Search PubMed⌕ Search

Biomedical subjects

Sheila A Doggrell

Publications and source records attributed to Sheila A Doggrell.

At least 73 records · Page 4Linked to original sources
PubMed2005

Neuromedin U--a new target in obesity.

With the increasing prevalence of obesity, effective therapies are urgently required. When neuromedin U was administered intracerebroventricularly to rats there was a marked decrease in weight, whereas injection of an antibody to neuromedin U increased food intake. Unlike wild type, Nmu(-/-) mice become obese when freely fed ordinary mouse chow. The plasma levels of insulin, leptin, total cholesterol, triglycerides and free fatty acids were higher in the Nmu(-/-) than wild-type mice. Energy expenditure was lower in Nmu(-/-) mice. The anorexigenic effect of neuromedin U was independent of the leptin signalling pathway. Transgenic mice overexpressing neuromedin U have lower body weight, less somatic and liver fat, were hypophagic, and had improved insulin sensitivity. These data establish neuromedin U as a target in obesity.

Animals↗
PubMed2005

Stabilisation of calstabin2--a new approach in sudden cardiac death.

Calstablin2 stabilises the ryanodine receptor (RyR2), preventing aberrant activation of the channels during the resting phase of the cardiac muscle. Loss of this stabilisation may be associated with cardiac arrhythmias, the sudden death occasionally observed in people with structurally normal hearts, as well as the atrial fibrillation in heart failure. Calstabin2-deficient mice have structurally normal hearts but exhibit exercise-induced cardiac ventricular arrhythmias that cause sudden death. In arrhythmias, the calstabin2 stabiliser JTV519 did not prevent arrhythmias in calstabin2-/- mice, but reduced the arrhythmias in calstabin2+/- mice, illustrating the antiarrhythmic potential of stabilising calstablin2. Familial polymorphic ventricular tachycardia in humans has been linked to missense mutants in the hRyR2 gene. In HEK293 cells, these RyR2 mutants showed less binding of 35S-calstabin2 than the wild type, indicating a reduced binding affinity. In human atrial fibrillation and heart failure, where there is excessive disassociation of calstabin2 from the RyR2 receptor in vitro, JTV519 is able to reverse this. In conclusion, calstabin2 is an important new target in sudden cardiac death associated with structurally normal hearts, and in the treatment of atrial fibrillation and heart failure.

Animals↗
PubMed2005

Evidence for, and importance of, cGMP-independent mechanisms with NO and NO donors on blood vessels and platelets.

In the vasculature it is well established that cGMP is involved in the relaxant response to nitric oxide (NO) and NO donors. However, there is an increasing evidence that alternative/additional pathways that are cGMP-independent may also exist. A key criterion for a response to NO or a NO donor drug to be classified as cGMP-independent is lack of (or incomplete) inhibition by the selective inhibitor of soluble guanylate cyclase, ODQ (1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one). In many blood vessels cGMP-independent mechanisms contribute to the vasorelaxation, and in certain vascular beds cGMP-independent relaxation may be the predominant mechanism of action of NO and NO donors. NO donor drugs that generate NO "spontaneously", like authentic NO (i.e. solutions of NO gas), appear to exhibit a larger component of cGMP-independent vasorelaxation than do those drugs that require bioactivation in the tissue. The long lasting inhibition of responses to vasoconstrictors by S-nitrosothiols, persisting after removal of these NO donors, may be a cGMP-independent process, at least in some vessels. The mechanisms involved in the inhibition of vascular growth by NO and NO donors are predominantly cGMP-independent, as are the mechanisms responsible for the effects of NO donors on apoptosis in vascular smooth muscle and endothelial cells. The ability of NO and NO donors to inhibit platelet aggregation has a significant cGMP-independent component. cGMP-independent pathways are most often, though not exclusively, seen at high concentrations (microM - mM) of NO and NO donors. Hence, in relation to the actions of endogenous NO, these pathways may be particularly important in settings when the inducible isoform of NO-synthase is expressed. Furthermore, cGMP-independent pathways are enhanced in animal models of atherosclerosis and ischaemia. This suggests that it may be possible to target cGMP-independent mechanisms with selected NO donors in disease states.

Animals↗
PubMed2005

Conivaptan Yamanouchi.

Yamanouchi is developing conivaptan, a diuretic and active vasopressin V1a and V2 antagonist, which has an aquaretic effect, for the potential treatment of hyponatremia and heart failure. In January 2004, Yamanouchi submitted an NDA in the US for injectable conivaptan for the treatment of hyponatremia and, in December 2004, the FDA issued approval, although additional safety data were requested.

Animals↗
PubMed2005

New targets and new drugs down under in 2004.

The Second Australian Health and Medical Research Congress, held November 21-26, 2004, in Sydney, Australia, brought together 28 specialist societies across a broad range of scientific endeavor. The topics of the plenary lectures included signal transduction by stress-activated mitogen-activated protein kinases, whether human cancer can be treated before it is symptomatic, the modeling of human cardio-myopathies via genetic manipulation in animal models, and biological individuality and the response to regular exercise. The symposia included translating basic research to clinical practice, molecular mechanisms and anticancer therapies, modulating signaling pathways to treat/prevent disease, therapeutic frontiers in bone and joint disease, pleiotropic effects of statins in the cardiovascular system, and angiogenesis inhibitors in cancer and atherosclerosis therapy.

Animals↗
PubMed2005

Clinical potential of nitric oxide-independent soluble guanylate cyclase activators.

A major problem with using nitrates in the treatment of ischemic heart disease is that tolerance develops to their vasodilatory actions. YC-1 was used as the lead compound to synthesize further nitric oxide-independent soluble guanylate cyclase activators, including BAY-41-2272 and BAY-41-8543. A nitric oxide and heme-independent activator of soluble guanylate cyclase, BAY-58-2667, was subsequently discovered by high-throughput screening. Tolerance to the vasodilatory actions of BAY-41-8543 and BAY-58-2667 does not develop. Results from animal studies have suggested that these compounds may have potential in the treatment of ischemic heart disease, essential and pulmonary hypertension, congestive heart failure, glomerulonephritis and erectile dysfunction.

Animals↗
PubMed2005

Taking the 20-HETE out of the cardiovascular system: the potential of 20-HETE synthesis inhibitors.

In addition to being metabolized by cyclooxygenase and lipooxygenase to prostaglandins and leukotrienes, arachidonic acid can be metabolized to 20-hydroxyeicosatetraenoic acid (20-HETE) by cytochrome P450 enzymes omega-hydroxylases. As 20-HETE has both pro-hypertensive and antihypertensive actions, inhibitors of 20-HETE synthase may not be useful as antihypertensives in all forms of hypertension. However, 20-HETE synthase inhibitors can have cardioprotective and cerebroprotective effects in animal models, and can inhibit angiogenesis; therefore they may have clinical potential in these areas.

Amidines↗
PubMed2005

BG-9928 (Biogen Idec).

Biogen Idec, under license from CV Therapeutics, is developing BG-9928, a selective oral adenosine A, receptor antagonist, for the potential treatment of congestive heart failure. By January 2003, phase II trials of BG-9928 were ongoing.

Adenosine A1 Receptor Antagonists↗
PubMed2005

Inflammation, the key to much pathology.

From the World Congress on Inflammation, held August 20-24, 2005 in Melbourne, Australia, new targets and new drugs for inflammation of the respiratory system (asthma, allergic rhinitis, chronic obstructive pulmonary disease and cystic fibrosis), inflammatory bowel disease (ulcerative colitis and Crohn's disease), arthritis (rheumatoid and osteoarthritis), atherosclerosis and cancer are discussed.

Animals↗
PubMed2004

Vascular chymase: pathophysiological role and therapeutic potential of inhibition.

Chymase is a chymotrypsin-like serine protease secreted from mast cells. Mammalian chymases are classified into two subgroups (alpha and beta) according to structure and substrate specificity; human chymase is an alpha-chymase. An important action of chymase is the ACE-independent conversion of Ang I to Ang II, but chymase also degrades the extracellular matrix, activates TGF-beta1 and IL-1beta, forms 31-amino acid endothelins and is involved in lipid metabolism. Under physiological conditions, the role of chymase in blood vessels is uncertain. In pathological situations, however, chymase may be important. In animal models of hypertension and atherosclerosis, chymase may be involved in lipid deposition and intimal and smooth muscle hyperplasia, at least in some vessels. In addition, chymase has pro-angiogenic properties. In human diseased blood vessels (e.g. atherosclerotic and aneurysmal aorta; remodeled pulmonary blood vessels), there are increases in chymase-containing mast cells and/or in chymase-dependent conversion of Ang I to Ang II. These findings have raised the possibility that inhibition of chymase may have a role in the therapy of vascular disease. The effects of chymase can theoretically be attenuated either by reducing availability of the enzyme, with a mast cell stabiliser, or alternatively with specific chymase inhibitors. The mast cell stabiliser, tranilast, was shown to be beneficial in animal models of atherosclerosis, where a prevention protocol was used, but was not effective in clinical trials where it was administered after angioplasty. Chymase inhibitors could have the advantage of being effective even if used after injury. Several orally active inhibitors, including SUN-C8257, BCEAB, NK3201 and TEI-E548, are now available. These have yet to be tested in humans, but promising results have been obtained in animal models of atherosclerosis and angiogenesis. It is concluded that orally active inhibitors of chymase may have a place in the treatment of vascular diseases where injury-induced mast cell degranulation contributes to the pathology.

Aging↗
PubMed2004

The potential of activation of somatostatinergic neurotransmission with FK960 in Alzheimer's disease.

Somatostatin levels are reduced in post mortem brains of patients with Alzheimer's disease (AD). FK960 is a somatostatin-releasing agent. After oral administration to rhesus monkeys, FK960 is distributed to the entire brain. In patients with AD, regional cerebral blood flow and regional cerebral metabolic rate of glucose correlate with cognitive decline and the appearance of pathological changes. Aged rhesus monkeys are a good animal model of AD as they develop age-associated cognitive impairment. FK960 (1 mg/kg) caused modest increases in regional cerebral blood flow and regional cerebral metabolic rate of glucose in aged monkeys, suggesting that FK960 will improve cognition. Thus, the activation of somatostatinergic neurotransmission, with FK960 or a similar drug, has considerable potential in the treatment of cognitive impairment.

Alzheimer Disease↗
PubMed2004

Suramin: potential in acute liver failure.

Apoptosis is the first cellular response of the liver to many toxic events, including viral hepatitis, alcohol-induced liver disease and ischaemia/reperfusion injury. When apoptosis is induced with an antibody to APO-1, suramin is antiapoptotic in a variety of cell lines (e.g., Jurkat cells, HepG2). Jo2 is an antibody to mouse CD95, which kills C57Bl/6 mice, and was used as a model of fulminant liver failure in mice. Suramin protected 40% of Jo2-treated mice from death and delayed death in the other mice. In mice, D-galactosamine and endotoxin cause apoptotic liver damage, which is mediated by TNF. Suramin reduced this liver damage as assessed by serum aminotransferase levels, gross liver appearance and apoptosis levels. In contrast, suramin does not inhibit necrotic cell death in a rat model of liver transplantation. Inhibition of apoptosis with suramin or other more selective agents is an approach that should be further investigated in liver failure.

Animals↗
PubMed2004

Raising high-density lipoprotein cholesterol with inhibitors of cholesteryl ester transfer protein - a new approach to coronary artery disease.

Although the low-density lipoprotein (LDL) cholesterol-lowering statins reduce the mortality and morbidity associated with coronary artery disease, considerable mortality and morbidity remains. Increasing high-density lipoprotein (HDL) cholesterol reduces coronary artery disease mortality and morbidity. In healthy subjects with mild dyslipidaemia, treatment with JTT-705 decreased cholesteryl ester transfer protein (CETP) activity, increased HDL-cholesterol and decreased LDL-cholesterol. Similarly, another CETP inhibitor, torcetrapib 120 mg/day has recently been shown to increase HDL-cholesterol by 46%, decrease LDL-cholesterol by 8% and have no effect on triglycerides in subjects with HDL-cholesterol < 1 mmol/l. In subjects treated with atorvastatin to lower their LDL-cholesterol levels, torcetrapib further lowered LDL-cholesterol while increasing HDL-cholesterol. In conclusion, raising HDL-cholesterol with inhibitors of CETP is a new approach to coronary artery disease that requires further investigation, especially in patients with coronary artery disease.

Carrier Proteins↗
PubMed2004

A neuroprotective derivative of erythropoietin that is not erythropoietic.

In addition to its well-known erythropoetic effect, erythropoietin (EPO) has also been shown to be neuroprotective in various animal models. In contrast to EPO, carbamylated EPO (CEPO) does not bind to the EPO receptor on UT7 cells or have any haematopoietic/proliferative activity on these cells. In vivo studies in mice and rats showed that even high doses of CEPO for long periods are not erythropoietic. However, in common with EPO, CEPO does inhibit the apoptosis associated with glutamate toxicity in hippocampal cells. Like EPO, CEPO is neuroprotective in a wide range of animal models of neurotoxicity: middle cerebral artery occlusion model of ischaemic stroke, sciatic nerve compression, spinal cord depression, experimental autoimmune encephalomyelitis and peripheral diabetic neuropathy. To date, EPO and CEPO have been exciting developments in the quest for the treatment of various types of neurotoxicity. The development of CEPO should continue.

Animals↗