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C Chamorro

Publications and source records attributed to C Chamorro.

At least 37 records · Page 2Linked to original sources
PubMed2001

Identification of a putative binding site for [2',5'-bis-O-(tert-butyldimethylsilyl)-beta-D-ribofuranosyl]-3'-spiro-5''-(4''-amino-1'',2''-oxathiole-2'',2''-dioxide)thymine (TSAO) derivatives at the p51-p66 interface of HIV-1 reverse transcriptase.

A binding site for TSAO-m(3)T at the interface between the p66 and p51 subunits of HIV-1 reverse transcriptase (RT) and distinct from that of "classical" HIV-1 non-nucleoside inhibitors is proposed. The feasibility of the binding mode was assessed by carrying out nanosecond molecular dynamics simulations for the complexes of TSAO-m(3)T with reduced models of both the wild-type enzyme and a more sensitive R172A mutant. The molecular model is in agreement with a previous proposal, with known structure-activity and mutagenesis data for this unique class of inhibitors, and also with recent biochemical evidence indicating that TSAO analogues can affect enzyme dimerization. The relative importance of residues involved in dimer formation and TSAO-RT complex stabilization was assessed by a combination of surface area accessibility, molecular mechanics, and continuum electrostatics calculations. A structure-based modification introduced into the lead compound yielded a new derivative with improved antiviral activity.

Amino Acid Substitution↗
PubMed2001

Exploring the role of the 5'-position of TSAO-T. Synthesis and anti-HIV evaluation of novel TSAO-T derivatives.

Various analogues of the anti-HIV-1 agent TSAO-T, [1-[2',5'-bis-O-(tert-butyldimethylsilyl)-beta-D-ribofuranosyl]thymine]-3'-spiro-5"-(4"-amino-1",2"-oxathiole-2",2"-dioxide) have been synthesized in which the 5'-TBDMS group has been replaced by alkyl-, alkenyl- or aromatic ether groups, substituted amines, carbamoyl or (thio)acyl groups. The compounds synthesized were evaluated for their inhibitory effect on HIV-1 and HIV-2 replication in cell culture. Replacement of the 5'-TBDMS group by an acyl, aromatic or a cyclic moiety markedly diminish or even eliminate the anti-HIV activity. However, the presence at that position of an alkyl or alkenyl chain, partially retain antiviral activity. These observations suggest that the 5'-TBDMS group of the TSAO molecule plays a crucial role.

Antiviral Agents↗
PubMed2000

Novel ribofuranosylnucleoside lead compounds for potent and selective inhibitors of mitochondrial thymidine kinase-2.

The ribonucleoside analogues (E)-5-(2-bromovinyl)uridine (5-BV-Urd) and 3'-spiro-(4'-amino-1',2'-oxathiole-2',2'-dioxide)-5-methyluridine (3'-AOD-5-MeUrd) emerged as potent and selective competitive inhibitors of mitochondrial thymidine kinase (TK)-2 with respect to thymidine (K(i)/K(m) values of 9.0 and 1.2 respectively). Cytosolic TK-1 did not show measurable affinity for these compounds. [(32)P]Phosphate transfer studies from [gamma-(32)P]ATP to 5-BV-Urd and 3'-AOD-5-MeUrd revealed extremely poor substrate activity but potent inhibitory potential of the compounds. It was concluded that the ribonucleosides 5-BV-Urd and 3'-AOD-5-MeUrd represent two new lead compounds for potent and selective inhibitors of mitochondrial TK-2.

Adenosine Triphosphate↗
PubMed2000

Gas embolism.

Explore the source record for details and available documents.

Catheterization, Central Venous↗
PubMed2000

TSAO-T analogues bearing amino acids at position N-3 of thymine: synthesis and anti-human immunodeficiency virus activity.

Novel analogues of the anti-HIV-1 lead compound [1-[2',5'-bis-O-(tert-butyldimethylsilyl)-beta-D-ribofuranosyl]thymine]- 3'-spiro-5'-(4"-amino-1",2"-oxathiole-2',2'-dioxide) (TSAO-T) bearing different amino acids at position N-3 of thymine were prepared and evaluated as inhibitors of HIV replication. The synthesis of the target compounds was accomplished by coupling of the appropriate TSAO intermediate with a conveniently protected (L) amino acid in the presence of BOP and triethylamine, followed by deprotection of the amino acid moiety. Several TSAO derivatives, bearing at N-3 position of the thymine base an L-amino acid retaining the free carboxylic acid, acquired activity against HIV-2, in addition to their inhibitory effect on HIV-1.

Anti-HIV Agents↗
PubMed1999

Potential multifunctional inhibitors of HIV-1 reverse transcriptase. Novel [AZT]-[TSAO-T] and [d4T]-[TSAO-T] heterodimers modified in the linker and in the dideoxynucleoside region.

In an attempt to combine the anti-HIV-inhibitory capacity of nucleoside reverse transcriptase (RT) inhibitors (NRTI) and non-nucleoside RT inhibitors (NNRTI), several heterodimer analogues of the previously reported [AZT]-(CH(2))(3)-[TSAO-T] prototype have been prepared. In these novel series, other NRTIs, an expanded range of linkers with different conformational freedom and other attachment sites for these linkers on the base part of the NRTI analogue have been explored. Moreover, in order to circumvent the dependence of the NRTI moiety of the heterodimer on activation by cellular nucleoside kinases, novel heterodimers in which the NRTI is bearing a masked monophosphate group at the 5'-position are described. Among the novel heterodimers, several derivatives show a potent anti-HIV-1 activity, which proved comparable, or even superior, to that of the AZT heterodimer prototype. The nature of the NRTI was important for the eventual anti-HIV-1 activity. In particular, the d4T heterodimer derivative containing a propyl linker between the N-3 positions of the base of TSAO-T and d4T was approximately 5- to 10-fold more inhibitory to HIV-1 than the corresponding AZT heterodimer prototype.

Anti-HIV Agents↗
PubMed1998

Abasic analogues of TSAO-T as the first sugar derivatives that specifically inhibit HIV-1 reverse transcriptase.

With the aim of assessing the role that the thymine base of TSAO-T may play in the interaction of TSAO compounds with HIV-1 reverse transcriptase (RT), we have designed, synthesized, and evaluated for their anti-HIV-1 activity a series of 3-spiro sugar derivatives substituted at the anomeric position with nonaromatic rings or with amine, amide, urea, or thiourea moieties that mimic parts or the whole thymine base of TSAO-T. Also, a dihydrouracil TSAO analogue and O-glycosyl 3-spiro sugar derivatives substituted at the anomeric position with methyloxy or benzyloxy groups have been prepared. Compounds substituted at the anomeric position with an azido, amino, or methoxy group, respectively, were devoid of marked antiviral activity (EC50: 10-200 microM). However, the substituted urea sugar derivatives led to an increase in antiviral potency (EC50: 0.35-4 microM), among them those urea derivatives that mimic most closely the intact TSAO-T molecule retained the highest antiviral activity. Also, the dihydrouracil TSAO derivative retained pronounced anti-HIV-1 activity. None of the compounds showed any anti-HIV-2 activity. The results described herein represent the first examples of sugar derivatives that interact in a specific manner with HIV-1 RT. Molecular modeling studies carried out with a prototype urea derivative indicate that a heteroaromatic ring is not an absolute requirement for a favorable interaction between TSAO-T and HIV-1 RT. Urea derivatives, which can mimic to a large extent both the shape and the electrostatic potential of a thymine ring, can effectively replace this nucleic acid base when incorporated into a TSAO molecular framework with only moderate loss of activity.

Animals↗
PubMed1998

An approach towards the synthesis of potential metal-chelating TSAO-T derivatives as bidentate inhibitors of human immunodeficiency virus type 1 reverse transcriptase.

Novel derivatives of the potent human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) inhibitor TSAO-T have been designed, synthesized and tested for their in vitro antiretroviral activity against HIV. These TSAO-T derivatives have been designed as potential bidentate inhibitors of HIV-1 RT, which combine in their structure the functionality of a non-nucleoside RT inhibitor (TSAO-T) and a bivalent ion-chelating moiety (a beta-diketone moiety) linked through an appropriate spacer to the N-3 of thymine of TSAO-T. Some of the new compounds have an anti-HIV-1 activity comparable to that of the parent compound TSAO-T, but display a markedly increased antiviral selectivity. There was a clear relationship between antiviral activity and the length of the spacer group that links the TSAO molecule with the chelating moiety. A shorter spacer invariably resulted in increased antiviral potency. None of the TSAO-T derivatives were endowed with anti-HIV-2 activity.

Anti-HIV Agents↗
PubMed1996

Comparative study of propofol versus midazolam in the sedation of critically ill patients: results of a prospective, randomized, multicenter trial.

OBJECTIVES: To compare the effectiveness, characteristics, duration of action, hemodynamic and biochemical effects, and side effects of propofol and midazolam used for continuous intravenous sedation of ventilated critically ill patients. DESIGN: Multicenter, prospective, randomized, nonblinded study. SETTING: Nine Spanish general intensive care units (ICUs). PATIENTS: Ninety-eight patients admitted to the ICU who were mechanically ventilated and required sedation for a minimum of 48 hrs. INTERVENTIONS: Propofol or midazolam was used for induction and maintenance of continuous intravenous sedation for a maximum of 5 days. The effectiveness of those two regimens was assessed according to their effects on ventilatory management and the presence of agitation. MEASUREMENTS AND MAIN RESULTS: In 93% of the patients studied, there was a medical cause necessitating mechanical ventilation. The mean (+/-SD) duration of sedation was 81 +/- 25 hrs and 88 +/- 27 hrs for the propofol and midazolam groups, respectively. The induction dose was 2.24 +/- 0.43 mg/kg over 318 +/- 363 secs for propofol, and 0.22 +/-0.07 mg/kg over 33 +/-29 secs for midazolam. The maintenance dose was 2.8 +/-1.1 mg/kg/hr for propofol and 0.14 +/- 0.10 mg/kg/hr for midazolam. There was no difference regarding the opiate and muscle relaxant requirements between the two groups. Sedation with propofol was more effective in achieving patient-ventilator synchrony than that with midazolam after the first hour of treatment (p < .01). Patients sedated with propofol awoke more rapidly and with less variability that those patients sedated with midazolam (23 +/- 16 mins vs. 137 +/- 185 mins, respectively, p < .05), particularly in those patients requiring deep sedation (27 +/- 16 mins vs. 237 +/- 222 mins, respectively, p < .01). No hemodynamic or biochemical changes were detected in any of the treatment groups. During induction, five patients in the propofol group and two patients in the midazolam group had hypotension. CONCLUSIONS: In this population of critically ill patients, propofol is an effective and safe alternative for sedation, with some advantages, such as short duration of action and high effectiveness over the conventional regimen with benzodiazepines and opiates.

Adolescent↗
PubMed1995

[The adult respiratory stress syndrome and septic shock associated with tuberculosis].

The increase in the incidence of tuberculosis infection in the last few years has caused a recurrence of atypical clinical forms, as well as the development of associations and uncommon complications during the clinical course, which include the adult respiratory distress syndrome (ARDS) and septic shock. Three patients with ARDS are here reported; two patients had findings of septic shock and negative serology to human immunodeficiency virus and the only etiological agent documented was M. tuberculosis. The three patients required hemodynamic support and two of them mechanical ventilation. None of the patients survived the episode. Tuberculosis, particularly the disseminated forms, should be considered as possible etiology in high risk patients with septic shock, ARDS or both.

Adult↗
PubMed1992

Delamination of neuroepithelium and nonneural ectoderm and its relation to the convergence step in chick neurulation.

We have analysed the characteristics of the neuroectoderm-nonneural ectoderm meeting point at several axial levels in relation to the mechanics of neurulation in each level. The results show wide differences at cephalic and somitic levels. At cephalic levels, where convergence plays an important role, the delamination process appears at the beginning of the convergence step. This phenomenon produces a major isolation of the basal lamina, forming a space between this structure and the epithelial sheet in whose basal surface a new basal lamina begins to form. This cavity contains abundant extracellular matrix stained with ruthenium red (RR) and tannic acid (TA), and its increase in volume correlates with the progressive convergence of neural folds. At somitic levels, where the convergence is not important, delamination involves the progressive formation of a half-moon-shaped cavity. This structure appears between a dorsal attachment point, in the tip of neuroectodermal wall, and a ventral attachment point which coincides with the point of bending that determines the bilateral furrow, if it exists. In this small cavity, delamination is not related to an isolation of basal lamina. The RR-staining of the extracellular matrix in this cavity is scarce and the volume increase is smaller than in the cephalic region. These results are discussed in terms of neural fold convergence and neural tube closure.

Animals↗
PubMed1988

Sequential epidemic outbreaks of septicaemias by Serratia and Klebsiella species on a medical intensive care unit.

The high rate of septicaemias (20%, 19% and 14%) observed in our Intensive Care Unit (ICU) during the first 3 years was due to an epidemic incidence of Serratia sp. (S) (26% during the first year) and Klebsiella sp. (K) (25% during the third) and decreased significantly in the following 6 years (mean incidence of 11%) (p less than 0.01). During this epidemic phase these organisms were isolated quite frequently (between a 14% and a 6%) from all patients admitted. The K was more regularly present, for the mean time intervals free of its bacteriological presence were shorter (11 days) than those of S (27 days) (p less than 0.01). The K was isolated in more patients (160) than S (79) (p less than 0.01) and in more samples (360) than S (235) (p less than 0.01), but caused less secondary septicaemias per colonized patient (7% versus 29%) (p less than 0.01). In 59% of all S septicaemias the organism was previously isolated in other culture, while this was observed in only 34% of K septicaemias (x2 = 3.78, p = 0.052). The large variations in the incidence of septicaemias within our ICU, the appearance of sequential epidemic outbreaks, with a different behaviour of S and K and the individual risk of septicaemia of patients colonized by these organisms are noted.

Cross Infection↗
PubMed1988

Prognostic assessment of the acute complications of bone marrow transplantation requiring intensive therapy.

Patients with bone marrow transplant may present with acute, life-threatening complications which frequently (40% of our cases) require intensive care unit treatment and result in an increased mortality (76% in this series). In an attempt to reach a more objective prognostic assessment, we have analyzed those factors related to the worst outcome in the 25 patients with bone marrow transplant admitted into our intensive care unit. Respiratory failure was the most frequent complication (72%), with an 83% mortality. Graft-versus-host disease and neutropenia led to a greater number of infectious complications with a poor outcome. Failure of more than three organ systems, septic shock and mechanical ventilation were statistically associated with mortality (p less than 0.05), and all patients who required mechanical ventilation for more than seven days or needed intensive therapy for more than 10 days died. The presence of septic shock, multisystem failure and severe neutropenia on admission should be considered as initial indicators of a poor prognosis. More than 7 days of mechanical ventilation and an intensive care unit stay of more than 10 days could be critical points in the reassessment of the intensity and prolongation of treatment.

Adolescent↗
PubMed1986

Prolonged high-frequency jet ventilation in a patient with bronchopleural fistula. An alternative mode of ventilation.

We report a case of bronchopleural fistula (BPF) in a patient submitted to conventional mechanical ventilation in which high frequency jet ventilation (HFJV) was applied during five consecutive days. Gas exchange was adequate, the bronchial secretions could easily be cleared and the patient adapted comfortably to HFJV. In spite of PEEP levels between 4 and 8 mm Hg, the leak through the BPF ceased completely.

Bronchial Fistula↗