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Biomedical subjects

A Saavedra

Publications and source records attributed to A Saavedra.

18 recordsLinked to original sources
PubMed2004

A phase I-II, dose-escalating trial of ZD9331 in combination with irinotecan (CPT11) in previously pretreated metastatic colorectal cancer patients.

BACKGROUND: To establish the recommended dose (RD) of the thymidylate-synthase inhibitor ZD9331 administered with irinotecan (CPT-11) in patients with pretreated metastatic colorectal cancer, and to assess toxicity profile, pharmacokinetics (PK), and anti-tumor activity in a phase I/II open, multicenter, intrapatient chemotherapy dose escalating trial. PATIENTS AND METHODS: Twenty-one patients who failed first-line therapy (5-fluorouracil/leucovorin +/- oxaliplatin) received every 2 weeks CPT-11 180 mg/m2 D1, followed by ZD9331 30-minute infusion D2 at three dose levels: 90, 120 and 150 mg/m2. RESULTS: RD of ZD9331 was established at 90 mg/m2 for the first two cycles, with possibility to escalate at 120 mg/m2 according to safety evaluation. Grade 3-4 toxicities were neutropenia (67% of patients), grade 3 vomiting (14%), grade 3 nausea (10%) and grade 3 diarrhea (5%). ZD9331 dose level does not affect the PK of CPT-11 or SN-38. Tumor growth control (PR + SD) was achieved for 14 (66.7%) patients. Median time to progression was 6 months, and median survival was 8.4 months. CONCLUSION: ZD9331 90 mg/m2 combined with CPT-11 180 mg/m2 may be a viable option for treatment of metastatic colorectal cancer, with possible escalation to 120 mg/m2 of ZD9331 according to safety evaluation.

Adult↗
PubMed2001

Coordinated regulation of Rap1 and thyroid differentiation by cyclic AMP and protein kinase A.

Originally identified as an antagonist of Ras action, Rap1 exhibits many Ras-independent effects, including a role in signaling pathways initiated by cyclic AMP (cAMP). Since cAMP is a critical mediator of the effects of thyrotropin (TSH) on cell proliferation and differentiation, we examined the regulation of Rap1 by TSH in a continuous line of rat thyroid-like cells. Both cAMP and protein kinase A (PKA) contribute to the regulation of Rap1 activity and signaling by TSH. TSH activates Rap1 through a cAMP-mediated and PKA-independent mechanism. TSH phosphorylates Rap1 in a PKA-dependent manner. Interference with PKA activity blocked phosphorylation but not the activation of Rap1. Rather, PKA inhibitors prolonged Rap1 activation, as did expression of a Rap1A mutant lacking a PKA phosphorylation site. These results indicate that PKA elicits negative feedback regulation on cAMP-stimulated Rap1 activity in some cells. The dual regulation of Rap1 by cAMP and PKA extends to downstream effectors. The ability of TSH to stimulate Akt phosphorylation was markedly enhanced by the expression of activated Rap1A and was repressed in cells expressing a putative dominant-negative Rap1A mutant. Although the expression of activated Rap1A was sufficient to stimulate wortmannin-sensitive Akt phosphorylation, TSH further increased Akt phosphorylation in a phosphatidylinositol 3-kinase- and PKA-dependent manner. The ability of TSH to phosphorylate Akt was impaired in cells expressing a Rap1A mutant that could be activated but not phosphorylated. These findings indicate that dual signals, Rap1 activation and phosphorylation, contribute to TSH-stimulated Akt phosphorylation. Rap1 plays an essential role in cAMP-regulated differentiation. TSH effects on thyroid-specific gene expression, but not its effects on proliferation, were markedly enhanced in cells expressing activated Rap1A and repressed in cells expressing a dominant-negative Rap1A mutant. These findings reveal complex regulation of Rap1 by cAMP including PKA-independent activation and PKA-dependent negative feedback regulation. Both signals appear to be required for TSH signaling to Akt.

Animals↗
PubMed1997

In vitro proliferative response of human peripheral blood mononuclear cells to concanavalin A.

The proliferation response of human peripheral blood mononuclear cells (PBMC) to concanavalin A (con A) was tested in a medium with or without addition of fetal calf serum (FCS) or a serum substitute. The time profile of the proliferative response of PBMC to con A was different in cells cultured in a medium supplemented with or without FCS. This different pattern occurred for the con A-induced DNA-synthesis as well as for the RNA- or protein-synthesis. The peak proliferation rate and the stimulation index of proliferation of human PBMC to con A was also higher when the cells were cultured in a medium with 10% FCS compared to cells cultured in a FCS-free medium. Substitution of the fetal calf serum by a serum substitute even induced a profound inhibition of the de novo synthesis of DNA in human PBMC. The results indicate that a lymphocyte proliferation response to con A can still be obtained in a culture medium where no FCS was added, although a weaker stimulation occurred in comparison to a culture medium with FCS. However, addition of a serum substitute caused a marked inhibition of the lymphocyte proliferation rate.

Blood Proteins↗
PubMed1996

Gap junctions play a role in the 'bystander effect' of the herpes simplex virus thymidine kinase/ganciclovir system in vitro.

Tumor cells transduced with the herpes simplex virus thymidine kinase (HSVtk) gene are sensitive to the anti-viral drug ganciclovir (GCV). However, nearby untransduced tumor cells are also efficiently killed. The mechanism of this 'bystander effect' was studied by comparing pairs of tumor cell lines transfected with connexin genes that differed only in their degree of gap junctional communication. More efficient cell killing was uniformly seen in connexin transfectants compared with the less coupled cell lines. These results provide direct evidence that gap junctional communication plays an important role in mediating the bystander effect of the HSVtk/GCV system in vitro and have important prognostic and therapeutic implications for future gene therapy trials.

Adenoviruses, Human↗
PubMed1995

Changes in nutritional pattern, insulin sensitivity and glucose tolerance during weight loss in obese patients from a Mediterranean area.

In order to study the nutritional pattern in obese subjects living in an area with a Mediterranean diet, as well as the modifications in nutritional behaviour, cardiovascular risk factors and insulin sensitivity induced by changes in nutritional pattern, 54 obese patients completed a 20-week behaviour programme. They prospectively fulfilled a food records diary in order to ascertain their nutritional pattern. Weight, body mass index (BMI). waist-to-hip ratio (WHR), blood pressure (BP), cholesterol, HDL-c, LDL-c, triglycerides, fasting and 2 h-post glucose load plasma glucose were determined at the onset and at the end of the study. Insulin sensitivity index (SI), and glucose effectiveness (Sg) were assessed by using the modified FSIVGTT. The usual diet in obese patients living in a Mediterranean country is low in carbohydrates (35%) and high in fats (43%), 55% of the latter being monounsaturated fatty acids (MUFAs), especially olive oil. After the educational programme they decreased the caloric intake to slightly over 700 Kcal/day, with a reduction of 36% in carbohydrates consumption, 18% in proteins and 43% in fats (46% in MUFAs). These modifications resulted in a decrease in weight, BMI, WHR, BP, and fasting and 2 h-post glucose load plasma glucose (all p < 0.05), whereas the lipoprotein profile did not change. In a similar way SI and Kg (glucose disappearance rate) increased, while fasting plasma insulin (FPI) decreased (p < 0.05) and Sg and I1+3 remained unaffected. Our results indicate that weight loss induced by caloric restriction improves insulin sensitivity rather insulin secretory capacity or glucose effectiveness, and all the cardiovascular risk factors but lipoproteic profile, that remains unchanged, probably because of the lower MUFAs consumption. These facts should be taken into account when recommending changes in the diet of obese patients with a Mediterranean-style diet.

Adult↗
PubMed1990

[Antitubercular agents: pharmacogenetic factors in the development of adverse effects].

We studied the distribution of the acetylator phenotype in 47 patients aged 15 to 77 years receiving isonyazid as antituberculous therapy. 62% were fast and 32% slow acetylators. Ethnical, socio-economic and biologic factors were not related to acetylator type. The incidence of liver alterations, mainly elevated transaminase levels, was higher than reported in the literature and was not shown to be influenced by acetylator type. Adverse reactions to isonyacid were not related to drug serum levels.

Acetylation↗
PubMed1989

[Genetic polymorphism of isoniazid acetylation in Chilean patients with tuberculosis].

We studied genetic polymorphism of isoniazid acetylation in 47 tuberculous patients treated with 4 drugs between Aug 1987 and Dec 1988. Inactivation of isoniazid was estimated from urine samples after administration of the drug (10 mg/kg). There were 18 slow and 29 fast acetylators. The frequency of the slow mutant gene was estimated at 0.612, which is intermediate between values found in american natives (0.46) and western europeans (0.73). No associations of the presence of slow gene with sex, ABO group, ancestors, socioeconomic level, undernutrition, alcoholism or tobacco consumption were found.

Acetylation↗
PubMed1980

Interaction of S-carboxymethylated uteroglobin with progesterone.

S-Carboxymethylated uteroglobin, a small progesterone-binding globular protein, was studied by means of high-field proton magnetic resonance spectroscopy. Conformational changes induced by the steroid have been observed and indicate a well-defined rearrangement of the structure of the protein. The unusual stoichiometry of one progesterone to two uteroglobin dimers is confirmed by 1H NMR. His-8 plays a central role in the mechanism of interaction of uteroglobin with progesterone. The pH dependence of affinity constant for the complexation of the steroid parallels the titration of this histidine. Although it is not a part of the active site, it influences a crucial conformational transition of the protein through the charge carried by its imidazole ring. Formation of a tetramer of uteroglobin subunits able to bind progesterone is critically compared to a kinetic scheme involving only dimers.

Animals↗
PubMedDate not supplied

Cardiorespiratory reflex effects induced by intravenous administration of ethanol in rats.

Intravenous administration of a bolus of ethanol (40 mg/100 g b.w.) to rats induced bradycardia, hypotension and apnea. Bradycardia was dose dependent (r = -0.78, p less than 0.001). Acute bilateral vagotomy blocked bradycardia and hypotension. Apnea, however, persisted in all cases but was of short duration and occurred after a significant delay as compared to an untreated group. Atropine (0.1 mg/100 g b.w.) and hexamethonium (0.75 mg/100 g b.w.) blocked bradycardia and early hypotension. Pretreatment with reserpine (0.25 mg/100 g b.w. IP 24 and 48 hours before the experiment) significantly increased bradycardia induced by ethanol as compared to untreated animals. In rats pretreated with reserpine and vagotomized, IV ethanol did not induce bradycardia, early hypotension or apnea. A bolus of ethanol (20 mg/100 g b.w.) given directly into the left ventricle did not induce reflex changes in heart rate or respiration, while the same dose of alcohol given IV decreased heart rate by 53 +/- 8.9%. Thus, the ethanol effect seems to be initiated in pulmonary J receptors. Bradycardia appeared to be mediated both by increase in vagal tone, and to a lesser extent, by sympathetic withdrawal. Hypotension was due mainly to bradycardia, and apnea might be caused by a dual mechanism, reflex (early) and direct on the respiratory center (late).

Animals↗
PubMedDate not supplied

Cardiorespiratory inhibitory reflex induced by intravenous administration of acetaldehyde in rats.

In urethane anesthetized rats, intravenous administration of a bolus of acetaldehyde (diluted 50 times its volume in Ringer Locke solution) induced after a latency of about 1 second, a triple reflex response characterized by transient bradycardia, hypotension and apnea. Intensity of both bradycardia (r = -0.78) and hypotension (r = -0.74) were dose dependent (p less than 0.001). The triple response was blocked by vagotomy. Atropine and hexamethonium blocked bradycardia and hypotension and pretreatment of rats with reserpine (0.5 mg/100 g b.wt., IP) did not change the magnitude of the reflex response. The bolus effect was discarded by injecting the same volume of Ringer Locke solution in control test experiments. Administration of acetaldehyde directly into the left ventricle induced neither bradycardia nor hypotension, thus discarding a Bezold-Jarish reflex response. Administration of acetaldehyde directly into the right ventricle induced an increase in reflex bradycardia, hypotension and apnea with a shorter latency as compared to the intravenous route. The results suggest that the response induced by acetaldehyde is mediated by a reflex increase in vagal tone and probably is initiated in pulmonary vagal afferent fibers associated with the pulmonary J receptors.

Acetaldehyde↗