Biomedical subjects

J L Manzano

Publications and source records attributed to J L Manzano.

At least 19 recordsLinked to original sources

PubMed2006

Determination of the DNA-binding characteristics of ethidium bromide, proflavine, and cisplatin by flow injection analysis: usefulness in studies on antitumor drugs.

Flow injection analysis was used to study the reactions occurring between DNA and certain compounds that bind to its double helix, deforming this and even breaking it, such that some of them (e.g., cisplatin) are endowed with antitumoral activity. Use of this technique in the merging zones and stopped-flow modes afforded data on the binding parameters and the kinetic characteristics of the process. The first compound studied was ethidium bromide (EtdBr), used as a fluorescent marker because its fluorescence is enhanced when it binds to DNA. The DNA-EtdBr binding parameters, the apparent intrinsic binding constant (0.31+/-0.02 microM(-1)), and the maximum number of binding sites per nucleotide (0.327+/-0.009) were determined. The modification introduced in these parameters by the presence of proflavine (Prf), a classic competitive inhibitor of the binding of EtdBr to the DNA double helix, was also studied, determining the value of the intrinsic binding constant of Prf (K(Prf) = 0.119+/-9x10(-3) microM(-1)). Finally, we determined the binding parameters between DNA and EtdBr in the presence of the antitumor agent cisplatin, a noncompetitive inhibitor of such binding. This provided information about the binding mechanism as well as the duration and activity of the binding of the compound in its pharmacological use.

Antineoplastic Agents↗

PubMed2002

Phase I study of weekly CPT-11 (irinotecan)/docetaxel in patients with advanced solid tumors.

Based on the synergistic cytotoxicity demonstrated in vitro by topoisomerase I inhibitors followed by docetaxel and the feasibility of giving both drugs on a weekly schedule avoiding overlapping toxicities, we designed a phase I trial of weekly CPT-11 (irinotecan)/docetaxel to determine the dose-limiting toxicities (DLT) and the maximum-tolerated dose (MTD) of this combination. Eighteen patients with advanced solid tumors treated with at least one prior chemotherapy regimen were included in this trial. CPT-11 was administered as a 90-min (intravenous) IV infusion followed immediately by docetaxel as a 30-min IV infusion. Both drugs were given on days 1, 8 and 15 in 4-week cycles. Four escalating dose levels of CPT-11/docetaxel (level I: 60/20 mg/m(2), level II: 60/25 mg/m(2), level III: 70/25 mg/m(2), and level IV: 70/30 mg/m(2)) were studied. Forty-seven cycles were administered (range, 1-5 courses) with a median number of 2.6 cycles per patient. Grade 4 leukopenia was the DLT reached at dose-level IV (CPT-11/docetaxel 70/30 mg/m(2)). Four patients had grade 3 anemia at dose levels III (two patients) and IV (two patients), while grade 3/4 thrombocytopenia was not seen. Grade 3/4 non-hematologic toxicities included grade 3 diarrhea in two patients (dose levels II and IV), grade 3 asthenia in one patient (dose level II) and grade 3 stomatitis in one patient (dose level I). The recommended dose of this weekly schedule is CPT-11 70 mg/m(2) and docetaxel 25 mg/m(2). DLT of this regimen is leukopenia, although toxicity is manageable at the recommended dose level. The activity of this regimen is being evaluated in a phase II study in previously treated patients with advanced non-small cell lung cancer.

Adult↗

PubMed2001

Prognostic value of K-ras mutations and allelic imbalance on chromosome 18q in patients with resected colorectal cancer.

PURPOSE: We designed this study to assess the frequency of K-ras mutations in patients with resected colorectal tumors and their association with survival. A second objective was to analyze the prognostic value of different K-ras genotypes. In a subgroup of patients we also investigated the presence of allelic imbalance on chromosome 18q and its relationship to clinical outcome. METHODS: One hundred fourteen colorectal tumors resected between 1983 and 1986 were analyzed to detect K-ras point mutations at codons 12, 13, and 61 by polymerase chain reaction followed by allele specific oligonucleotide hybridization. A subgroup of 77 tumors was further screened to detect loss of heterozygosity on chromosome 18q using three polymorphic microsatellite markers (D18S67, D18S474 and D18S58). RESULTS: K-ras mutations were detected in 29 percent (33/114) of patients. K-ras mutations correlated with age and preoperative carcinoembryonic antigen levels, and there was some indication that they may be linked to poor survival, especially in Stage II tumors, where a subgroup of patients with aspartic and serine mutations showed significantly reduced survival (P = 0.03) compared with K-ras-negative patients. 18q loss of heterozygosity was present in 39 percent (25/63) of tumors. A multivariate analysis of Stage II tumors showed that 18q loss of heterozygosity was significantly associated with a worse prognosis (P = 0.006). A significant decrease in survival was identified in ten patients harboring both genetic alterations (K-i mutations and 18q loss of heterozygosity; P = 0.02). CONCLUSIONS: In colorectal tumors, K-ras mutations and 18q loss of heterozygosity are two genetic markers which may identify patients with more aggressive behavior, mainly in Stage II tumors. These findings warrant further research, because they can be useful in customizing adjuvant chemotherapy.

Allelic Imbalance↗

PubMed2001

Structural characterization and cytostatic activity of chlorobischolylglycinatogold(III).

Based on the ability of bile acids for vectorializing the cytostatic activity of other agents, we have designed and synthesized a new bile acid cholylglycinato Au(III) complex, named Bamet-A1. It has been characterized by means of EA (elemental analysis), FT-IR, NMR, FAB-MS (fast atom bombardment-mass spectrometry) and Vis-UV techniques. This characterization allowed us to propose a structure of the type [Au CG(O) CG(N,O) Cl] for the neutral complex, which has the composition C522H84N2O12AuCl and is very soluble in water, methanol, ethanol and DMSO (dimethylsulfoxide). The study in aqueous solution suggested a redox process for its transformation, which is accompanied by the appearance of colloidal gold phase. The behavior in 4 mM NaCl water (in order to mimic the cytoplasmatic fluid) was similar to that observed in water, while in a 150 mM NaCl (similar to extracellular fluid and serum), the apparition of a dark blue precipitate was observed. This complex displays fluorescence, which does not change when incubated with DNA obtained from E. coli. Bamet-A1 was found to inhibit the growth of a variety of cell lines. The cytostatic effect was mild against human hepatoma HepG2, mouse hepatoma Hepa 1-6, rat hepatoma McA RH-7777 and human colon adenocarcinoma LS-174T, and stronger against mouse sarcoma S180-II and mouse leukemia L-1210 cells. The appearance of colloidal Au during the process of hydrolysis under physiological conditions may explains the low cytostatic activity.

Animals↗

PubMed2001

The role of chemotherapy in early non-small-cell lung cancer management.

Great advances have been made in chemotherapy in advanced and metastatic non-small-cell lung cancer (NSCLC), and a major milestone was reached with the administration of neoadjuvant chemotherapy in stage IIIA N2 disease. The systemic nature of lung cancer has been confirmed by many genetic analyses documenting micrometastases in negative lymph nodes and bone marrow, and mRNA gene overexpression as a surrogate of cancer cells has been identified in peripheral blood. Furthermore, serum or plasma cell-free tumor DNA has been observed even in tumors with a diameter of less than 2 cm. Pharmacogenetic screening can lead to tailored chemotherapy even in patients with early disease through the use of a genetic tool kit that will allow us to optimize the use of chemotherapy by using serial measurements of serum DNA that can help to detect residual disease and re-assess the chemosensitivity of sub-clinical micrometastatic disease. The ongoing (neo)adjuvant taxol/carboplatin hope (NATCH) trial is testing the value of three cycles of chemotherapy given pre- or post-operatively compared with surgery alone and will analyze genetic abnormalities in serum DNA at three different points during patient follow-up. Our major concern in this review is to analyze the pros and cons of chemotherapy in NSCLC. Although this review is not a formal meta-analysis, we have discussed the most relevant published studies in this field. We conclude that not only is there no evidence of detrimental effects of chemotherapy, in fact, there are many indications that chemotherapy induces response in up to 80% of patients and downgrades N2 disease in up to 50% of patients. This translates into significantly better survival when accompanied by complete resection. Since at least 50% of patients with stage IB disease develop distant metastases, it seems logical to explore the role of chemotherapy in early disease.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2000

Diffuse axonal injury with or without an evacuated intracranial hematoma in head injured patients. Are they different lesions?

The general classification of head injury proposed by Marshall et al., based on admission CT scan findings, might mask a group of patients who have Diffuse Brain Injury (DI) in addition to intracranial haematomas. The aim of this study was to assess possible differences in outcome with respect to the level of intracranial pressure (ICP) and cerebral perfusion pressure (CPP) between a group of patients with DI: III-IV (Marshall's classification) after the evacuation of an intracranial haematoma (group A) and another group with DI: III-IV in the absence of a mass lesion (group B). We prospectively studied 129 patients with isolated and closed severe head injury (GCS < 9). In group A (n = 61), the median percentage of hours with ICP > 20 mmHg and CPP < 70 mmHg was 42.8 and 18, respectively and 17 (28%) survived with GOS 4-5. In group B (n = 68), median values of 20 and 5.5 hours were obtained for ICP > 20 and CPP < 70 respectively, whilst 39 (57.3%) survived with favourable outcomes. When we analysed the effects of the DI: III-IV in both groups of patients, we found that the differences in percentage of time with ICP > 20 and CPP < 70 were statistically significant (p < 0.01) and patients in group A had a higher morbidity and mortality (p < 0.05). This study has demonstrated that the levels of ICP, morbidity and mortality in patients with DI: III-IV and an evacuated mass lesion were higher than in patients with DI: III-IV without a mass lesion.

Adolescent↗

PubMed1999

[Pneumonias in patients with malignant hemopathies. Their etiology, response to treatment and prognostic factors in 69 patients (88 episodes)].

BACKGROUND: To analyze the etiology, treatment response and prognostic factors in 88 episodes of pneumonia in patients with hematological malignancies diagnosed in one center during a period of 30 months. PATIENTS AND METHODS: 88 episodes of pneumonia in 69 adult patients were studied. Age, sex, hematological malignancy and its treatment, existence of neutropenia and hypogammaglobulinemia, administration of immunosuppressive agents, type (hospital or community-acquired) and localization of pneumonia, presence of respiratory failure and treatment response were reported. For etiologic diagnosis of pneumonias, cultures of blood, sputum, pleural fluid and bronchoalveolar lavage (BAL), as well as Legionella pneumophila, Aspergillus fumigatus and Streptococcus pneumoniae antigen detection in urine were performed. Univariate and multivariate analyses of prognostic factors for pneumonia evolution were carried out. RESULTS: The median age was 63 years. Acute leukemias (AL) were the predominant hematological malignancies. Microbiologic documentation was obtained in 40 (45%) of pneumonias. Fiberoptic bronchoscopy with BAL (71%) was the diagnostic procedure with highest yield followed by blood cultures (25%). Streptococcus pneumoniae (13) was the most frequent isolated pathogen, followed by Legionella pneumophila (6) and Pseudomonas aeruginosa (6). A significantly higher prevalence of Streptococcus pneumoniae was observed in community-acquired pneumonia. The overall mortality rate was 20%. Respiratory failure (p = 0.0009), existence of neutropenia (p = 0.0023), age equal or higher than 60 years (p = 0.012) and prolonged administration of immunosuppressive agents (p = 0.015) were the prognostic factors associated with unfavourable evolution of pneumonias in the multivariate analysis. CONCLUSIONS: The etiologic diagnosis of pneumonia in patients with hematological malignancies was only achieved in a half of cases. In our series, the high prevalence of Legionella pneumophila can be attributed to the special epidemiologic characteristics of our hospital. Prognostic factors of pneumonia are related to individual factors as well as to the hematological status of patients.

Adolescent↗

PubMed1996

[Effects of surfactant administration in premature infants with severe respiratory distress syndrome].

BACKGROUND: From January 1992 to June 1993 a study was performed to show whether the administration of surfactant to low birth weight infants with respiratory distress decreased the need for ventilatory support and improved survival. METHOD: Twenty three infants born at a single hospital received the surfactant (one dose of a 100 mg/kg divided in four aliquots) and they were eligible for the treatment if they met the following criteria: 1) Weight between 650 g and 2000 g; 2) postnatal age 4 to 24 hours; 3) clinical-radiographic signs of respiratory distress, and 4) need of mechanical ventilation with FiO2 > or = 0.6. The results of the treatment were evaluated comparing the arterial-alveolar oxygenation ratio, maximal inspiratory pressure and the oxygenation index before and after the administration of surfactant. The last consecutive eighteen infants born at our hospital, before our study was started, that met the same criteria were elected as control group. RESULTS: In the group of infants treated with surfactant the arterial-alveolar oxygenation ratio increased from 0.10 +/- 0.009 before treatment to 0.28 +/- 0.02 six hours after treatment (p < 0.01); the oxygenation index decreased from 37.79 +/- 4.27 to 12.71 +/- 1.17 (p < 0.01) and the maximal inspiratory pressure from 22.13 +/- 0.81 cmH2O to 19.52 +/- 0.76 (p < 0.001) in the same period of time. This improvement was maintained during the following 72 hours. In the group of infants treated with surfactant, mortality decreased (p < 0.01), the frequency of pneumothorax diminished (p < 0.001) and the frequency of pulmonary haemorrhage increased (p < 0.05). The ventilatory time was similar in both groups of infants but the global length of stay of the newborn that received surfactant was longer due to the fact that the non survivors of the control group died before the 72 hours of life. CONCLUSIONS: Treatment with surfactant improves the initial evolution of the respiratory distress syndrome of the newborn and decreases mortality.

Age Factors↗

PubMed1996

Bedside sonographic-guided versus blind nasoenteric feeding tube placement in critically ill patients.

OBJECTIVE: To compare a blind manual bedside method for placing feeding tubes into the small bowel vs. a sonographic bedside technique in critically ill patients. DESIGN: Prospective study with a random sample. SETTING: Multidisciplinary intensive care unit in a tertiary care university hospital. PATIENTS: Thirty-five adult patients. All patients were hemodynamically stable, mechanically ventilated, and required a nasoenteric tube placement for short-term enteral feeding due to impaired gastric emptying. INTERVENTIONS: A well-known, blind, manual, bedside method for postpyloric tube placement was always attempted first in all cases. The technique was considered successful when a postpyloric location of the tip of the tube was achieved as shown by abdominal roentgenogram. However, if after 30 mins we failed to enter the small bowel, a radiologist attempted a sonographic bedside technique for postpyloric tube insertion. Finally, when the feeding tube was in place, before starting enteral nutrition, a nasogastric tube was inserted into the stomach. MEASUREMENTS AND MAIN RESULTS: The blind manual method was successful in nine (25.7%) of the 35 patients and the final location of these feeding tubes was the proximal jejunum. The average time for placement of the feeding tubes with this manual technique was 13.9 +/- 7.4 mins (range 5 to 30). The sonographic technique was successful in 22 (84.6%) of the remaining patients and the final location of the feeding tubes was three (11%) tubes in the second portion of the duodenum, eight (31%) tubes in the third portion of the duodenum, and 11 (42%) tubes in the proximal jejunum. The average time for placement with the sonographic technique was 18.3 +/- 8.2 mins (range 5 to 35). The pyloric outlet was sonographically akinetic or severely hypokinetic in 13 patients, and in four of them, we were unable to achieve postpyloric tube placement. In these four patients, the tubes were subsequently placed by endoscopy. CONCLUSIONS: The sonographic bedside technique for placing feeding tubes into the small bowel in critically III patients has a success rate of 84.6% (confidence interval 71% to 98%) after the failure of the blind bedside manual method, proving that the former is significantly more successful. This sonographic technique facilitates the insertion of the tubes in patients who cannot be moved and in those patients with severe impairment of the peristaltic activity of the stomach.

Critical Illness↗

PubMed1995

Removal of infected dual chambered transvenous pacemaker and implantation of a new epicardial dual chambered device with cardiopulmonary bypass: experience with seven cases.

Seven patients with infected transvenous dual chambered pacemakers have undergone removal of the device using cardiopulmonary bypass. There were four women and three men with a mean age of 58 years. Six patients had localized infection in the generator pocket (mean of 4.6 previous unsuccessful operations for surgical sterilization). Four infections were due to Staphylococcus epidermidis, two to Staphylococcus aureus, and one patient presented septicemia caused by Staphylococcus epidermidis and Pseudomonas aeruginosa. The atrial and ventricular transvenous electrodes were removed under direct vision using cardiopulmonary bypass. A new dual chambered epicardial pacemaker was implanted. The procedure was well-tolerated, and all patients are infection free with working pacemakers after a mean follow-up of 25.4 months.

Cardiopulmonary Bypass↗

PubMed1994