By Z. Alima. Agnes Scott College.

An ascending infection from the lower genital tract is thought to be the source of most intrauterine infections [179] rosuvastatin 20 mg. Once bacteria are in contact with placental tissues rosuvastatin 20 mg line, a pro-inflammatory response can be initiated which leads to preterm labour. The inflammatory mediators implicated in preterm birth include interleukin-1b, interleukin-6, interleukin-8 and tumour necrosis factor-alpha [180, 181]. Other important inflammatory mediators of infection-induced preterm labor include prostaglandins and matrix metalloproteinases, which enhance myometrial contractility and weaken the collagen structure of the membranes, respectively [182]. Human studies in pregnant women have not adequately clarified a temporal relationship between these inflammatory mediators and the onset of preterm birth. This would allow the study of the pathophysiology of preterm birth and lead to opportunities for preventative and therapeutic discovery [83]. Anti-infective treatment as intervention to prevent preterm birth During the last 20 years, several trials and observational studies were conducted to evaluate the efficacy of the interventions based on the use of anti-infective drugs to prevent preterm birth. The authors compared the efficacy of adjunctive therapy with intravenous ampicillin plus oral erythromycin in 103 women requiring parenteral tocolysis and with intact membranes. Compared with the placebo group, the adjunctive antibiotic group had a similar frequency of preterm birth (38% versus 44%), time to delivery (34 versus 34 days), and episodes of recurrent labor requiring parenteral tocolysis (0. Use of erythromycin and ampicillin was further evaluated in three different trials conducted by Eschenbach et al. Furthermore, there were no significant differences between erythromycin and placebo-treated women in infant birth weight, frequency of premature rupture of membranes, or neonatal outcome. No differences were noted between placebo (n= 43) and study patients (n= 43) in gestational age at delivery, term deliveries, or neonatal outcome. The third trial enrolled 277 women with singleton pregnancies and preterm labor with intact membranes (24 to 34 weeks), and randomly allocated them to receive either antibiotics or placebo (n= 133 for antibiotics group vs n= 144 for placebo group). No significant difference 46 between the treatment group and the placebo group was found in maternal outcomes, including duration of randomization-to-delivery interval, frequency of preterm delivery (< 37 weeks), frequency of preterm premature rupture of membranes, clinical chorioamnionitis, endometritis, and number of subsequent admissions for preterm labor. Intravenous treatment with another beta-lactam drug, mezlocillin in association with and erythromycin was compared to tocolytic treatment in women in preterm labor [187]. Women in the antibiotic group had a significantly lower incidence of postpartum infections compared with women in the placebo group. In a prospective, randomized, double-blinded, placebo-controlled trial, Gordon et al. The groups consisted of women receiving either 2 g of ceftizoxime (n= 58) or a placebo (n= 59) every 8 hours. Thirty-nine women with preterm labor received antimicrobial therapy and 39 received placebos. The effect of amoxicillin was further investigated in another trial conducted by Oyarzún et al. The authors randomly allocated 196 women with singleton pregnancies and preterm labor with intact membranes (22-36 weeks) to receive antibiotics or placebo, plus adjunctive parenteral tocolysis. In those receiving ampicillin and metronidazole the pregnancy was significantly 48 prolonged (median 15 days versus 2. Compared to the placebo group, patients in the metronidazole group had significantly fewer hospital admissions for preterm labor (27% versus 78%), preterm births (18% versus 39%) and premature rupture of membranes (5% versus 33%). The potential benefit of metronidazole showed by these studies leaded to the conduction of several trials that evaluated the efficacy of this drug during gestation. Twenty-six percent of women assigned to metronidazole and erythromycin delivered prematurely, as compared with 36% assigned to placebo (p= 0. When compared to placebo, treatment was associated with a significant prolongation of pregnancy (admission to delivery 47. Intention-to-treat analysis showed no difference between metronidazole and placebo groups in overall preterm birth (7. In the subgroup of women with a previous preterm birth, the use of metronidazole was associated with a significant reduction in spontaneous preterm birth (9. Nevertheless, these results suggested that benefit could be obtained with treatment of women with a previous preterm birth. The same team also showed in another trial, that pregnant women diagnosed with asymptomatic trichomoniasis had an 80% increase in the risk of preterm birth after use of metronidazole treatment, when compared to placebo [198]. The authors randomly assigned 617 women with asymptomatic trichomoniasis who were 16 to 23 weeks pregnant to receive two doses of metronidazole (320 women) or placebo (297 women) 48 hours apart. The infection resolved in 92% women in the metronidazole 50 group and in 35% of women in the placebo group. Faillure of metronidazole to prevent preterm birth was also demonstrated by Odendaal et al. In this former trial, 900 pregnant women with at least one previous risk factor for preterm delivery (including mid-trimester loss or previous preterm delivery, uterine abnormality, cervical surgery or cerclage) were screened for fetal fibronectin at 24 and 27 weeks of gestation.

So far purchase 20mg rosuvastatin mastercard, molecular modeling studies have been performed buy 10mg rosuvastatin amex, but highly similar binding sites and the lack of selective ligand data limited their explanatory power (Pallo et al. Concluding remarks Membrane transport proteins are responsible for one of the most important processes in living cells: directed transport across barriers. They comprise about 30% of known proteomes and constitute about 50% of pharmacological targets. Thus, computational methods have been utilized extensively to provide significant new insights into protein structure and function. As shown on basis of recent research examples, in silico methods in many cases can provide additional information to biological experiments, either underpinning pharmacological results or they may even lead to new insight, not being biologically accessible. Structure of P-glycoprotein reveals a molecular basis for poly-specific drug binding. Location of the antidepressant binding site in the serotonin transporter: importance of Ser-438 in recognition of citalopram and tricyclic antidepressants. Elucidation of the structure-activity studies leading to the choice of (R)-1-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3-piperidinecarboxylic acid (tiagabine) as an anticonvulsant drug candidate. Toward the estimation of the absolute quality of individual protein structure models. The development of a simple empirical scoring function to estimate the binding constant for a protein-ligand complex of known three-dimensional structure. Prediction of binding constants of protein ligands: a fast method for the prioritization of hits obtained from de novo design or 3D database search programs. Charmm - a Program for Macromolecular Energy, Minimization, and Dynamics Calculations. Consensus scoring: A method for obtaining improved hit rates from docking databases of three- dimensional structures into proteins. On searching in, sampling of, and dynamically moving through conformational space of biomolecular systems: A review. A Second Generation Force Field for the Simulation of Proteins, Nucleic Acids, and Organic Molecules. An evaluation of automated homology modelling methods at low target template sequence similarity. Limitations and lessons in the use of X- ray structural information in drug design. A single amino acid residue contributes to distinct mechanisms of inhibition of the human multidrug transporter by stereoisomers of the dopamine receptor antagonist flupentixol. The development of a fast empirical scoring function to 398 Medicinal Chemistry and Drug Design estimate the binding affinity of ligands in receptor complexes. Successful virtual screening for a submicromolar antagonist of the neurokinin-1 receptor based on a ligand-supported homology model. A juxtamembrane mutation in the N terminus of the dopamine transporter induces preference for an inward-facing conformation. Computational approaches to identifying and characterizing protein binding sites for ligand design. Stereoisomers of calcium antagonists which differ markedly in their potencies as calcium blockers are equally effective in modulating drug transport by P-glycoprotein. Physics-based scoring of protein-ligand complexes: enrichment of known inhibitors in large-scale virtual screening. Scoring functions and their evaluation methods for protein-ligand docking: recent advances and future directions. An iterative knowledge-based scoring function to predict protein-ligand interactions: I. Probing the stereoselectivity of P-glycoprotein-synthesis, biological activity and ligand docking studies of a set of enantiopure benzopyrano[3,4-b][1,4]oxazines. Molecular recognition of receptor sites using a genetic algorithm with a description of desolvation. Docking and scoring in virtual screening for drug discovery: methods and applications. Exhaustive sampling of docking poses reveals binding hypotheses for propafenone type inhibitors of P-glycoprotein. Diaryloxime and diarylvinyl ether derivatives of nipecotic acid and guvacine as anticonvulsant agents. X-ray structures of LeuT in substrate-free outward- open and apo inward-open states. How different amino acid sequences determine similar protein structures: the structure and evolutionary dynamics of the globins. Simultaneous binding of two different drugs in the binding pocket of the human multidrug resistance P-glycoprotein. Human P-glycoprotein is active when the two halves are clamped together in the closed conformation. The transmembrane domains of the human multidrug resistance P-glycoprotein are sufficient to mediate drug binding and trafficking to the cell surface. Location of the rhodamine-binding site in the human multidrug resistance P-glycoprotein.

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