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Biomedical subjects

P Gillespie

Publications and source records attributed to P Gillespie.

15 recordsLinked to original sources
PubMed2006

Application and utilization of chemoinformatics tools in lead generation and optimization.

The process of Drug Discovery is a complex and high risk endeavor that requires focused attention on experimental hypotheses, the application of diverse sets of technologies and data to facilitate high quality decision-making. All is aimed at enhancing the quality of the chemical development candidate(s) through clinical evaluation and into the market. In support of the lead generation and optimization phases of this endeavor, high throughput technologies such as combinatorial/high throughput synthesis and high throughput and ultra-high throughput screening, have allowed the rapid analysis and generation of large number of compounds and data. Today, for every analog synthesized 100 or more data points can be collected and captured in various centralized databases. The analysis of thousands of compounds can very quickly become a daunting task. In this article we present the process we have developed for both analyzing and prioritizing large sets of data starting from diversity and focused uHTS in support of lead generation and secondary screens supporting lead optimization. We will describe how we use informatics and computational chemistry to focus our efforts on asking relevant questions about the desired attributes of a specific library, and subsequently in guiding the generation of more information-rich sets of analogs in support of both processes.

Chemistry, Pharmaceutical↗
PubMed2002

A critical review of vascular endothelial growth factor (VEGF) analysis in peripheral blood: is the current literature meaningful?

Vascular endothelial growth factor (VEGF) is a potent angiogenic growth factor with a key role in many physiological and pathological processes. Investigation into the implications of circulating levels of this cytokine is progressing at an exponential rate. However, there are important inconsistencies between reports ranging from method of sample collection, processing, software manipulation and data interpretation and controversy as to whether plasma, serum or whole blood will provide the best prognostic information. Different techniques of centrifugation and temperature on sample handling and the impact of in vitro collection of blood on subsequent VEGF results have not been fully appreciated. We provide a critical review of the literature, report the results of our further investigations, suggest a uniform protocol for handling blood samples and highlight previously unsuspected problems in data interpretation.

Blood Specimen Collection↗
PubMed2001

Translational control is required for the unfolded protein response and in vivo glucose homeostasis.

The accumulation of unfolded protein in the endoplasmic reticulum (ER) attenuates protein synthesis initiation through phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 (eIF2alpha) at Ser51. Subsequently, transcription of genes encoding adaptive functions including the glucose-regulated proteins is induced. We show that eIF2alpha phosphorylation is required for translation attenuation, transcriptional induction, and survival in response to ER stress. Mice with a homozygous mutation at the eIF2alpha phosphorylation site (Ser51Ala) died within 18 hr after birth due to hypoglycemia associated with defective gluconeogenesis. In addition, homozygous mutant embryos and neonates displayed a deficiency in pancreatic beta cells. The results demonstrate that regulation of translation through eIF2alpha phosphorylation is essential for the ER stress response and in vivo glucose homeostasis.

Activating Transcription Factors↗
PubMed2001

Total intravenous versus inhalational anaesthesia for colonoscopy: a prospective study of clinical recovery and psychomotor function.

A randomized, prospective study was conducted on 69 patients comparing recovery after two different anaesthetic techniques for ambulatory colonoscopy. Thirty-five patients received an intravenous fentanyl (1 microg/kg), midazolam (0.05 to 0. 075 mg/kg) and propofol (10 to 20 mg boluses as required) combination. 34 patients received sevoflurane in 67% nitrous oxide. Drug administration was titrated to clinical signs. At baseline and 30, 60, 90 and 120 minutes after the procedure patient performance on a comprehensive battery of psychomotor tests was recorded. Emergence times were noted. Depth of sedation was assessed at 5 minute intervals for 30 minutes after the end of the procedure. Emergence times were faster in the fentanyl/midazolam/propofol group by 2.2 minutes. A lower sedation score was detected at 20 minutes in the sevoflurane/nitrous oxide group. Psychomotor impairment was of a greater magnitude and more prolonged by 30 to 90 minutes in the fentanyl/midazolam/propofol group. It is concluded that a sevoflurane/nitrous oxide anaesthetic has a suitable recovery profile for ambulatory colonoscopy and results in faster recovery of cognitive function compared with a fentanyl, midazolam and propofol combination.

Adolescent↗
PubMed2000

Peptide and peptide mimetic inhibitors of antigen presentation by HLA-DR class II MHC molecules. Design, structure-activity relationships, and X-ray crystal structures.

Molecular features of ligand binding to MHC class II HLA-DR molecules have been elucidated through a combination of peptide structure-activity studies and structure-based drug design, resulting in analogues with nanomolar affinity in binding assays. Stabilization of lead compounds against cathepsin B cleavage by N-methylation of noncritical backbone NH groups or by dipeptide mimetic substitutions has generated analogues that compete effectively against protein antigens in cellular assays, resulting in inhibition of T-cell proliferation. Crystal structures of four ternary complexes of different peptide mimetics with the rheumatoid arthritis-linked MHC DRB10401 and the bacterial superantigen SEB have been obtained. Peptide-sugar hybrids have also been identified using a structure-based design approach in which the sugar residue replaces a dipeptide. These studies illustrate the complementary roles played by phage display library methods, peptide analogue SAR, peptide mimetics substitutions, and structure-based drug design in the discovery of inhibitors of antigen presentation by MHC class II HLA-DR molecules.

Antigen Presentation↗
PubMed2000

Cannula related suppurative thrombophlebitis in the burned patient.

Suppurative thrombophlebitis is a well recognised and potentially fatal complication of intravenous cannulation in burns patients. We report a case of an Afro-Caribbean patient with noninsulin-dependent diabetes who developed signs of systemic sepsis two weeks after a 14% total body surface area flame burn. Despite an initial paucity of clinical signs at the cannulation site, exploratory venotomy revealed frank suppuration within the long saphenous vein from the ankle to the groin. This was treated successfully by total excision of the vein and its tributaries and delayed wound closure. Following this, a retrospective analysis of the measured clinical parameters and blood tests revealed no obvious, missed pointers to the impending sepsis other than a dramatic increase in the overall daily insulin requirement. This had doubled over a 48-h period, preceding the clinical diagnosis by three days. The relevant literature and guidelines for management are reviewed.

Adult↗
PubMed1998

Design and synthesis of small molecule interleukin-1 receptor antagonists based on a benzene template.

The interleukin-1 proteins (IL-1 alpha and IL-1 beta) are key mediators of inflammatory and immunological responses, and several in vitro and in vivo studies with protein-based antagonists have demonstrated the potential usefulness of IL-1 receptor antagonists to treat various inflammation related diseases. Based on the X-ray crystal structures of IL-1 ligands and site-directed mutagenesis data, a noncontiguous binding epitope encompassing Arg4, Phe46, Ile56, Lys93, Lys103, and Glu105 for IL-1 beta was proposed. In this paper we describe the synthesis and binding assay results of small molecule IL-1 receptor antagonists designed on the basis of the three-dimensional structure of the binding epitope. Among these, the compound 45 was found to inhibit IL-alpha binding to the Type I receptor with an IC50 value of 3 microM. A hypothesis generated using BioCad CATALYST program is also presented to rationalize these observations.

Benzene Derivatives↗
PubMed1996

Solution structure of a pyrimidine-purine-pyrimidine triplex containing the sequence-specific intercalating non-natural base D3.

We have used NMR spectroscopy to study a pyrimidine-purine-pyrimidine DNA triplex containing a non-natural base, 1-(2-deoxy-beta-D-ribofuranosyl)-4-(3-benzamido)phenylimidazole (D3), in the third strand. The D3 base has been previously shown to specifically recognize T-A and C-G base-pairs via intercalation on the 3' side (with respect to the purine strand) of the target base pair, instead of forming sequence-specific hydrogen bonds. 1H resonance assignments have been made for the D3 base and most of the non-loop portion of the triplex. The solution structure of the triplex was calculated using restrained molecular dynamics and complete relaxation matrix refinement. The duplex portion of the triplex has an over-all helical structure that is more similar to B-DNA than to A-DNA. The three aromatic rings of the D3 base stack on the bases of all three strands and mimic a triplet. The conformation of the D3 base and its sequence specificity are discussed.

Base Sequence↗
PubMed1990

The role of fibre optics in gastroenterology.

Diagnostic fibre optic endoscopy has a well established role in clinical gastroenterology. The authors highlight the expanding therapeutic applications of this technology.

Cholangiopancreatography, Endoscopic Retrograde↗
PubMed1985

Celiac axis compression syndrome: factors predicting a favorable outcome.

There is still considerable doubt about the existence of the celiac axis compression syndrome. Asymptomatic compression or narrowing of the celiac artery is common, and it is difficult to understand why some patients have significant symptoms while others have none. One major problem emerges from a study of the literature, in that there is no precise definition of the clinical features of a syndrome. Patients with all kinds of abdominal symptoms and varying psychiatric and medical backgrounds have been included in previous studies. It is not surprising, then, that there is no agreement on whether surgery is ever justified. We reported a small series of 11 patients whose clinical features have been carefully documented. Regression analysis of results suggests that good surgical results can be achieved in selected patients by decompression of the artery and restoration of the normal arterial lumen. Patients likely to benefit are those with epigastric pain related to food or hunger who do not have a galaxy of other unrelated symptoms. It is suggested that these factors be included in subsequent definitions of the celiac axis compression syndrome, so that some uniformity be introduced into the writing and thinking about this confusing problem.

Abdomen↗
PubMed1979

Cimetidine and gastric ulcer healing: a double-blind controlled trial.

The effect of cimetidine in the daily dose of 1200 mg on the healing rate of chronic gastric ulcer was assessed in a randomized double-blind trial in 48 patients. Cimetidine was found to accelerate the healing of chronic gastric ulcers in the ambulant patients, but it conferred no additional benefit on the patients in hospital. No significant side effects were observed.

Chronic Disease↗
PubMed1978

Idiopathic fatty liver of pregnancy with maternal and fetal survival.

A case of idiopathic fatty liver of pregnancy with survival of mother and child is reported. The management of this condition is essentially supportive; coagulation disturbances may require special attention. Maternal survival should be the major consideration and is favourably influenced by early delivery. Fetal monitoring aids obstetric management and may indirectly improve fetal survival. Evidence from the literature suggests that the condition does not usually recur in subsequent pregnancies.

Adult↗
PubMed1977

Amodiaquine agranulocytosis.

A case of profound neutropenia and severe infection after the administration of amodiaquine is presented. The recommended dose for malaria prophylaxis was administered.

Adult↗