Biomedical subjects

Emma D Deeks

Publications and source records attributed to Emma D Deeks.

7 recordsLinked to original sources

PubMed2006

Pioglitazone/metformin.

A fixed-dose pioglitazone/metformin tablet is approved in the US and the EU for the treatment of adult patients with type 2 diabetes mellitus who currently have inadequate glycaemic control with metformin monotherapy. In the US, the combination tablet is also approved for the treatment of adult patients with type 2 diabetes who currently have inadequate glycaemic control with pioglitazone monotherapy and for those already receiving a combination of pioglitazone and metformin. Bioequivalence, based on absorption and bioavailability parameters, has been established between the fixed-dose tablets and equivalent doses of pioglitazone and metformin coadministered as separate agents. Combination therapy with pioglitazone plus metformin was significantly more effective at improving both glycaemic and lipid control than metformin plus placebo in patients with type 2 diabetes in a 16-week, well designed trial. Pioglitazone plus metformin demonstrated similar antihyperglycaemic efficacy to that of rosiglitazone plus metformin in a well designed 12-month trial; however, pioglitazone plus metformin was the superior combination in terms of lipid control. In several comparative trials of 1-3.5 years' duration, pioglitazone plus metformin was at least as effective as combination therapy with a sulphonylurea plus metformin in terms of antihyperglycaemic efficacy, but provided superior lipidaemic control with regard to levels of triglyceride and high-density lipoprotein-cholesterol. Pioglitazone plus metformin was generally well tolerated in patients with type 2 diabetes, with adverse events common to metformin monotherapy observed at a similar incidence to that with metformin plus placebo.

Diabetes Mellitus, Type 2↗

PubMed2006

Sunitinib.

Sunitinib and its active metabolite (SU012662) are selective inhibitors of multiple receptor tyrosine kinases associated with tumour growth and angiogenesis. The clinical efficacy of oral sunitinib has been demonstrated in patients with advanced gastrointestinal stromal tumours (GIST). In a phase III, randomised, double-blind, placebo-controlled, multicentre trial in patients with metastatic and/or unresectable GIST following unsuccessful imatinib therapy, the median time to tumour progression and median progression-free survival time were > or =4-fold longer in patients receiving sunitinib 50 mg/day than in those receiving placebo, in 6-week cycles consisting of 4 weeks of treatment followed by a 2-week rest period. Sunitinib also exhibited antitumour activity in patients with advanced renal cell carcinoma (RCC) following unsuccessful cytokine therapy. In two multicentre, single-arm, phase II clinical trials in patients with cytokine-refractory metastatic RCC, partial responses were reported in 40% and 43% of patients receiving sunitinib 50 mg/day for 4 weeks followed by 2 weeks without treatment in 6-week cycles; 27% and 22% of patients achieved stable disease for > or =3 months. Sunitinib was more effective than interferon-alpha as a first-line therapy in patients with metastatic RCC. In a large, well designed, phase III trial in previously untreated patients, progression-free survival was significantly longer in patients receiving sunitinib 50 mg/day in 6-week cycles (4 weeks of treatment followed by a 2-week rest period) compared with those receiving interferon-alpha 9MU three times weekly (47.3 vs 24.9 weeks). In general, sunitinib was well tolerated in patients with GIST and RCC, with adverse events usually being of mild or moderate severity.

Antineoplastic Agents↗

PubMed2006

Rufinamide.

Rufinamide, a triazole derivative, reduces the recovery capacity of neuronal sodium channels after inactivation, limiting neuronal sodium-dependent action potential firing and mediating anticonvulsant effects. In children, adolescents and adults, adjunctive oral rufinamide was more effective than placebo in treating seizures associated with treatment-resistant Lennox-Gastaut syndrome in a well designed 16-week trial. Rufinamide recipients experienced significantly greater reductions from baseline than placebo recipients in the median frequency of total seizures and tonic-atonic seizures per 28 days and demonstrated improvements in seizure severity. Furthermore, these beneficial effects of rufinamide on seizure frequency were maintained throughout a subsequent 3-year, open-label extension study. Relative to placebo, adjunctive rufinamide significantly reduced the frequency of partial seizures per 28 days in adult patients with inadequately controlled partial seizures in two well designed trials of approximate, equals3 months duration, with a higher proportion of rufinamide recipients achieving a reduction of >or=50% in partial seizure frequency per 28 days. Rufinamide was generally well tolerated in patients with Lennox-Gastaut syndrome and in those with partial seizures, with adverse events being mostly mild or moderate in severity.

Animals↗

PubMed2006

Oral paricalcitol.

black triangle An oral formulation of paricalcitol has been developed for the prevention and treatment of secondary hyperparathyroidism in patients with stage 3 or 4 chronic kidney disease.black triangle Paricalcitol is a synthetic vitamin D analog that binds to the vitamin D receptor inducing suppression of parathyroid hormone (PTH) secretion.black triangle Oral paricalcitol was significantly more effective than placebo in treating secondary hyperparathyroidism in patients with stage 3 or 4 chronic kidney disease. In a pooled analysis of three well designed, 24-week trials, two consecutive reductions from baseline in intact PTH levels of >/=30% were achieved by significantly more paricalcitol than placebo recipients (91% vs 13%).black triangle In addition, mean levels of the biochemical bone markers serum bone-specific alkaline phosphatase, serum osteocalcin, and urinary pyridinoline were reduced from baseline to a significantly greater extent with paricalcitol than with placebo, indicating a reduction in bone turnover.black triangle Oral paricalcitol was well tolerated; there was no significant difference between paricalcitol and placebo recipients in the incidence of hypercalcemia, hyperphosphatemia, or elevated calcium-phosphorus product.

Calcium↗

PubMed2004

The ataxia-oculomotor apraxia 1 gene product has a role distinct from ATM and interacts with the DNA strand break repair proteins XRCC1 and XRCC4.

Ataxia-oculomotor apraxia 1 (AOA1) is an autosomal recessive neurodegenerative disease that is reminiscent of ataxia-telangiectasia (A-T). AOA1 is caused by mutations in the gene encoding aprataxin, a protein whose physiological function is currently unknown. We report here that, in contrast to A-T, AOA1 cell lines exhibit neither radioresistant DNA synthesis nor a reduced ability to phosphorylate downstream targets of ATM following DNA damage, suggesting that AOA1 lacks the cell cycle checkpoint defects that are characteristic of A-T. In addition, AOA1 primary fibroblasts exhibit only mild sensitivity to ionising radiation, hydrogen peroxide, and methyl methanesulphonate (MMS). Strikingly, however, aprataxin physically interacts in vitro and in vivo with the DNA strand break repair proteins XRCC1 and XRCC4. Aprataxin possesses a divergent forkhead associated (FHA) domain that closely resembles the FHA domain present in polynucleotide kinase, and appears to mediate the interactions with CK2-phosphorylated XRCC1 and XRCC4 through this domain. Aprataxin is therefore physically associated with both the DNA single-strand and double-strand break repair machinery, raising the possibility that AOA1 is a novel DNA damage response-defective disease.

Apraxias↗

PubMed2004

Sperm proteome mapping of a patient who experienced failed fertilization at IVF reveals altered expression of at least 20 proteins compared with fertile donors: case report.

The aim of this study was to compare the sperm protein expression profile (proteome map) from a patient who experienced failed fertilization at IVF with fertile controls. One patient and three fertile donor sperm samples were characterized using two-dimensional electrophoresis. Differences in protein expression were established using gel analysis software before attempted protein identification. Gel analysis of the fertile donor proteome maps revealed excellent reproducibility as well as very low intra-donor and inter-donor variability in the presence of protein spots. In the patient samples, we have noted 20 consistent differences in protein expression (six spots missing, three additional spots, four less abundant, seven more abundant) compared with the controls. Two proteins that were more intense in the patient have been conclusively identified as secretory actin-binding protein and outer dense fibre protein 2/2. In conclusion proteome variation between different fertile donors was very low. In contrast, the patient proteome exhibited 20 differences compared with controls, which we believe is an underestimate. These proteins merit further investigation to determine whether failed fertilization at IVF might be caused by abnormalities in their expression. This case report represents a proof of principle that proteomics may be useful to study defects in sperm function.

Case-Control Studies↗

PubMed2002

The low lysine content of ricin A chain reduces the risk of proteolytic degradation after translocation from the endoplasmic reticulum to the cytosol.

Several protein toxins, including the A chain of ricin (RTA), enter mammalian cells by endocytosis and subsequently reach their cytosolic substrates by translocation across the endoplasmic reticulum (ER) membrane. To achieve this export, such toxins exploit the ER-associated protein degradation (ERAD) pathway but must escape, at least in part, the normal degradative fate of ERAD substrates. Toxins that translocate from the ER have an unusually low lysine content. Since lysyl residues are potential ubiquitination sites, it has been proposed that this paucity of lysines reduces the chance of ubiquitination and subsequent ubiquitin-mediated proteasomal degradation [Hazes, B., and Read, R. J. (1997) Biochemistry 36, 11051-11054]. Here we provide experimental support for this hypothesis. The two lysyl residues within RTA were changed to arginyl residues. Their replacement in RTA did not have a significant stabilizing effect, suggesting that the endogenous lysyl residues are not the usual sites for ubiquitin attachment. However, when four additional lysines were introduced into RTA in a way that did not compromise the activity, structure, or stability of the toxin, degradation was significantly enhanced. Enhanced degradation resulted from ubiquitination that predisposed the toxin to proteasomal degradation. Treatment with the proteasome inhibitor clasto-lactacystin beta-lactone increased the cytotoxicity of the lysine-rich RTA to a level approaching that of wild-type ricin. The introduction of four additional lysyl residues into a second ribosome-inactivating protein, abrin A chain, also dramatically decreased the cytotoxicity of the holotoxin compared to wild-type abrin. This effect could also be reversed by proteasomal inhibition. Our data support the hypothesis that the evolution of a low lysine content is a degradation-avoidance strategy for toxins that retrotranslocate from the ER.

Animals↗