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Biomedical subjects

Jill Davies

Publications and source records attributed to Jill Davies.

11 recordsLinked to original sources
PubMed2007

Changes in bowel function: pregnancy and the puerperium.

Pregnancy is a time when women are susceptible to bowel habit perturbations. The purpose of this study was to provide new baseline data for a range of bowel habit parameters. Prospective 7-day bowel habit diaries were completed during each of the three trimesters of pregnancy and after birth. Sensations of incomplete evacuation and time spent defecating were significantly increased during all three trimesters of pregnancy compared with after birth (P < 0.05). Symptoms of urgency were higher in nonlactating mothers (41% of occasions) compared with lactating women (17% pf occasions) (P=0.07). This study has confirmed the importance of investigating a range of bowel habit parameters during and after pregnancy-investigation of constipation per se may obscure changes in individual bowel habit parameters.

Adult↗
PubMed2006

Synthesis of 1,2,4-trioxepanes via application of thiol-olefin co-oxygenation methodology.

Thiol-olefin co-oxygenation (TOCO) of substituted allylic alcohols generates beta-hydroxy peroxides that can be condensed in situ with various ketones, to afford a series of functionalised 1,2,4-trioxepanes in good yields. Manipulation of the phenylsulfenyl group in 8a-8c allows for convenient modification to the spiro-trioxepane substituents. Surprisingly, and in contrast to the 1,2,4-trioxanes examined, 1,2,4-trioxepanes are inactive as antimalarials up to 1000 nM and we rationalize this observation based on the inherent stability of these systems to ferrous mediated degradation. FMO calculations clearly show that the sigma* orbital of the peroxide moiety of 1,2,4-trioxane derivatives 4a and 14b are lower in energy and more accessible to attack by Fe(II) compared to their trioxepane analogues 8b and 9b.

Alkenes↗
PubMed2006

Diels-Alder/thiol-olefin co-oxygenation approach to antimalarials incorporating the 2,3-dioxabicyclo[3.3.1]nonane pharmacophore.

A Diels-Alder/thiol-olefin co-oxygenation approach to the synthesis of novel bicyclic endoperoxides 17a-22b is reported. Some of these endoperoxides (e.g., 17b, 19b, 22a and 22b) have potent nanomolar in vitro antimalarial activity equivalent to that of the synthetic antimalarial agent arteflene. Iron(II)-mediated degradation of sulfone-endoperoxide 19b and spin-trapping with TEMPO provide a spin-trapped adduct 25 indicative of the formation of a secondary carbon centered radical species 24. Reactive C-radical intermediates of this type may be involved in the expression of the antimalarial effect of these bicyclic endoperoxides.

Alkanes↗
PubMed2006

Diet, physical inactivity and the prevalence of constipation throughout and after pregnancy.

Few studies appear to have investigated the prevalence of constipation for all three trimesters of the gestative period, or indeed after birth. Using a prospective 4- to 7-day weighed food diary, International Physical Activity Questionnaire and 7-day bowel habit diary, dietary factors, physical activity levels and bowel habit parameters were assessed and examined concurrently at weeks 13, 25, 35 of pregnancy and 6 weeks post-partum. Ninety-four primiparous pregnant women were initially recruited, and 72, 59, 62 and 55 completed the first, second, third trimester and post-partum study stages, respectively. Key dietary factors and physical activity levels were compared between the constipated and non-constipated groups from each of the three trimesters and after parturition. Compared with non-constipated mothers-to-be, constipated participants consumed statistically significantly less water in the first trimester (P = 0.04), more food in the second trimester (P = 0.04), and less iron (P = 0.02) and food (P = 0.04) in the third trimester and after birth, respectively. No statistically significant differences were identified between light, moderate and vigorous physical activity levels when groups were compared. This study demonstrates that dietary factors may play a role in terms of preventing, or alleviating, bowel habit perturbations both throughout and after pregnancy. Further research is required to investigate the interrelationship between physical activity and constipation during and after pregnancy.

Adult↗
PubMed2005

Enantiomeric 1,2,4-trioxanes display equivalent in vitro antimalarial activity versus Plasmodium falciparum malaria parasites: implications for the molecular mechanism of action of the artemisinins.

The aim of this study was to synthesise pure enantiomers of potent antimalarial 1,2,4-trioxanes, which are related to the natural antimalarial artemisinin, and then to assay each against a panel of Plasmodium falciparum strains. The working hypothesis was that if the artemisinin derivatives interact with a specific protein-target site, then there should be stereoselective differences in their activity. In five different P. falciparum isolates, however, the trioxane enantiomers (+)-7 a, (-)-7 a and (+)-7 b, (-)-7 b, showed the same level of in vitro antiparasitic activity.

Animals↗
PubMed2005

Randomised-controlled trial of a fibre supplement on the symptoms of irritable bowel syndrome.

The aim of this study was to assess the effect of coarse wheat bran on specific bowel function parameters and symptoms in patients with irritable bowel syndrome (IBS). A longitudinal, prospective, randomised, placebo-controlled trial was undertaken. The duration of treatment was eight to 12 weeks and this consisted of 10-20 g/day of coarse wheat bran or a low fibre placebo taken in addition to the normal diet. Twenty-eight outpatients fulfilling the Rome criteria for constipation-predominant IBS were recruited to the trial (14 in the treatment group; 14 in the placebo group). Twelve people completed the trial in the treatment group and ten in the placebo group. The main outcome measures included changes in symptoms recorded in a diary, changes in objective measurements of bowel function and subjective overall feelings of improvement. The bran group significantly increased their non-starch polysaccharide (NSP) intake over that of the placebo group (p < 0.05). Mean stool wet weight increased significantly more in the bran group than in the placebo group (p < 0.05), but other bowel function measurements and all recorded symptoms were not different. Many patients reported changes in bowel habit that were not reflected in the objective measurements. The addition of coarse wheat bran to the diet increased NSP ingestion and stool wet weight in this group of IBS patients, but no evidence was obtained that such treatment was of benefit to these patients, other than a placebo effect on symptoms.

Abdominal Pain↗
PubMed2004

Application of thiol-olefin co-oxygenation methodology to a new synthesis of the 1,2,4-trioxane pharmacophore.

[reaction: see text] Thiol-olefin co-oxygenation (TOCO) of substituted allylic alcohols generates alpha-hydroxyperoxides that can be condensed in situ with various ketones to afford a series of functionalized 1,2,4-trioxanes in good yields. Manipulation of the phenylsulfenyl group in 4a allows for convenient modification to the spiro-trioxane substituents, and we describe, for the first time, the preparation of a new class of antimalarial prodrug.

Alkenes↗
PubMed2004

Antimalarial and antitumor evaluation of novel C-10 non-acetal dimers of 10beta-(2-hydroxyethyl)deoxoartemisinin.

Four series of C-10 non-acetal dimers were prepared from key trioxane alcohol 10beta-(2-hydroxyethyl)deoxoartemisinin (9b). All of the dimers prepared displayed potent low nanomolar antimalarial activity versus the K1 and HB3 strains of Plasmodium falciparum. The most potent compound assayed was phosphate dimer 14a, which was greater than 50 times more potent than the parent drug artemisinin and about 15 times more potent than the clinically used acetal artemether. In contrast to their potent activity versus malaria parasites, virtually all of the dimers expressed poor anticancer activity apart from the trioxane phosphate ester dimers 14a and 14b, which expressed nanomolar growth inhibitory (GI50) values versus a range of cancer cell lines in the NCI 60 human cell line screen. Further detailed studies on these dimers in vitro in HL60 cells demonstrate that both phosphate ester dimers (14a and 14b) are more potent than the anticancer agent doxorubicin. Interestingly, phosphate ester monomers 9c and 9d, antimalarially active in the low nanomolar region versus P. falciparum, are inactive as anticancer agents even at concentrations in the millimolar region. This observation emphasizes the importance of two trioxane units for high antiproliferative activity, and we propose that the nature of the linker in dimers of this type plays a crucial role in imparting potent anticancer activity.

Acetals↗
PubMed2004

Single versus weekly courses of antenatal corticosteroids in preterm premature rupture of membranes.

OBJECTIVE: This study was performed to evaluate the efficacy of weekly courses of antenatal corticosteroids compared with a single course in women with preterm premature rupture of membranes (PROM). METHODS: A planned secondary analysis of women with preterm PROM who participated in a multicenter, randomized trial of weekly courses of antenatal corticosteroids versus single-course therapy was performed. After their first course of standard antenatal steroid therapy, administered between 24 to 32-6/7 weeks of gestation, consenting women were randomly assigned to receive betamethasone versus placebo injections weekly until 34-0/7 weeks of gestation. Maternal and neonatal morbidities were compared between the 2 groups. RESULTS: Of the 161 women with preterm PROM, 81 women were assigned to receive weekly courses of steroids and 80 to the single-course group. There were no significant differences in composite morbidity between the groups (27 [34.2%] of 81 patients versus 33 [41.8%] of 80 patients, P =.41). Chorioamnionitis was higher in patients who received weekly courses of antenatal steroids (39 [49.4%] of 81 patients versus 25 [31.7%] of 80 patients, P =.04). CONCLUSION: Weekly courses of antenatal steroids in women with preterm PROM did not improve neonatal outcomes beyond that achieved with single-course therapy and was associated with an increased risk of chorioamnionitis. Antenatal steroid therapy should not be routinely repeated in patients with preterm PROM. LEVEL OF EVIDENCE: I

Adult↗
PubMed2002

Mechanism-based design of parasite-targeted artemisinin derivatives: synthesis and antimalarial activity of new diamine containing analogues.

The potent antimalarial activity of chloroquine against chloroquine-sensitive strains can be attributed, in part, to its high accumulation in the acidic environment of the heme-rich parasite food vacuole. A key component of this intraparasitic chloroquine accumulation mechanism is a weak base "ion-trapping" effect whereupon the basic drug is concentrated in the acidic food vacuole in its membrane-impermeable diprotonated form. By the incorporation of amino functionality into target artemisinin analogues, we hoped to prepare a new series of analogues that, by virtue of increased accumulation into the ferrous-rich vacuole, would display enhanced antimalarial potency. The initial part of the project focused on the preparation of piperazine-linked analogues (series 1 (7-16)). Antimalarial evaluation of these derivatives demonstrated potent activity versus both chloroquine-sensitive and chloroquine-resistant parasites. On the basis of these observations, we then set about preparing a series of C-10 carba-linked amino derivatives. Optimization of the key synthetic step using a newly developed coupling protocol provided a key intermediate, allyldeoxoartemisinin (17) in 90% yield. Further elaboration, in three steps, provided nine target C-10 carba analogues (series 2 (21-29)) in good overall yields. Antimalarial assessment demonstrated that these compounds were 4-fold more potent than artemisinin and about twice as active as artemether in vitro versus chloroquine-resistant parasites. On the basis of the products obtained from biomimetic Fe(II) degradation of the C-10 carba analogue (23), we propose that these analogues may have a mode of action subtly different from that of the parent drug artemisinin (series 1 (7-16)) and other C-10 ether derivatives such as artemether. Preliminary in vivo testing by the WHO demonstrated that four of these compounds are active orally at doses of less than 10 mg/kg. Since these analogues are available as water-soluble salts and cannot form dihydroartemisinin by P450-catalyzed oxidation, they represent useful leads that might prove to be superior to the currently used derivatives, artemether and artesunate.

Animals↗