Luis G. Guijarro
University of Alcalá
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Featured researches published by Luis G. Guijarro.
The American Journal of Gastroenterology | 2006
Javier P. Gisbert; Pilar Niño; Luis Rodrigo; Carlos Cara; Luis G. Guijarro
AIM:To prospectively evaluate whether a relationship between thiopurine methyltransferase (TPMT) activity and incidence of adverse effects (especially myelotoxicity) exists, in a long-term follow-up study of a large group of patients with inflammatory bowel disease treated with azathioprine.METHODS:TPMT activity in red blood cells (RBC) was measured by a radiochemical method in 394 consecutive patients with Crohns disease (238) or ulcerative colitis (156) starting treatment with azathioprine. The relationship among several variables and TPMT values was assessed, and the correlation between such levels and the incidence of adverse effects was evaluated.RESULTS:Mean TPMT value was 18.6 ± 4 U/mL RBCs (range 9.4–33.7). No patient had low levels (<5), 7.1% had intermediate levels (5–13.7), and 92.9% had high levels (>13.8). Differences (P < 0.001) were demonstrated in TPMT activity depending on the type of inflammatory bowel disease, but not on the remaining variables (including treatment with 5-aminosalycilates). Adverse effects were reported in 74 patients (18.8%), the most frequent being gastrointestinal intolerance (9.1%) and myelotoxicity (4.3%). No patient having adverse effects had low TPMT levels. However, mean TPMT activity was lower in those with adverse effects (16.6 ± 3 vs 19.1 ± 4 U/mL, P < 0.001). Moreover, the probability of suffering myelotoxicity in the high TPMT group was only 3.5%, compared with 14.3% in the TPMT intermediate group (95% CI = 1.37–14.9; OR = 4.5).CONCLUSIONS:The strategy of determining TPMT activity in all patients prior to initiating treatment with azathioprine could help to minimize the risk of myelotoxicity, as patients with intermediate TPMT activity had fourfold more risk than high TPMT activity patients.
Digestive Diseases and Sciences | 2007
Javier P. Gisbert; Fernando Gomollón; Carlos Cara; Marta Luna; Yago González-Lama; José María Pajares; J. Maté; Luis G. Guijarro
We sought to assess the activity of thiopurine methyltransferase (TPMT) in 14,545 Spanish patients with different diseases amenable to treatment with azathioprine/6-mercaptopurine (6-MP), and to evaluate the proportion of patients with low TPMT activity and therefore a higher risk of myelotoxicity with these drugs. TPMT activity in red blood cells (RBCs) was measured by a radiochemical method. The association between several clinical variables and TPMT activity was assessed by multiple linear regression. We included 14,545 patients: autoimmune hepatitis (n=359 patients), inflammatory bowel disease (n=7,046), multiple sclerosis (n = 814), myasthenia gravis (n=344), pemphigus (n=133), and other diseases (n=5,849). Mean TPMT activity was 20.1 ± 6 U/mL, but differed depending on the disease (P < .001). TPMT distribution was low (<5) in 0.5%; intermediate (5.0–13.7) in 11.9%; or high (≥13.8) in 87.6%. Only when TPMT activity was considered separately in each disease did it reveal a normal distribution. In the multivariate analysis, gender, hematocrit, and treatment with 5-aminosalicylates/steroids/azathioprine/6-MP statistically influenced TPMT activity, although, probably, in a clinically irrelevant manner. This study shows, in a large sample of 14,545 patients, that 0.5% had low TPMT activity, indicating a higher risk of myelotoxicity with azathioprine/6-MP, a figure similar or slightly higher than that reported in other areas. Nevertheless, the trimodal distribution of TPMT activity varied depending on disease, and the proportion of patients with low activity values ranged from 0–0.8%. The drugs prescribed for the treatment of autoimmune diseases, including azathioprine/6-MP, modified TPMT activity, but the magnitude of this effect was very small and the differences found are probably irrelevant from the clinical point of view.
Biochimica et Biophysica Acta | 1984
E. Arilla; M.Pilar López-Ruiz; Luis G. Guijarro; Juan C. Prieto; Antonio Gomez-Pan; Barry H. Hirst
Specific binding sites for somatostatin have been characterized in cytosolic fraction of rat intestinal mucosa by using 125I-labelled Tyr11-somatostatin and a variety of physicochemical conditions. The binding depended on time, temperature and pH, and was reversible, saturable and specific. At apparent equilibrium, the specific binding of 125I-Tyr11-somatostatin was competitively inhibited by native somatostatin in the 1 nM-4 microM concentration range. Binding studies suggested the presence of two classes of binding sites: a class with high affinity (Kd = 0.07 microM) and low capacity (4.6 pmol/mg protein) and a class with low affinity (Kd = 1.05 microM) and high capacity (277 pmol/mg protein) at 25 degrees C. Somatostatin exhibited competitive inhibition of tracer binding, while neuropeptides such as neurotensin, substance P, Leu-enkephalin, and vasoactive intestinal peptide were ineffective. The presence of somatostatin binding sites in cytosolic fraction of intestinal mucosa, together with the known occurrence of somatostatin in D-cells and nerve endings in the small intestine, strongly suggest that this peptide may be involved in the physiology and physiopathology of intestinal epithelium.
Inflammatory Bowel Diseases | 2007
Juan L. Mendoza; Elena Urcelay; R. Lana; M. Carmen Martín; Natalia López; Luis G. Guijarro; Julio Mayol; Carlos Taxonera; Emilio G. de la Concha; Amado Salvador Peña; Manuel Díaz-Rubio
Background To investigate the contribution of multidrug resistance 1 (MDR1) gene pharmacogenetics (G2677T/A and C3435T) to the efficacy of azathioprine in inducing remission in patients with Crohns disease (CD). Methods A cohort of 327 unrelated Spanish patients with CD recruited from a single center was studied. All patients were rigorously followed up for at least 2 years (mean time, 11.5 years). A case‐control analysis of MDR1 G2677T/A and C3435T SNPs and 2 loci haplotypes in 112 steroid‐dependent CD patients treated with azathioprine was performed. Patients were classified on the basis of response to azathioprine. Results A total 76 patients treated with azathioprine for longer than 3 months were included. Remission was achieved in 42 CD patients (55.3%). A higher frequency of the 2677TT genotype was found in nonresponders than in responders (17.65% versus 7.14%; OR = 2.8; 95% CI; 0.6–12.1; P = 0.11). Nonresponders to azathioprine were found to have a higher frequency of the 3435TT genotype than did CD patients who had achieved clinical remission (17.64% versus 4.76%; OR = 4.3; 95% CI, 0.8–22.8; P = 0.06). The 2677T/3435T haplotype was also more abundant in nonresponders (29.4% versus 20.2%), whereas the 2677G/3435C haplotype was more frequent in responders (58.3% versus 47.1%). Lack of response to azathioprine therapy in CD patients was 1.8‐fold greater in carriers of the 2677T/3435T haplotype than in carriers of the 2677G/3435C haplotype (OR = 1.8; 95% CI, 0.82–3.9; P = 0.14). Conclusions The results of our study indicate higher frequencies of the 2677TT and 3435TT genotypes and the 2677T/3435T haplotype in CD patients who did not respond to azathioprine. Additional replications in independent populations would confirm the real impact of these polymorphisms in response to azathioprine therapy. (Inflamm Bowel Dis 2007)
American Journal of Physiology-lung Cellular and Molecular Physiology | 1999
Rebeca Busto; Isabel Carrero; Luis G. Guijarro; Rosa M. Solano; José Zapatero; Fernando Noguerales; Juan C. Prieto
Pituitary adenylate cyclase-activating peptide (PACAP) type 1 (PAC1) and common PACAP/vasoactive intestinal peptide (VIP) type 1 and 2 (VPAC1 and VPAC2, respectively) receptors were detected in the human lung by RT-PCR. The proteins were identified by immunoblotting at 72, 67, and 68 kDa, respectively. One class of PACAP receptors was defined from125I-labeled PACAP-27 binding experiments (dissociation constant = 5.2 nM; maximum binding capacity = 5.2 pmol/mg protein) with a specificity: PACAP-27 ≈ VIP > helodermin ≈ peptide histidine-methionine (PHM) ≫ secretin. Two classes of VIP receptors were established with 125I-VIP (dissociation constants of 5.4 and 197 nM) with a specificity: VIP ≈ helodermin ≈ PACAP-27 ≫ PHM ≫ secretin. PACAP-27 and VIP were equipotent on adenylyl cyclase stimulation (EC50 = 1.6 nM), whereas other peptides showed lower potency (helodermin > PHM ≫ secretin). PACAP/VIP antagonists supported that PACAP-27 acts in the human lung through either specific receptors or common PACAP/VIP receptors. The present results are the first demonstration of the presence of PAC1 receptors and extend our knowledge of common PACAP/VIP receptors in the human lung.Pituitary adenylate cyclase-activating peptide (PACAP) type 1 (PAC(1)) and common PACAP/vasoactive intestinal peptide (VIP) type 1 and 2 (VPAC(1) and VPAC(2), respectively) receptors were detected in the human lung by RT-PCR. The proteins were identified by immunoblotting at 72, 67, and 68 kDa, respectively. One class of PACAP receptors was defined from (125)I-labeled PACAP-27 binding experiments (dissociation constant = 5.2 nM; maximum binding capacity = 5.2 pmol/mg protein) with a specificity: PACAP-27 approximately VIP > helodermin approximately peptide histidine-methionine (PHM) >> secretin. Two classes of VIP receptors were established with (125)I-VIP (dissociation constants of 5.4 and 197 nM) with a specificity: VIP approximately helodermin approximately PACAP-27 >> PHM >> secretin. PACAP-27 and VIP were equipotent on adenylyl cyclase stimulation (EC(50) = 1.6 nM), whereas other peptides showed lower potency (helodermin > PHM >> secretin). PACAP/VIP antagonists supported that PACAP-27 acts in the human lung through either specific receptors or common PACAP/VIP receptors. The present results are the first demonstration of the presence of PAC(1) receptors and extend our knowledge of common PACAP/VIP receptors in the human lung.
Current Medicinal Chemistry | 2012
N. de las Cuevas; Sandra García-Gallego; Beatriz Rasines; F.J. de la Mata; Luis G. Guijarro; Muñoz-Fernández Ma; Rafael Gómez
Here we present a synthetic procedure for water-stable carbosilane dendrimers containing ammonium groups at the periphery of type Gn-{[Si(CH2)3N+(Me)(Et)CH2CH2N+Me3]x (CF3SO3 -)y} which have been used as non-viral vectors for transfecting different types of nucleic acids against two different medical problems, HIV and hepatocarcinoma. These systems have shown to be non-toxic in both PBMC and HepG2 cell lines under the experimental conditions and are able to form nanoconjugates with nucleic acids perfectly stable over time and in a wide range of pH values, which leads to the conclusion that the interaction between dendrimer and nucleic acid is very strong. In addition, a high degree of transfection using these nanoconjugates has been observed, ranging from 70-90% depending on the generation and in the particular case of PBMC transfection with anti-HIV oligonucleotides. However, besides of the good properties shown by the dendrimers here prepared as transfecting agents, only moderate effect was observed in functional experiments for hepatocarcinoma, as a result of the strong interaction between dendrimer and nucleic acid. Nevertheless, it is important to mention that an IRS-4 knock-down of 40% in HepG2 achieves an analogous degree of cell sensitization to cancer treatment, which may represent a major advance in the hepatocarcinoma treatment when appropriate dendrimers as transfection agents are used.
General Pharmacology-the Vascular System | 1994
M.Guillerma Juarranz; Luis G. Guijarro; Ana M. Bajo; María J. Carmena; Juan C. Prieto
1. The stimulatory effect of VIP on rat prostatic adenylyl cyclase changes during postnatal development. It peaks at 2 months (peripubertal period), remains in a plateau between 3 and 12 months (adult period), and decreases at 24 months (old period). 2. The stimulation of rat prostatic adenylyl cyclase by the beta-adrenergic agonist isoproterenol follows a pattern rather similar to that of VIP. 3. The values of VIP binding capacity correlate well with those observed for adenylyl cyclase between 1 and 12 months, whereas there appears to exist a great number of uncoupled VIP receptors at 0.5 and 24 months. 4. The apparent molecular mass (51 kDa) of the rat prostatic VIP-receptor complex remains unaltered during ontogenic development.
Regulatory Peptides | 1985
Luis G. Guijarro; E. Arilla; Maria P. Lopez-Ruiz; Juan C. Prieto; Carol Whitford; Barry H. Hirst
Specific binding sites for somatostatin have been identified and characterized in cytosolic fraction of rabbit gastric mucosa at both antrum and fundus levels. The binding depended on time, temperature and pH, and was reversible and saturable. The stoichiometric data suggested the presence of two classes of binding sites: a class with high affinity (Kd = 26.7 and 37.0 nM in antrum and fundus, respectively) and low capacity (2.1 and 4.1 pmol somatostatin/mg protein in antrum and fundus, respectively), and a class with low affinity (Kd = 246.4 and 162.5 nM in antrum and fundus, respectively) and high capacity (134.1 and 110.9 pmol somatostatin/mg protein in antrum and fundus, respectively) at 25 degrees C and pH 7.4. The binding sites were shown to be highly specific for somatostatin since neuropeptides such as Leu-enkephalin, neurotensin and substance P behaved as ligands with very low affinity.
Cellular Signalling | 1999
Rosa M. Solano; María J. Carmena; Rebeca Busto; Manuel Sánchez-Chapado; Luis G. Guijarro; J.C. Prieto
Pituitary adenylate cyclase activating peptide (PACAP) is a novel neuropeptide with regulatory and trophic functions that is related to vasoactive intestinal peptide (VIP). Here we investigate the expression of specific PACAP receptors (PAC1) and common VIP/PACAP receptors (VPAC1 and VPAC2) in the human hyperplastic prostate by immunological methods. The PAC1 receptor corresponded to a 60-KDa protein whereas the already known VPAC1 and VPAC2 receptors possessed molecular masses of 58 and 68 KDa, respectively. The heterogeneity of VIP/PACAP receptors in this tissue was confirmed by radioligand binding studies using [125I]PACAP-27 by means of stoichiometric and pharmacological experiments. At least two classes of PACAP binding sites showing different affinities could be resolved, with Kd values of 0.81 and 51.4 nM, respectively. The order of potency in displacing [125I]PACAP-27 binding was PACAP-27 approximately equal to PACAP-38 > VIP. PACAP-27 and VIP stimulated similarly adenylate cyclase activity, presumably through common VIP/PACAP receptors. The PAC1 receptor was not coupled to activation of either adenylate cyclase, nitric oxide synthase, or phospholipase C. It appears to be a novel subtype of PAC1 receptor because PACAP-27 (but not PACAP-38 or VIP) led to increased phosphoinositide synthesis, an interesting feature because phosphoinositides are involved via receptor mechanisms in the regulation of cell proliferation.
Biochimica et Biophysica Acta | 1994
Nieves Rodríguez-Henche; M.Sol Rodríguez-Pena; Luis G. Guijarro; Juan C. Prieto
The stoichiometric, pharmacological and molecular properties of vasoactive intestinal peptide (VIP) receptors have been analyzed in human liver membranes and compared in parallel with those in rat liver membranes. The binding of [125I]VIP was rapid, saturable and specific. The stoichiometric data indicated the presence of two classes of binding sites in both human and rat liver membranes with Kd values of 0.22 (human) and 0.20 (rat) nM for the high-affinity site, and 27.3 (human) and 3.6 (rat) nM for the low-affinity site. Tracer binding was displaced by structurally related peptides with an order of potency: VIP = PACAP-27 > helodermin > secretin in human liver, and VIP = PACAP-27 = helodermin > secretin in rat liver. GTP inhibited [125I]VIP binding in a dose-dependent manner suggesting the involvement of a G protein in the signal transduction pathway. Cross-linking experiments revealed an apparent molecular mass for the VIP-receptor complex that was 67,500 +/- 2700 and 50,500 +/- 900 in human and rat preparations, respectively. VIP receptors were functional, since VIP stimulated adenylyl cyclase activity in a dose dependent manner with similar efficacy but different potency in human (ED50 = 1.2 nM) and rat (ED50 = 5.8 nM) liver membranes.