Evaluation of the RAPID score as a predictor of postoperative morbidity and mortality in patients undergoing pulmonary decortication for stage III pleural empyema.

OBJECTIVE: This study aims to correlate the RAPID score with the 3-month survival and surgical results of patients undergoing lung decortication with stage III pleural empyema. METHODS: This was a retrospective study with the population of patients with pleural empyema who underwent pulmonary decortication between January 2019 and June 2022. Data were collected from the institution's database, and patients were classified as low, medium, and high risk according to the RAPID score. The primary outcome was 3-month mortality. Secondary outcomes were the length of hospital stay, readmission rate, and the need for pleural re-intervention. RESULTS: Of the 34 patients with pleural empyema, according to the RAPID score, patients were stratified into low risk (23.5 %), medium risk (47.1 %), and high risk (29.4 %). The high-risk group had a 3-month mortality of 40 %, while the moderate-risk group had a 6.25 % and the low-risk group had no deaths within 90 days, confirming a good correlation with the RAPID score (p < 0.05). Sensitivity and specificity for the primary outcome in the high-risk score were 80.0 % and 79.3 %, respectively. The secondary outcomes did not reach statistical significance. CONCLUSIONS: In this retrospective series, the RAPID score had a good correlation with 3-month mortality in patients undergoing lung decortication. The morbidity indicators did not reach statistical significance. The present data justifies further studies to explore the capacity of the RAPID score to be used as a selection tool for treatment modality in patients with stage III pleural empyema.

Safety and immunogenicity of shorter interval schedules of the novel oral poliovirus vaccine type 2 in infants: a phase 3, randomised, controlled, non-inferiority study in the Dominican Republic.

BACKGROUND: The novel oral poliovirus vaccine type 2 (nOPV2) is now authorised by a WHO emergency use listing and widely distributed to interrupt outbreaks of circulating vaccine-derived poliovirus type 2. As protection of vulnerable populations, particularly young infants, could be facilitated by shorter intervals between the two recommended doses, we aimed to assess safety and non-inferiority of immunogenicity of nOPV2 in 1-week, 2-week, and 4-week schedules. METHODS: In this phase 3, open-label, randomised trial, healthy, full-term, infants aged 6-8 weeks from a hospital or a clinic in the Dominican Republic were randomly allocated (1:1:1 ratio) using a pre-prepared, computer-generated randomisation schedule to three groups to receive two doses of nOPV2 immunisations with a 1-week interval (group A), 2-week interval (group B), or 4-week interval (group C). The nOPV2 vaccine was given at a 0·1 mL dose and contained at least 105 50% cell culture infective dose. Neutralising antibodies against poliovirus types 1, 2, and 3 were measured before each immunisation and 4 weeks after the second dose. The primary outcome was the type 2 seroconversion rate 28 days after the second dose, and the non-inferiority margin was defined as a lower bound 95% CI of greater than -10%. Safety and reactogenicity were assessed through diary cards completed by the parent or guardian. The trial is registered with ClinicalTrials.gov, NCT05033561. FINDINGS: We enrolled 905 infants between Dec 16, 2021, and March 28, 2022. 872 infants were included in the per-protocol analyses: 289 in group A, 293 in group B, and 290 in group C. Type 2 seroconversion rates were 87·5% (95% CI 83·2 to 91·1) in group A (253 of 289 participants), 91·8% (88·1 to 94·7) in group B (269 of 293 participants), and 95·5% (92·5 to 97·6) in group C (277 of 290 participants). Non-inferiority was shown for group B compared with group C (difference in rates -3·7; 95% CI -7·9 to 0·3), but not for group A compared with group C (-8·0; -12·7 to -3·6). 4 weeks after the second nOPV2 dose, type 2 neutralising antibodies increased in all three groups such that over 95% of each group was seroprotected against polio type 2, although final geometric mean titres tended to be highest with longer intervals between doses. Immunisation with nOPV2 was well tolerated with no causal association to vaccination of any severe or serious adverse event; one death from septic shock during the study was unrelated to the vaccine. INTERPRETATION: Two nOPV2 doses administered 1 week or 2 weeks apart from age 6 weeks to 8 weeks were safe and immunogenic. Immune responses after a 2-week interval were non-inferior to those after the standard 4-week interval, but marked responses after a 1-week interval suggest that schedules with an over 1-week interval can be used to provide flexibility to campaigns to improve coverage and hasten protection during circulating vaccine-derived poliovirus type 2 outbreaks. FUNDING: Bill & Melinda Gates Foundation.

Evaluation of the RAPID score as a predictor of postoperative morbidity and mortality in patients undergoing pulmonary decortication for stage III pleural empyema

Abstract Objective: This study aims to correlate the RAPID score with the 3-month survival and surgical results of patients undergoing lung decortication with stage III pleural empyema. Methods: This was a retrospective study with the population of patients with pleural empyema who underwent pulmonary decortication between January 2019 and June 2022. Data were collected from the institution's database, and patients were classified as low, medium, and high risk according to the RAPID score. The primary outcome was 3-month mortality. Secondary outcomes were the length of hospital stay, readmission rate, and the need for pleural re-intervention. Results: Of the 34 patients with pleural empyema, according to the RAPID score, patients were stratified into low risk (23.5 %), medium risk (47.1 %), and high risk (29.4 %). The high-risk group had a 3-month mortality of 40 %, while the moderate-risk group hada 6.25 % and the low-risk group had no deaths within 90days, confirmingagood correlation with the RAPID score (p < 0.05). Sensitivity and specificity for the primary outcome in the high-risk score were 80.0 % and 79.3%, respectively. The secondary outcomes did not reach statistical significance. Conclusions: In this retrospective series, the RAPID score had a good correlation with 3-month mortality in patients undergoing lung decortication. The morbidity indicators did not reach statistical significance. The present data justifies further studies to explore the capacity of the RAPID score to be used as a selection tool for treatment modality in patients with stage III pleural empyema.

Genetic and phenotypic stability of poliovirus shed from infants who received novel type 2 or Sabin type 2 oral poliovirus vaccines in Panama: an analysis of two clinical trials.

BACKGROUND: Sabin strains used in oral poliovirus vaccines (OPV) can revert to virulence and, in rare instances, cause disease or generate vaccine-derived strains leading to outbreaks in areas of low immunisation coverage. A novel OPV2 (nOPV2) was designed to stabilise the viral genome against reversion and reduce recombination events that might lead to virulent strains. In this study, we evaluated the genetic and phenotypic stability of shed poliovirus following administration of one dose of monovalent OPV2 (mOPV2) or nOPV2 to infants aged 18-22 weeks. METHODS: In two similarly designed clinical trials (NCT02521974 and NCT03554798) conducted in Panama, infants aged 18-22-weeks, after immunisation with three doses of bivalent OPV (types 1 and 3) and one dose of inactivated poliovirus vaccine, were administered one or two doses of mOPV2 or nOPV2. In this analysis of two clinical trials, faecally shed polioviruses following one dose of mOPV2 or nOPV2 were isolated from stools meeting predetermined criteria related to sample timing and viral presence and quantity and assessed for nucleotide polymorphisms using next-generation sequencing. A transgenic mouse neurovirulence test was adapted to assess the effect of the possible phenotypic reversion of shed mOPV2 and nOPV2 with a logistic regression model. FINDINGS: Of the 91 eligible samples, 86 were able to be sequenced, with 72 evaluated in the transgenic mouse assay. Sabin-2 poliovirus reverts rapidly at nucleotide 481, the primary attenuation site in domain V of the 5' untranslated region of the genome. There was no evidence of neurovirulence-increasing polymorphisms in domain V of shed nOPV2. Reversion of shed Sabin-2 virus corresponded with unadjusted paralysis rates of 47·6% at the 4 log10 50% cell culture infectious dose (CCID50) and 76·7% at the 5 log10 CCID50 inoculum levels, with rates of 2·8% for 4 log10 CCID50 and 11·8% for 5 log10 CCID50 observed for shed nOPV2 samples. The estimated adjusted odds ratio at 4·5 log10 of 0·007 (95% CI 0·002-0·023; p<0·0001) indicates significantly reduced odds of mouse paralysis from virus obtained from nOPV2 recipients compared with mOPV2 recipients. INTERPRETATION: The data indicate increased genetic stability of domain V of nOPV2 relative to mOPV2, with significantly lower neurovirulence of shed nOPV2 virus compared with shed mOPV2. While this vaccine is currently being deployed under an emergency use listing, the data on the genetic stability of nOPV2 will support further regulatory and policy decision-making regarding use of nOPV2 in outbreak responses. FUNDING: Bill & Melinda Gates Foundation.

Alternative caregivers` role in food choices for young children in semi-urban and urban Mexico.

Alternative caregivers (i.e., someone besides the primary caregiver who also takes care of children) make food choices for children. This study investigated what alternative caregivers consider when making food choices for children and their perspectives on their role in making food choices to feed children. In-depth interviews were conducted with 16 alternative caregivers of children aged 1-5 years old in semi-urban and urban areas of the State of Mexico in Mexico. Interviews were recorded, transcribed, coded, and analyzed using constant comparative method. Alternative caregivers described spaces and situations that exposed children to food while under their care. Alternative caregivers who spent longer periods of time with the child described more involvement in what the child ate. Healthy or nutritious food, cost of food and affection for children were important considerations for alternative caregivers when deciding what to feed the child. Alternative caregivers had a substantial role in child feeding, decisions about cooking, and advising mothers on how to feed their children. Efforts to promote healthy food choices for children should include targeting of alternative caregivers.

Terapia de presión negativa para el manejo de abdomen catastrófico secundario a íleo biliar / Negative Pressure Therapy for Managing Catastrophic Abdomen following Gallstone Ileus

Introducción: El abdomen catastrófico o abdomen hostil es una entidad quirúrgica de gran importancia por la pérdida de los distintos espacios entre los órganos de la cavidad abdominal y las estructuras de la cavidad abdominal. Estas alteraciones producen cambios anatómicos grandes por un síndrome adherencial severo. Objetivo: Demostrar la presentación de un abdomen catastrófico posterior a manejo de íleo biliar en un paciente adulto. Caso clínico: Paciente masculino de 43 años que producto de un abdomen agudo obstructivo por íleo biliar evolucionó tórpidamente en otra casa asistencial. Se realizaron 3 intervenciones quirúrgicas, hasta llegar a nuestra casa asistencial donde se le trata de manera multidisciplinaria e integral. Estuvo 120 días hospitalizado y se le realizó 5 intervenciones quirúrgicas para aplicación y recambio de terapia de presión negativa abdominal abierta (ABThera). Durante la última intervención al encontrar una cavidad limpia y sin fugas se realiza gastroentero anastomosis en Y de Roux con una buena evolución clínico-quirúrgica hasta el alta, con seguimiento dos meses posteriores por consulta externa. Conclusiones: El abdomen catastrófico es un reto para el manejo por los cirujanos porque se requiere aparte de un vasto conocimiento también el apoyo de otras especialidades para poder combatir esta entidad(AU)

Introduction: Catastrophic abdomen or hostile abdomen is a surgical entity of great significance due to the loss of the different spaces between organs and the structures of the abdominal cavity. These alterations produce major anatomical changes due to a severe adhesive syndrome. Objective: To show the presentation of a catastrophic abdomen following gallstone ileus management in an adult patient. Clinical case: A 43-year-old male patient who, as a consequence of an acute obstructive abdomen due to gallstone ileus, had a torpid evolution into another care facility. Three surgical interventions were performed before he arrived at our care facility, where he was treated in a multidisciplinary and comprehensive way. He was hospitalized for 120 days and underwent five surgical interventions for application and replacement of the open abdomen negative pressure therapy (ABThera). During the last intervention, upon finding a clean cavity without leaks, a Roux-en-Y gastroenteric anastomosis was performed, with a good clinical-surgical evolution until discharge and follow-up of two months thereafter in the outpatient clinic. Conclusions: Catastrophic abdomen is a challenge to be managed by surgeons because it requires, apart from vast knowledge, the support of other specialties to combat this entity(AU)

Evisceración de intestino delgado por periné posterior como presentación de hernia interrecto-vaginal: reporte de un caso / Evisceration of the small intestine through the posterior perineum aspresentation of interrecto-vaginal hernia: a case report

Introducción. El enterocele es causado por un defecto herniario del piso pélvico, siendo el más común la hernia interrecto-vaginal. Se produce por un debilitamiento del piso pélvico, por diversos factores, entre ellos, las cirugías en la región pélvica, el estreñimiento crónico o las patologías que aumentan la presión intraabdominal, el antecedente de prolapso rectal o vaginal, y también, factores congénitos. Presentación de caso. Paciente femenina de 84 años de edad, con antecedentes de un parto eutócico y múltiples procedimientos quirúrgicos, entre ellos histerectomía hace 40 años y rectosigmoidectomía por enfermedad diverticular complicada hace 6 años, quien cuatro meses antes presenta constipación crónica, que empeora en los días previos a su ingreso, con dolor perineal intenso y salida de asas intestinales a nivel de la región perineal, que la obliga a consultar a Urgencias. Al encontrarse con asas intestinales expuestas, con cambios de coloración, es intervenida quirúrgicamente con resultado satisfactorio, postquirúrgico inmediato optimo y seguimiento por consulta externa por 3 meses sin evidencia de recidiva. Discusión. La hernia interrecto-vaginal tiene una incidencia baja y una presentación clínica variada. El único tratamiento es quirúrgico

Introduction. The enterocele is produced by an hernia defect of the pelvic floor, being the most common the interrecto-vaginal hernia. It is produced by weakness of the pelvic floor for multiples factors, among them surgeries of the pelvic region, chronic constipation or pathologies that increase intra-abdominal pressure, a history of rectal or vaginal prolapse, and congenital factors. Case report. A 84-year-old female patient, with a history of eutocic delivery and multiple surgical procedures, including hysterectomy 40 years ago and rectosigmoidectomy for complicated diverticular disease 6 years ago, presented four months earlier with chronic constipation, which worsens in the days before her admission, with intense perineal pain and exit of intestinal loops at the level of the perineal region, which forced her to consult the emergency room. At examination the intestinal loops were found exposed, with color changes, she underwent surgery with satisfactory results, optimal immediate postoperative and outpatient follow-up for 3 months with no evidence of recurrence. Discussion. Interrecto-vaginal hernia has a low incidence and a varied clinical presentation. The only treatment is surgery

Safety and immunogenicity of two novel type 2 oral poliovirus vaccine candidates compared with a monovalent type 2 oral poliovirus vaccine in children and infants: two clinical trials.

BACKGROUND: Continued emergence and spread of circulating vaccine-derived type 2 polioviruses and vaccine-associated paralytic poliomyelitis from Sabin oral poliovirus vaccines (OPVs) has stimulated development of two novel type 2 OPV candidates (OPV2-c1 and OPV2-c2) designed to have similar immunogenicity, improved genetic stability, and less potential to reacquire neurovirulence. We aimed to assess safety and immunogenicity of the two novel OPV candidates compared with a monovalent Sabin OPV in children and infants. METHODS: We did two single-centre, multi-site, partly-masked, randomised trials in healthy cohorts of children (aged 1-4 years) and infants (aged 18-22 weeks) in Panama: a control phase 4 study with monovalent Sabin OPV2 before global cessation of monovalent OPV2 use, and a phase 2 study with low and high doses of two novel OPV2 candidates. All participants received one OPV2 vaccination and subsets received two doses 28 days apart. Parents reported solicited and unsolicited adverse events. Type 2 poliovirus neutralising antibodies were measured at days 0, 7, 28, and 56, and stool viral shedding was assessed up to 28 days post-vaccination. Primary objectives were to assess safety in all participants and non-inferiority of novel OPV2 day 28 seroprotection versus monovalent OPV2 in infants (non-inferiority margin 10%). These studies were registered with ClinicalTrials.gov, NCT02521974 and NCT03554798. FINDINGS: The control study took place between Oct 23, 2015, and April 29, 2016, and the subsequent phase 2 study between Sept 19, 2018, and Sept 30, 2019. 150 children (50 in the control study and 100 of 129 assessed for eligibility in the novel OPV2 study) and 684 infants (110 of 114 assessed for eligibility in the control study and 574 of 684 assessed for eligibility in the novel OPV2 study) were enrolled and received at least one study vaccination. Vaccinations were safe and well tolerated with no causally associated serious adverse events or important medical events in any group. Solicited and unsolicited adverse events were overwhelmingly mild or moderate irrespective of vaccine or dose. Nearly all children were seroprotected at baseline, indicating high baseline immunity. In children, the seroprotection rate 28 days after one dose was 100% for monovalent OPV2 and both novel OPV2 candidates. In infants at day 28, 91 (94% [95% CI 87-98]) of 97 were seroprotected after receiving monovalent OPV2, 134 (94% [88-97]) of 143 after high-dose novel OPV2-c1, 122 (93% [87-97]) of 131 after low-dose novel OPV2-c1, 138 (95% [90-98]) of 146 after high-dose novel OPV2-c2, and 115 (91% [84-95]) of 127 after low-dose novel OPV2-c2. Non-inferiority was shown for low-dose and high-dose novel OPV2-c1 and high-dose novel OPV2-c2 despite monovalent OPV2 recipients having higher baseline immunity. INTERPRETATION: Both novel OPV2 candidates were safe, well tolerated, and immunogenic in children and infants. Novel OPV2 could be an important addition to our resources against poliovirus given the current epidemiological situation. FUNDING: Fighting Infectious Diseases in Emerging Countries and Bill & Melinda Gates Foundation.

Tumor desmoide / Desmoid tumor

Introducción. El tumor desmoide grado I, es una patología rara, se consideraba la intervención quirúrgica como primera opción, pero su recidiva posquirúrgica tendía a obscurecer la evolución satisfactoria ya que este tipo de tumores tienden a comprometer planos cada vez más profundos, en algunos casos ha provocado la amputación de extremidades sin lograr éxito, generando un grave impacto psicológico en el paciente y su pronóstico. Caso clínico. Paciente masculino, a los 18 años de edad, presentó una masa en el tercio distal del brazo izquierdo, en Italia le realizan exéresis quirúrgica, la misma que reporta positivo para tumor desmoide, presentando varias recidivas años después, estudios histopatológicos reportan recidiva de tumor desmoide. Actualmente se encuentra en seguimiento con controles tomográficos. Discusión. El tumor desmoide carece de potencial metastásico, con un comportamiento local muy agresivo, las técnicas de imagen permiten realizar su diagnóstico diferencial de otros tumores que afectan los tejidos blandos, su diagnóstico definitivo es con biopsia y su estudio histopatológico. Nuestro paciente a los 18 años se le diagnostica de un tumor desmoide a nivel del brazo izquierdo, presentando por varias ocasiones recidivas posterior a varias exéresis de los mismos, cabe recalcar, que este tipo de tumor tiene una elevada tasa de recurrencia incluso después de una resección completa del tumor; por lo que la cirugía no está indicada como tratamiento de primera elección, indica el manejo expectante está indicado con la estrategia O-E (Observar-Esperar), cuando el paciente es referido al HECAM se decide mantener controles expectantes. Como lo recomienda las ultimas guías de tratmiento.

Introduction. Grade I desmoid tumor is an uncommon pathology where treatment was the surgery as first option, but its post-surgical recurrence tends to obscure satisfactory evolution due to these kinds of tumors have to compromise deep layers, and there are cases where patients needed amputation of their arms or legs without any success; therefore, it causes a huge psychological impact in the patients and their prognosis. Clinical case. An eighteen-year old male presented with a mass in the distal portion of the left arm. In Italy, he had a surgical resection, and the sample was positive for a desmoid tumor, presenting several recurrences years later. Histological studies reports recurrence of desmoid tumor. Is currently in follow-up with tomographic controls. Discussion. The desmoid tumor lacks metastatic potential, with a very aggressive local behavior, the imaging techniques allow its differential diagnosis of other tumors that affect the soft tissues, and its definitive diagnosis is with biopsy and its histopathological study. In summary, our eighteen-year old patient's diagnose was a desmoid tumor on his left arm, presenting several recurrences after several exeresis of the same, it should be emphasized that this type of tumor has a high rate of recurrence even after a complete tumor resection. Thus, surgery is not indicated as first-line of treatment, so it´s recommended expectant treatment based on the O-E strategy (Observe-Wait). When the patient was referred to Hospital de Especialidades Carlos Andrade Marin, the doctors decided to continue with observational management. As recommended by the latest treatment guidelines.

Penfigoide ampollar: análisis retrsopectivo de 45 casos / Bullous pemphigoid: a retrospective analysis of 45 cases

Introducción. El penfigoide ampollar (PA) es una enfermedad autoinmune que afecta con mayor frecuencia a personas de edad avanzada.Objetivos. Identificar la edad de presentación, sexo y variantes clínicas del PA. Establecer la asociación con otras enfermedades, la respuesta terapéutica y comparar los resultados con las estadísticas publicadas.Materiales y métodos. Se realizó un análisis retrospectivo y descriptivo de los pacientes que consultaron en el Servicio de Dermatología del Policlínico Bancario en el período comprendido entre agosto de 1995 y el mismo mes de 2010. Se incluyeron aquellos pacientes con diagnóstico de PA. La recolección de datos se obtuvo de los registros histológicos y de las correspondientes historias clínicas.Resultados. Se registraron 45 pacientes; 25 (55,5%) femeninos y 20 (44,5%) masculinos. La edad media fue de 75,9 años. Variantes clínicas: 35 pacientes (77,7%) clásica; 5 (11,1%) localizada; 1(2,2%) vesicular; 2 (4,4%) nodular. Asociación con DBT: 15 pacientes (33,3%); HTA: 29 (64,4%); otras enfermedades sistémicas: 19 (42,2%); enfermedades dermatológicas: 7 (15,5%). La respuesta terapéutica fue buena.Conclusiones. La edad promedio al momento del diagnóstico fue avanzada. No hallamos marcada diferencia en cuanto a la distribución por sexo. La forma clásica predominó sobre las otras variantes clínicas. La asociación con enfermedades sistémicas podría deberse a que estas patologías se dan con mayor frecuencia en el mismo grupo etario. La asociación con enfermedades dermatológicas fue conpsoriasis (la de mayor representación). La respuesta terapéutica fue altamente satisfactoria. En general, nuestros datos son similares a las estadísticas publicadas.

5-Nitro-2-furyl derivative actives against Trypanosoma cruzi: preliminary in vivo studies.

Ten 5-nitro-2-furyl derivatives, with good to excellent in vitro anti-Trypanosoma cruzi activity, and nifurtimox were tested oral and intraperitoneally on healthy animals for its acute toxicity on murine models. According to animals' survival percentage, organ histological results, biochemical and haematological findings, three new derivatives, with toxicity like nifurtimox, were selected to test in vivo as antichagasic agents. Clearly, dependences between chemical structure and both acute toxicity and in vivo anti-T. cruzi activity were observed. 4-Hexyl-1-[3-(5-nitro-2-furyl)-2-propenylidene]semicarbazide displayed good profile as anti-T. cruzi agent and better acute toxicity profile than nifurtimox.

Platinum-based complexes of bioactive 3-(5-nitrofuryl)acroleine thiosemicarbazones showing anti-Trypanosoma cruzi activity.

Eight new platinum(II) complexes with 3-(5-nitrofuryl)acroleine thiosemicarbazones showing anti-trypanosomal activity were synthesized, characterized and in vitro evaluated. Most of the complexes showed IC(50) values in the micromolar range against two different strains of Trypanosoma cruzi, causative agent of Chagas disease (American Trypanosomiasis). In addition, most of the newly developed complexes, together with the analogous platinum 5-nitrofuraldehyde containing thiosemicarbazones previously reported, resulted more active than the reference trypanocidal drug nifurtimox on the infective trypomastigote form of the parasite. Their capacity to produce free radicals that could lead to parasite death was evaluated by ESR experiments in the parasite and by respiration measurements. Compounds were tested for their DNA interaction ability. Results showed that some of the compounds could act as dual inhibitors in the parasite, through production of toxic free radicals and interaction with DNA. All the results were compared with those previously reported for the free ligands, the analogous palladium(II) compounds and the previously reported series of platinum(II) compounds.

Synthesis, trypanocidal activity and docking studies of novel quinoxaline-N-acylhydrazones, designed as cruzain inhibitors candidates.

In this paper, we report the structural design, synthesis, trypanocidal activity and docking studies of novel quinoxaline-N-acylhydrazone (NAH) derivatives, planned as cruzain inhibitors candidates, a cysteine protease essential for the survival of Trypanosoma cruzi within the host cell. The salicylaldehyde N-acylhydrazones 7a and 8a presented IC(50) values of the same magnitude order than the standard drug nifurtimox (Nfx), when tested in vitro against epimastigote forms of Trypanosoma cruzi (Tulahuen 2 strain) and were non-toxic at the highest assayed doses rendering selectivity indexes (IC(50) (macrophages)/IC(50) (Trypanosoma cruzi)) of >25 for 7a and >20 for 8a, with IC(50) values in macrophages >400 microM.

Study of 5-nitroindazoles' anti-Trypanosoma cruzi mode of action: electrochemical behaviour and ESR spectroscopic studies.

New indazole derivatives have been developed to know about structural requirements for adequate anti-Trypanosoma cruzi activity. In relation to position 1 of indazole ring, we have observed that a butylaminopentyl substituent (14) affords good activity, but N-oxidation of omega-tertiary amino moiety yields completely inactive compounds (17, 18); the substituent at position 3 of indazole ring affects drastically the in vitro activity, 3-OH derivative 13 being completely inactive. On the other hand, since compound 22, denitro-analogue of active compound 4, does not show activity, the 5-nitro substituent of indazole ring seems to be essential. Intramolecular cyclization of side chain at position 1 also affords inactive compounds (19, 20). The electrochemical studies showed that the trypanocidal 5-nitroindazole derivatives yielded nitro-anion radical via one-electron process at physiological pH. This electrochemical behaviour occurs in the parasite according to ESR experiment with the T. cruzi microsomal fraction showing that 5-nitroindazole derivatives suffer bio-reduction without reactive oxygen species generation.

Furoxan-, alkylnitrate-derivatives and related compounds as anti-trypanosomatid agents: mechanism of action studies.

A series of over a hundred furoxans, alkylnitrates and related compounds were studied as growth inhibitors of the two major kinetoplastids of Latin America, Trypanosoma cruziand Leishmania spp., in in vitro assays. The most active compounds showed 50% inhibitory doses of the same order of that of Nifurtimox and Miltefosine, reference drugs used to treat Chagas Disease and Leishmaniasis respectively. Among the studied compounds derivative 4, presenting excellent inhibitory activity against the tryposmastigote and amastigote forms of T. cruzi, has emerged as a lead compound. Mechanism of action seems to involve mitochondrial dehydrogenases as a distinct effect with respect to Nifurtimox. Excreted metabolites, studied by NMR, showed a significant decrease in succinate, confirming the observed effect on the mitochrondrial dehydrogenases.

Potent in vitro anti-Trypanosoma cruzi activity of pyridine-2-thiol N-oxide metal complexes having an inhibitory effect on parasite-specific fumarate reductase.

In the search for new therapeutic tools against Chagas disease (American trypanosomiasis) palladium and platinum complexes of the bioactive ligand pyridine-2-thiol N-oxide were exhaustively characterized and evaluated in vitro. Both complexes showed high in vitro growth inhibition activity (IC(50) values in the nanomolar range) against Trypanosoma cruzi, the causative agent of the disease. They were 39-115 times more active than the antitrypanosomal drug Nifurtimox. The palladium complex showed an approximately threefold enhancement of the activity compared with the parent compound. In addition, owing to their low unspecific cytotoxicity on mammalian cells, the complexes showed a highly selective antiparasite activity. To get an insight into the mechanism of action of these compounds, DNA, redox metabolism (intraparasite free-radical production) and two parasite-specific enzymes absent in the host, namely, trypanothione reductase and NADH-fumarate reductase, were evaluated as potential parasite targets. Additionally, the effect of metal coordination on the free radical scavenger capacity previously reported for the free ligand was studied. All the data strongly suggest that trypanocidal action of the complexes could mainly rely on the inhibition of the parasite-specific enzyme NADH-fumarate reductase.

Platinum(II) metal complexes as potential anti-Trypanosoma cruzi agents.

In the search for new therapeutic tools against Chagas' disease (American Trypanosomiasis) two series of new platinum(II) complexes with bioactive 5-nitrofuryl containing thiosemicarbazones as ligands were synthesized, characterized and in vitro evaluated. Most of the complexes showed IC50 values in the muM range against two different strains of Trypanosoma cruzi, causative agent of the disease, being as active as the anti-trypanosomal drug Nifurtimox. In particular, the coordination of L3 (4-ethyl-1-(5-nitrofurfurylidene)thiosemicarbazide) to Pt(II) forming [Pt(L3)2] lead to almost a five-fold activity increase in respect to the free ligand. Trying to get an insight into the trypanocidal mechanism of action of these compounds, DNA and redox metabolism (intra-parasite free radical production) were evaluated as potential parasite targets. Results suggest that the complexes could inhibit parasite growth through a dual mechanism of action involving production of toxic free radicals by bioreduction and DNA interaction.

4-nitroacetophenone-derived thiosemicarbazones and their copper(II) complexes with significant in vitro anti-trypanosomal activity.

N(4)-methyl-4-nitroacetophenone thiosemicarbazone (H4NO(2)Ac4M, 1), N(4),N(4)-dimethyl-4-nitroacetophenone thiosemicarbazone (H4NO(2)Ac4DM, 2) and N(4)-piperidyl-4-nitroacetophenone thiosemicarbazone (H4NO(2)Ac4Pip, 3) and their copper(II) complexes [Cu(4NO(2)Ac4M)(2)] (4), [Cu(4NO(2)Ac4DM)(2)] (5) and [Cu(4NO(2)Ac4Pip)(2)] (6) were tested for their in vitro ability to inhibit the growth of Trypanosoma cruzi epimastigote forms. H4NO(2)Ac4DM (2), [Cu(4NO(2)Ac4M)(2)] (4) and [Cu(4NO(2)Ac4DM)(2)] (5) proved to be as active as the clinical reference drugs nifurtimox and benznidazol. Taking into consideration the serious side effects and the poor efficacy of the reference drugs, as well as the appearance of resistance during treatment, the studied compounds could constitute a new class of anti-trypanosomal drug candidates.

Pyrimido[1,2-a]quinoxaline 6-oxide and phenazine 5,10-dioxide derivatives and related compounds as growth inhibitors of Trypanosoma cruzi.

Two different families of N-oxide containing heterocycles were evaluated as in vitro growth inhibitors of T. cruzi. Both families of heterocycles were selected from our in-house library of compounds as analogues of active anti-T. cruzi N-oxide containing heterocycles. Derivatives from pyrimido[1,2-a]quinoxaline 6-oxide family were poorly active at the assayed doses. However, phenazine 5,10-dioxide derivatives displayed good to excellent anti-T. cruzi activities. The anti-T. cruzi activity of phenazine derivatives was related to substituent' electronic descriptors, sigma(p)(-). Derivatives 19, 20 and 23 were the most cytotoxic compounds against the protozoan and became excellent hit for further structural modifications.

In vivo anti-Chagas vinylthio-, vinylsulfinyl-, and vinylsulfonylbenzofuroxan derivatives.

New benzofuroxans were developed and studied as antiproliferative Trypanosoma cruzi agents. Compounds displayed remarkable in vitro activities against different strains, Tulahuen 2, CL Brener and Y. Its unspecific cytotoxicity was evaluated using human macrophages being not toxic at a concentration at least 8 times, and until 250 times, that of its T. cruzi IC50. Some biochemical pathways were studied, namely parasite respiration, cysteinyl active site enzymes and reaction with glutathione, as target for the mechanism of action. Not only T. cruzi respiration but also Cruzipain or trypanothione reductase were not affected, however the most active derivatives, the vinylsulfinyl- and vinylsulfonyl-containing benzofuroxans, react with glutathione in a redox pathway. Furthermore, the compounds showed good in vivo activities when they were studied in an acute murine model of Chagas' disease. The compounds were able to reduce the parasite loads of animals with fully established T. cruzi infections.