Paracetamol versus ibuprofen for early postpartum pain control: a randomized controlled trial.

Introduction: To evaluate the effectiveness of paracetamol and ibuprofen as non-opioid treatments for postpartum pain control after vaginal delivery.

Materials And Methods: This randomized controlled study at a university-affiliated medical center involved parturient who received blindly oral tablets of either 1000 mg of paracetamol or 400 mg of ibuprofen, post-vaginal birth. Pain levels were assessed using a numeric rating scale (NRS) at four time points: before treatment, and 1, 4, and 6 h post-treatment (T0, T1, T4, and T6, respectively).

Average maternal hemoglobin decline after first elective cesarean section compared to higher order cesarean sections.

Introduction: Lower uterine segment scarring after cesarean section can decrease intraoperative bleeding during subsequent surgery. We examined whether first elective cesarean section is associated with greater average blood loss compared to repeated surgery.

Methods: Decrease in maternal hemoglobin and hematocrit after surgery was retrospectively compared between three study groups, women in their first, second and third or more cesarean section.

Structure-guided design of a series of MCL-1 inhibitors with high affinity and selectivity.

Myeloid cell leukemia 1 (MCL-1) is a BCL-2 family protein that has been implicated in the progression and survival of multiple tumor types. Herein we report a series of MCL-1 inhibitors that emanated from a high throughput screening (HTS) hit and progressed via iterative cycles of structure-guided design. Advanced compounds from this series exhibited subnanomolar affinity for MCL-1 and excellent selectivity over other BCL-2 family proteins as well as multiple kinases and GPCRs.

Promoter activity dynamics in the lag phase of Escherichia coli.

Background: Lag phase is a period of time with no growth that occurs when stationary phase bacteria are transferred to a fresh medium. Bacteria in lag phase seem inert: their biomass does not increase. The low number of cells and low metabolic activity make it difficult to study this phase.

Negative auto-regulation increases the input dynamic-range of the arabinose system of Escherichia coli.

Background: Gene regulation networks are made of recurring regulatory patterns, called network motifs. One of the most common network motifs is negative auto-regulation, in which a transcription factor represses its own production. Negative auto-regulation has several potential functions: it can shorten the response time (time to reach halfway to steady-state), stabilize expression against noise, and linearize the gene's input-output response curve.

Robust control of nitrogen assimilation by a bifunctional enzyme in E. coli.

Bacteria regulate the assimilation of multiple nutrients to enable growth. How is balanced utilization achieved, despite fluctuations in the concentrations of the enzymes that make up the regulatory circuitry? Here we address this question by studying the nitrogen system of E. coli.

N-aryl-benzimidazolones as novel small molecule HSP90 inhibitors.

We describe the development of a novel series of N-aryl-benzimidazolone HSP90 inhibitors (9) targeting the N-terminal ATP-ase site. SAR development was influenced by structure-based design based around X-ray structures of ligand bound HSP90 complexes. Lead compounds exhibited high binding affinities, ATP-ase inhibition and cellular client protein degradation.

Comparison of the oxidative folding of lysozyme at a high protein concentration using aromatic thiols versus glutathione.

The production of proteins using recombinant DNA technology often requires the use of in vitro protein folding. In order to facilitate in vitro protein folding, a redox buffer is added to the protein folding mixture. The redox buffer is composed of a small molecule disulfide and/or a small molecule thiol.

Pyrrolidine-constrained phenethylamines: The design of potent, selective, and pharmacologically efficacious dipeptidyl peptidase IV (DPP4) inhibitors from a lead-like screening hit.

A novel series of pyrrolidine-constrained phenethylamines were developed as dipeptidyl peptidase IV (DPP4) inhibitors for the treatment of type 2 diabetes. The cyclohexene ring of lead-like screening hit 5 was replaced with a pyrrolidine to enable parallel chemistry, and protein co-crystal structural data guided the optimization of N-substituents. Employing this strategy, a >400x improvement in potency over the initial hit was realized in rapid fashion.

Discovery of ((4R,5S)-5-amino-4-(2,4,5- trifluorophenyl)cyclohex-1-enyl)-(3- (trifluoromethyl)-5,6-dihydro- [1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone (ABT-341), a highly potent, selective, orally efficacious, and safe dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes.

Dipeptidyl peptidase IV (DPP4) deactivates glucose-regulating hormones such as GLP-1 and GIP, thus, DPP4 inhibition has become a useful therapy for type 2 diabetes. Optimization of the high-throughput screening lead 6 led to the discovery of 25 (ABT-341), a highly potent, selective, and orally bioavailable DPP4 inhibitor. When dosed orally, 25 dose-dependently reduced glucose excursion in ZDF rats.

Discovery of 2-[4-{{2-(2S,5R)-2-cyano-5-ethynyl-1-pyrrolidinyl]-2-oxoethyl]amino]- 4-methyl-1-piperidinyl]-4-pyridinecarboxylic acid (ABT-279): a very potent, selective, effective, and well-tolerated inhibitor of dipeptidyl peptidase-IV, useful for the treatment of diabetes.

Dipeptidyl peptidase-IV (DPP-IV) inhibitors are poised to be the next major drug class for the treatment of type 2 diabetes. Structure-activity studies of substitutions at the C5 position of the 2-cyanopyrrolidide warhead led to the discovery of potent inhibitors of DPP-IV that lack activity against DPP8 and DPP9. Further modification led to an extremely potent (Ki(DPP)(-)(IV) = 1.

Synthesis and structural activity relationship of 11beta-HSD1 inhibitors with novel adamantane replacements.

A series of structurally novel and metabolically stable bridged bicyclic carbocycle and heterocycle adamantane replacements have been synthesized and biologically evaluated. Several of these compounds exhibit excellent human and mouse 11beta-HSD1 potency and 11beta-HSD2 selectivity.

Crystal structures of DPP-IV (CD26) from rat kidney exhibit flexible accommodation of peptidase-selective inhibitors.

Dipeptidyl peptidase IV (DPP-IV) belongs to a family of serine peptidases, and due to its indirect regulatory role in plasma glucose modulation, DPP-IV has become an attractive pharmaceutical target for diabetes therapy. DPP-IV inactivates the glucagon-like peptide (GLP-1) and several other naturally produced bioactive peptides that contain preferentially a proline or alanine residue in the second amino acid sequence position by cleaving the N-terminal dipeptide. To elucidate the details of the active site for structure-based drug design, we crystallized a natural source preparation of DPP-IV isolated from rat kidney and determined its three-dimensional structure using X-ray diffraction techniques.

Discovery, structure-activity relationship, and pharmacological evaluation of (5-substituted-pyrrolidinyl-2-carbonyl)-2-cyanopyrrolidines as potent dipeptidyl peptidase IV inhibitors.

A series of (5-substituted pyrrolidinyl-2-carbonyl)-2-cyanopyrrolidine (C5-Pro-Pro) analogues was discovered as dipeptidyl peptidase IV (DPPIV) inhibitors as a potential treatment of diabetes and obesity. X-ray crystallography data show that these inhibitors bind to the catalytic site of DPPIV with the cyano group forming a covalent bond with the serine residue of DPPIV. The C5-substituents make various interactions with the enzyme and affect potency, chemical stability, selectivity, and PK properties of the inhibitors.

Potential drug targets and progress towards pharmacologic inhibition of hepatic glucose production.

A number of therapeutic targets are currently under investigation for inhibition of hepatic glucose production with small molecules. Antagonists of the glucagon receptor, glycogen phosphorylase, 11-beta-hydroxysteroid dehydrogenase-1 and fructose 1,6-bisphosphatase are, or have been, under evaluation in human clinical trials. Other strategies, including glucocorticoid receptor antagonists and carnitine palmitoyltransferase inhibitors, are supported by proof of principle studies in man as well as rodents.

Prospects for pharmacologic inhibition of hepatic glucose production.

Type 2 diabetes is a widespread disease where effective pharmacologic therapies can have a profound beneficial public health impact. Increased hepatic glucose production (HGP) is observed in diabetics and its moderation by currently available agents provides therapeutic benefits. This review describes the challenges associated with the discovery of small molecules that inhibit HGP.

3,5-Bis(trifluoromethyl)pyrazoles: a novel class of NFAT transcription factor regulator.

A series of bis(trifluoromethyl)pyrazoles (BTPs) has been found to be a novel inhibitor of cytokine production. Identified initially as inhibitors of IL-2 synthesis, the BTPs have been optimized in this regard and even inhibit IL-2 production with a 10-fold enhancement over cyclosporine in an ex vivo assay. Additionally, the BTPs show inhibition of IL-4, IL-5, IL-8, and eotaxin production.

Inhibition of p56(lck) tyrosine kinase by isothiazolones.

Lck encodes a 56-kDa protein-tyrosine kinase, predominantly expressed in T lymphocytes, crucial for initiating T cell antigen receptor (TCR) signal transduction pathways, culminating in T cell cytokine gene expression and effector functions. As a consequence of a high-throughput screen for selective, novel inhibitors of p56(lck), an isothiazolone compound was identified, methyl-3-(N-isothiazolone)-2-thiophenecarboxylate(A-125800), which inhibits p56(lck) kinase activity with IC50 = 1-7 microM. Under similar assay conditions, the isothiazolone compound was equipotent in blocking the ZAP-70 tyrosine kinase activity but was 50 to 100 times less potent against the catalytic activities of p38 MAP kinase and c-Jun N-terminal kinase 2alpha.

Enhancing laboratory detection of disease. Part 3: Detecting a hantavirus disease event: a case study.

A purposive syndromic classification diagnostic system, with known means to ends, has been developed that extracts bits of structural information from endogenous laboratory data. An edifice of structural information for organization, regulation, and decision-making was built for determining future pathophysiological events by asking the fewest questions to define the next event uniquely. The structural information is based on laboratory ordering patterns of physicians for patient populations they serve.

Enhancing laboratory detection of disease. Part I: The concept of syndromic classification.

Syndromic classifications differ from other taxonomies because they build on an ideal theoretical information standard to amplify information. This ideal standard, a truth table with requisite variety, h, equal to or greater than the generated symbols or system it seeks to control, preserves all of the information about the disease state available in the database. Such a system, interestingly enough, theoretically has no beta errors (diagnostic misses) because all possible alternative disease hypotheses are created by the proper-sized truth table that controls the diagnostic system.

Synthesis of (+)-dynemicin A and analogs of wide structural variability: establishment of the absolute configuration of natural dynemicin A.

Background: Dynemicin A is an exceedingly potent antitumor antibiotic derived from microbial fermentation that cleaves double-stranded B-form DNA in vitro in the presence of activating factors such as NADPH or glutathione. Because of the structural complexity, high reactivity, and scarcity of natural dynemicin A, it has not been feasible to modify the structure to any significant extent. Previous studies have not determined the absolute configuration of the natural product.

Hantavirus pulmonary syndrome in the United States: a pathological description of a disease caused by a new agent.

An outbreak of an acute respiratory disease in the southwestern United States has led to the recognition of a new hantaviral illness. This report describes a unique spectrum of antemortem and postmortem pathological findings seen in a case series of nine surviving patients and 13 who died. Clinical, laboratory, and autopsy findings were derived from a consecutive series of individuals confirmed to have hantavirus pulmonary syndrome.

Outbreak of Hantavirus pulmonary syndrome in the southwestern United States. Response of pathologists and other laboratorians.

During late spring and early summer of 1993, national and international media called worldwide attention to a cluster of deaths in the southwestern United States. These patients succumbed to a rapidly progressive severe respiratory distress syndrome. After notification of state and national health agencies in mid-May, a major effort was launched to determine the cause of this often fatal respiratory distress syndrome, to advise the public on safety measures, and to determine the method of spread of this "mystery illness.