacological response in patients with renal and hepatic disease following the administration of a standard propofol dose, although due to interpatient variability careful titration can be recommended.

Adult↗
PubMed1996

Influence of plasma-protein binding on analgesic effect of methadone in rats with spontaneous withdrawal.

The effect of spontaneous withdrawal on alpha 1-acid glycoprotein (AAG) levels and methadone protein binding has been studied in the rat. Animals were made physically dependent on morphine by providing morphine HCl in drinking water for three weeks. The natural opiate withdrawal was induced in rats by substituting the morphine solution with drinking water. The severity of the abstinence syndrome was assessed at various time intervals. After 12 h of withdrawal, the animals showing abstinence signs and low morphine levels were injected with intravenous methadone (0.35 mg kg-1) and the analgesic effect was measured by the tail-flick method and compared with animals receiving water. The oral administration of morphine produced an increase in AAG levels from 0.64 +/- 0.05 g L-1 in control animals to 1.47 +/- 0.92 g L-1 in experimental animals at the point of withdrawal and 1.21 +/- 0.09 g L-1 24 h after withdrawal. The percentage of methadone unbound was significantly lower in morphine-treated than in control animals. A significant correlation between AAG levels and percentage of methadone bound was observed. A parallel analgesic effect after intravenous methadone, as measured by AUC in the tail-flick test, was less in abstinence animals than in control (287.6 +/- 24.8 compared with 401.0 +/- 37.06s min). We suggest that in the withdrawal syndrome an adjustment of methadone dose may be necessary because of changes in protein binding.

Analgesics, Opioid↗
PubMed1996

Regulation of uncoupling protein messenger ribonucleic acid and 5'-deiodinase activity by thyroid hormones in fetal brown adipose tissue.

We studied the regulation of type II 5'-deiodinase (5'D-II) activity and uncoupling protein (UCP) messenger RNA (mRNA) by thyroid hormones in fetal brown adipose tissue (BAT). Fetuses were obtained from hypothyroid pregnant rats infused with increasing doses of T4 or T3. Infusion of T4 into hypothyroid pregnant rats increased T4 and T3 concentrations and inhibited 5'D-II activity in fetal BAT. In contrast, infusion of T3 increased BAT 5'D-II activities at low, normal, or high BAT T3 concentrations. The relationship between thyroid hormone concentrations in fetal BAT and plasma showed that BAT T3 concentrations are relatively stable, increasing less than 2-fold over a wide range of circulating T4 (3-fold) or T3 (8-fold) concentrations. Most T3 in fetal BAT are locally derived from T4 and not from plasma T3. UCP mRNA expression decreased to 30% of control values in hypothyroid fetuses. UCP mRNA levels were restored to normal in parallel with BAT T3 concentrations after the infusion of either T4 or T3. UCP mRNA levels correlate well with BAT T3 concentrations. Supraphysiological doses of T4 did not further increase either BAT T3 or UCP mRNA levels. T3 might regulate basal UCP mRNA expression during fetal life.

Adipose Tissue, Brown↗
PubMed1996

Displacement of T4 from transthyretin by the synthetic flavonoid EMD 21388 results in increased production of T3 from T4 in rat dams and fetuses.

EMD 21388 displaces T4 from circulating transthyretin, is a potent in vitro inhibitor of outer-ring deiodination (5'D) of T4 and affects thyroid hormone secretion. To study its extrathyroidal effects on the thyroid hormone status of pregnant dams and their fetuses, we treated the dams with methimazole and infused them with T4 and with either 2.5 mg EMD 21388/rat per day [(EMD(+)], or placebo solution [EMD(-)]. EMD reduced total T4 and T3 in the maternal circulation, but free T4 increased and free T3 decreased. The total amount of T3 generated from T4 in the maternal compartment increased. Placental T3 also increased in EMD(+) animals, T4 remaining the same. EMD also reached the fetal circulation. The total fetal extrathyroidal T4 pool decreased to half that of EMD(-) fetuses, whereas T3 increased 1.8-fold, thus mitigating fetal T3 deficiency, especially in the lung. Thus, if the maternal supply of T4 is kept constant, EMD mitigates the T3 deficiency of many tissues of the hypothyroid fetus. Most of the effects of this dose of EMD could result from the displacement of T4 from circulating transthyretin. Liver 5'D-I activity did not decrease, but actually increased by 40% in dams and fetuses. The enhanced transfer of T4 into tissues would also increase the amount of substrate available to 5'D-I, leading to an increased amount of T3 in maternal and fetal pools. This had not been anticipated from the changes in circulating T4 and T3, whether maternal or fetal, total or free.

Adipose Tissue, Brown↗
PubMed1996

Pharmacokinetics and pharmacodynamics of penbutolol in healthy and cancer subjects: role of altered protein binding.

The pharmacokinetic and pharmacodynamic profiles of penbutolol were examined in healthy volunteers and in cancer patients using a pharmacokinetic/pharmacodynamic (pk/pd) model. After receiving a 40 mg single oral dose of penbutolol, the absorption rate constant, apparent volume of distribution and serum clearance of penbutolol were found to be reduced in the cancer group. Changes in the disposition of the conjugate metabolite were also observed in the cancer patients. Penbutolol unbound fraction in serum was statistically decreased (p < 0.005) in the cancer group, according to the increase in the serum levels of alpha 1-acid glycoprotein seen in that group (p < 0.05). The pharmacodynamic effect of penbutolol was measured as the reduction in heart rate (HR); in healthy volunteers, a linear relationship (p < 0.01) between effect and penbutolol serum concentrations (total or unbound) was found. In contrast, in cancer patients, values of HR did not vary statistically in respect to baseline values. These results show that in cancer patients, a change in the pharmacokinetics of penbutolol occurs (associated with changes in drug protein binding), together with an alteration in the pharmacodynamics.

Adult↗
PubMed1996

Interaction between propofol and sulfisoxazole in mice an in vivo and in vitro study.

The effect of sulfisoxazole on the propofol response has been investigated in an animal model. Doses of propofol (0, 50, 75 and 100 mg/Kg intraperitoneal route) were administered to control (n = 36) and sulfisoxazole pretreated mice (n = 36). The impairment of righting reflex and struggle response were evaluated before and 5, 10, 15, 20, 30, 40, 50 and 60 minutes after propofol administration. Ten minutes after administration of the different doses of propofol, total plasma concentration was measured in both groups by high performance liquid chromatography Protein binding displacement was evaluated in vitro by the ultrafiltration technique. Pretreatment with sulfisoxazole produced an important enhancement in the effect of propofol in both tests. This change was reflected in a significant increase in the area under the time-effect curve (p < 0.001) and in a shift of the log dose-effect relationship to the left. Sulfisoxazole itself did not produce any effect on either test. ED50 for the righting reflex was significantly reduced from 114 mg/kg to 64 mg/kg in sulfisoxazole pretreated groups and it fell from 87 mg/kg to 43 mg/kg for the struggle response test. No changes in the total plasma concentration and protein binding were observed. On the basis of these results, it was concluded that a clinical interaction could be expected but this cannot be explained by an alteration in the protein binding.

Animals↗
PubMed1996

Characteristics of serum protein binding of felodipine.

The protein binding of felodipine in concentrations ranging from 3 to 65 nmol L-1 has been characterized in pooled serum, and in isolated human plasma proteins: albumin (HSA) and a1-acid glycoprotein (AAG). Protein binding was determined by an ultrafiltration technique using an Amicon Micropartition System. Serum protein binding of felodipine (16 nmol L-1) was measured in five groups of individuals: I: healthy subjects (n = 16). II: patients with chronic renal disease before and after dialysis (n = 10). III: patients with liver disease (n = 9). IV: diabetics Type I (n = 10) and Type II (n = 12) and V: cancer patients (n = 12). Concentrations of HSA, AAG, lipoproteins and non esterified fatty acids (NEFA) were also measured. The drug was extensively bound in pooled serum and the protein binding was essentially unchanged over the concentrations of felodipine studied (99.60 +/- 0.31% at 3 nmol L-1; 99.70 +/- 0.15% at 65 nmol L-1). In albumin solution (40 g L-1) felodipine was also highly bound. The mean of percentage bound was not significantly different from that in serum and was also independent of the felodipine concentrations (98.57 +/- 0.35 at 3 nmol L-1; 98.31 +/- 0.90 at 65 nmol L-1). The extent of binding to AAG was significantly lower than in serum (p < 0.01) and HSA (p < 0.01) and was independent of felodipine concentrations (85.64 +/- 2.25 at 3 nmol L-1; 85.68 +/- 2.3 at 65 nmol L-1). The percentage of bound felodipine in group II (before dialysis) was significantly lower than in group I (p < 0.001). The variability in the percentage of bound felodipine was greater in group II, before dialysis, than in the rest of the groups. After dialysis, protein binding was similar to that in group I. HSA did not change and AAG was increased. NEFA was significantly higher after dialysis when compared with group I (p < 0.01). In vitro carbamylation of serum did not change felodipine protein binding. HSA was decreased significantly in group III patients (p < 0.05). However, protein binding did not change. Binding of felodipine in the rest of the groups was not significantly different from that in group I. Linear regression analysis of the data for all individuals indicated that the binding of felodipine was related to serum lipoproteins and that age, HSA, AAG, and NEFA were not significant determinants of binding.

Adult↗
PubMed1995

Influence of vitamin C on the absorption and first pass metabolism of propranolol.

The effect of ascorbic acid on the availability of propranolol has been examined. After oral administration of propranolol 80 mg with or without ascorbic acid pretreatment (2 g), the plasma concentrations and urinary excretion of propranolol and its metabolites, 4-hydroxy-propranolol and propranolol-conjugated, were determined by HPLC. Compared to controls, vitamin C decreased the maximum concentration of propranolol from 463 to 334 nmol.l-1, and the area under the propranolol concentration-time curve (from 0 to 24 hours) from 3.13 to 1.96 mumol.l-1.h. The time to reach maximum propranolol concentration was increased from 1.9 to 2.7. The total amount of drug recovered in urine has also significantly diminished (from 12.6 to 4.29 mg). No change in elimination rate was observed, indicating that ascorbic acid had affected both the absorption process and the first pass metabolism. The heart-rate decreased less when propranolol was administered with ascorbic acid in comparison to control subjects, although this interaction has little biological importance.

Administration, Oral↗
PubMed1995

Altered methadone analgesia due to changes in plasma protein binding: role of the route of administration.

1. The effect of experimental inflammation on methadone analgesia was evaluated in rats, by the tail-flick test, after single intravenous (0.35 mg/kg) and subcutaneous (3 mg/kg) doses. 2. After i.v. administration a significant decrease (P < 0.05) in the area under the methadone time-response curve was seen in rats with experimental inflammation, when compared with control. However, no differences in the analgesic response to methadone were detected between control rats and rats with inflammation when the drug was administered by s.c. injection. 3. Plasma mucoprotein levels were significantly increased (P < 0.001) and methadone free fraction was significantly decreased in rats with inflammation (P < 0.05). In addition, after i.v. methadone a decrease in brain uptake in rats with inflammation was detected. A significant correlation between brain uptake index and plasma free fraction was also observed. 4. These results suggest that a decreased immediate response to i.v. methadone may occur in circumstances in which there is an increase in alpha 1 acid glycoprotein, but that this is not likely to be observed when the absorption is not instantaneous.

Animals↗
PubMed1995

Resistance to atracurium in rats with experimental inflammation: role of protein binding.

The influence of altered protein binding on the neuromuscular effect of atracurium has been studied in rats with experimental inflammation induced by subcutaneous injection of turpentine oil. Doses of atracurium ranging from 0.45 to 1.5 mg.kg-1 were administered to control (n = 30) and to experimental inflammation induced rats (n = 30). Neuromuscular transmission was monitored by recording the twitch tension of the tibialis-anterior muscle elicited by stimulation of the sciatic nerve. Three effect parameters were recorded: (i) intensity of the effect, measured as percentage depression of baseline twitch tension, (ii) duration of drug action (min) and (iii) recovery time (min). The dose-intensity of the effect relationship was modelled using a sigmoid Emax model. The ED50 (effective dose eliciting 50% of the maximum effect) was significantly increased (P < 0.01) in the inflammation group as compared to the control group (0.94 vs. 0.68 mg.kg-1). This change was reflected in a shift of the dose-response curve to the right in the pretreated rats. For equipotent doses ED95 (defined as the effective dose eliciting 95% of maximum effect), no differences were found in recovery time and duration of action between the two groups of rats. Mucoproteins levels (index of alpha 1-acid glycoprotein (AAG) and protein binding were significantly increased in rats with experimental inflammation as compared to control rats. Based on these results, altered serum protein binding of atracurium appears to be responsible, at least in part, for the resistance to atracurium.

Animals↗
PubMed1995

Adult-onset hypothyroidism and the cerebral metabolism of (1,2-13C2) acetate as detected by 13C nuclear magnetic resonance.

The effects of adult-onset hypothyroidism on the metabolic compartmentation of the cerebral tricarboxylic acid cycle and the gamma-aminobutyric acid (GABA) shunt have been investigated by 13C nuclear magnetic resonance spectroscopy. Rats thyroidectomized as adults and age-matched controls were infused in the right jugular vein with unlabeled or (1,2-13C2) acetate solutions for 60 min. At the end of the infusion, the brains were frozen in situ and perchloric acid extracts were prepared and analyzed by 13C nuclear magnetic resonance and reverse-phase HPLC. Thyroidectomized animals showed a decrease in the incorporation of 13C from (1,2-13C2) acetate in cerebral metabolites and an increase in the concentrations of unlabeled glutamate and GABA. Computer-assisted interpretation of the 13C multiplets observed for the carbons of glutamate, glutamine, and GABA indicated that adult-onset hypothyroidism produced 1) a decrease in the contribution of infused (1,2-13C2) acetate to the glial tricarboxylic acid cycle; 2) an increase in the contribution of unlabeled acetyl-CoA to the neuronal tricarboxylic acid cycle; and 3) impairments in the exchange of glutamate, glutamine, and GABA between the neuronal and glial compartments. Despite the fact that the adult brain has often been considered metabolically unresponsive to thyroid hormone status, present results show metabolic alterations in the neuronal and glial compartments that are reversible with substitution therapy.

Acetates↗
PubMed1995

Protein binding of itraconazole and fluconazole in patients with cancer.

The serum protein binding of itraconazole and fluconazole, new azole antifungal agents, has been investigated in vitro, in serum from healthy volunteers and from patients with cancer. Protein binding was determined by ultrafiltration. Concentrations of both alpha 1-acid glycoprotein (AAG) and albumin (HSA) were measured in all serum samples. The serum protein binding of itraconazole was reduced in patients (96.02 +/- 1.41% vs 97.25 +/- 0.54%; p < 0.01) with respect to healthy volunteers. In contrast, fluconazole protein binding was increased in the same group of patients (22.96 +/- 3.60% vs 13.30 +/- 2.58%; p < 0.01). HSA levels in cancer patients were significantly decreased (p < 0.01) and AAG levels were found to be significantly elevated in patients with respect to control subjects (p < 0.05). A significant linear relationship between the bound/unbound concentration ratio of itraconazole and HSA (r2 = 0.3340; p < 0.01) was found. Similarly, a significant relation was established between the bound/unbound concentration ratio of fluconazole and AAG levels (r2 = 0.2235; p < 0.05). Thus, a weak association between the binding of these drugs and serum protein levels has been observed. It is concluded that both antifungal drugs show different protein binding behaviour in cancer patients.

Adult↗
PubMed1995

Changes in the analgesic effects of mianserin associated with altered plasma protein binding in experimental cancer.

In a group of mice bearing experimentally induced tumors, the protein binding of mianserin in vitro was measured and compared with a control group. The analgesic effect and the brain uptake of drug was also compared with a control group after an intraperitoneal dose of mianserin. The unbound percentage of mianserin in the plasma of mice with experimental cancer decreased with respect to control animals (5.20 +/- 0.12 vs 6.06 +/- 0.26; p<0.05) and alpha1-acid glycoprotein (AAG) levels, measured as plasma mucoprotein concentrations, were significantly increased (p<0.05). The brain/plasma drug concentration ratio of mianserin decreased in mice with experimental cancer when compared with control mice (1.11 +/- 0.03 vs 1.42 +/- 0.10; p<0.02). In both groups of mice, the mianserin analgesic effect was evaluated by the hot plate test after intraperitoneal drug administration. When the analgesia response-dose curve (0-60 mg/kg) was studied, a significant decrease in the response in mice with experimental cancer versus control mice was observed. These results suggest that resistance to the mianserin analgesic response may occur in animals with cancer disease. This resistance may be associated, in part, with an altered plasma protein binding, but other mechanisms could be involved.

Analgesics↗
PubMed1994

The in vitro pharmacological profile of SK&F 106760, a novel GPIIB/IIIA antagonist.

The properties of SK&F 106760 [N alpha-acetyl-cyclo(S,S)-cysteinyl-N alpha-methyl-arginyl-glycyl-aspartyl-penicillamine-amide] as a GPIIb/IIIa antagonist have been studied in vitro and compared with those of the parent molecule, Ac-RGDS-NH2. Ac-RGDS-NH2 inhibited biotinylated fibrinogen binding to purified human GPIIb/IIIa immobilized on plastic microtitre plates with a Ki of 530 +/- 73 nM. In canine platelet rich plasma Ac-RGDS-NH2 produced a concentration related inhibition of adenosine diphosphate-induced platelet aggregation following preincubation for 3 min with an IC50 of 91 +/- 1 microM. However, incubation in platelet rich plasma for 3 hr abolished the activity of Ac-RGDS-NH2. SK&F 106760 inhibited biotinylated fibrinogen binding to purified human GPIIb/IIIa immobilized on plastic microtitre plates with a Ki of 477 +/- 57 pM. SK&F 106760 inhibited adenosine diphosphate-induced platelet aggregation in human platelet rich plasma with an IC50 of 230 +/- 60 nM but did not inhibit the von Willebrand Factor receptor (GPIb/IX)-mediated platelet agglutination produced by ristocetin. In canine platelet rich plasma SK&F 106760 inhibited aggregation produced by adenosine diphosphate, collagen and epinephrine/U-46619 with IC50 values of 355 +/- 35, 260 +/- 20, and 490 +/- 90 nM, respectively and in gel filtered platelets inhibited thrombin-mediated aggregation with an IC50 of 188 +/- 10 nM. Preincubation of SK&F 106760 in platelet rich plasma for three hours had no significant effect on its ability to inhibit adenosine diphosphate-induced platelet aggregation. SK&F 106760 produced insurmountable inhibition of adenosine diphosphate-induced platelet aggregation in the presence of constant fibrinogen concentrations, but produced competitive inhibition of the concentration-response curve to fibrinogen in adenosine diphosphate-activated platelets with a Kb of 8.0 +/- 1.0 nM. Thus, SK&F 106760 is a potent, stable competitive GPIIb/IIIa antagonist with no detectable activity at the von Willebrand Factor receptor (GPIb/IX).

Amino Acid Sequence↗