Biphenyl Pyridazinone Derivatives as Inhaled PDE4 Inhibitors: Structural Biology and Structure-Activity Relationships.

Cyclic nucleotide cAMP is a ubiquitous secondary messenger involved in a plethora of cellular responses to biological agents involving activation of adenylyl cyclase. Its intracellular levels are tightly controlled by a family of cyclic nucleotide degrading enzymes, the PDEs. In recent years, cyclic nucleotide phosphodiesterase type 4 (PDE4) has aroused scientific attention as a suitable target for anti-inflammatory therapy in respiratory diseases, particularly in the management of asthma and COPD. Here we describe our efforts to discover novel, highly potent inhaled inhibitors of PDE4. Through structure based design, with the inclusion of a variety of functional groups and physicochemical profiles in order to occupy the solvent-filled pocket of the PDE4 enzyme, we modified the structure of our oral PDE4 inhibitors to reach compounds down to picomolar enzymatic potencies while at the same time tackling successfully an uncovered selectivity issue with the adenosine receptors. In vitro potencies were demonstrated in a rat lung neutrophilia model by administration of a suspension with a Penn-Century MicroSprayer Aerosolizer.

Prevención de la hemorragia posparto en una gestante afectada de síndrome de Hermansky-Pudlack / Prevention of postpartum hemorrhage in a patient with Hermansky-Pudlak syndrome

El síndrome de Hermansky-Pudlak es una enfermedad multisistémica de herencia autosómica recesiva. Se caracteriza principalmente por albinismo óculo-cutáneo y alteración de la agregación plaquetaria. Se presentan el seguimiento y la finalización de la gestación de una paciente de 30 años afectada de dicho síndrome. Se describen las medidas profilácticas realizadas durante el trabajo de parto con el objetivo de evitar complicaciones hemorrágicas debidas a la disfunción plaquetaria. La finalización de la gestación tuvo lugar a las 38,2 semanas mediante un parto eutócico sin anestesia peridural y con buena evolución materno-fetal(AU)

Hermansky-Pudlak syndrome is a multisystemic disease with autosomal recessive inheritance, mainly characterized by oculo-cutaneous albinism and impaired platelet aggregation. We describe the follow–up and end of pregnancy in a 30-year-old woman with this syndrome, as well as the measures carried out during labor to avoid bleeding complications due to platelet dysfunction. The pregnancy ended at 38.2 weeks through vaginal delivery, without epidural anesthesia and good maternal and fetal outcome(AU)

Synthesis and biological activity of pyrido[3',2':4,5]furo[3,2-d]pyrimidine derivatives as novel and potent phosphodiesterase type 4 inhibitors.

A series of pyrido[3',2':4,5]furo[3,2-d]pyrimidines (PFP) were synthesized and tested for phosphodiesterase type 4 (PDE4) inhibitory activity, with the potential to treat asthma and chronic obstructive pulmonary disease (COPD). Structure-activity relationships within this series, leading to an increase of potency on the enzyme, is presented. Both gem-dimethylcyclohexyl moieties fused to the pyridine ring and the substitution at the 5 position of the PFP scaffold, proved to be key elements in order to get a high affinity in the enzyme.

Synthesis and biological activity of pyrido[3',2':4,5]thieno[3,2-d]pyrimidines as phosphodiesterase type 4 inhibitors.

A series of pyrido[3',2':4,5]thieno[3,2-d]pyrimidines (PTP) has been synthesized and tested as phosphodiesterase IV inhibitors (PDE4), a target for the treatment of asthma and chronic obstructive pulmonary disease (COPD). Structure-activity relationships within this series, leading to an increase of potency on the enzyme, are presented. The gem-dimethylcycloalkyl moiety fused to the pyridine ring proved to be a key element of the scaffold in order to get a higher affinity in the enzyme.

Hepatic hydrothorax in the absence of ascites: respiratory failure in a cirrhotic patient.

The frequency of hepatic hydrothorax in cirrhotic patients is reported to be approximately 5%. The pleural effusion is predominantly right-sided (85% of cases) but may be bilateral. Although most often accompanied by significant ascites, it can occur in its absence. We report a case of a right-sided acute hepatic hydrothorax as a result of residual motor blockade during anesthesia recovery and without previous evidence of clinical ascites. This complication should be considered by the anesthesiologist in every cirrhotic patient, with or without clinical evidence of ascites.