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Biomedical subjects

Sheila A Doggrell

Publications and source records attributed to Sheila A Doggrell.

At least 37 records · Page 2Linked to original sources
PubMed2006

Nitrone spin on cerebral ischemia.

Clinical trials with radical scavenging antioxidants have shown little or no benefit in the treatment of ischemic stroke. The spin trap nitrones covalently bind with short-lived reactive radicals to inactivate them for longer than the conventional scavenging antioxidants. One of these agents, NXY-059, is effective in animal models of cerebral ischemia, and is in phase III clinical trials for ischemic stroke by AstraZeneca, under license from Renovis. Second-generation nitrones (azulenyl nitrones) have also been described and shown to be neuroprotective in animal models. Thus, at last, it seems that antioxidants that are potent enough to have considerable potential for the treatment of cerebral ischemia are in development.

Animals↗
PubMed2006

Bradykinin B2 receptors as a target in diabetic nephropathy.

Diabetic nephropathy is the leading cause of chronic renal failure in countries in the western world. Human polymorphism studies have suggested a nephroprotective effect that is mediated by bradykinin B2 receptors. Angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers have an additive nephroprotective effect in patients with diabetes, which may be due to ACE-inhibitor-mediated increases in the levels of bradykinin. There is also evidence from studies conducted in genetically altered mice to suggest that bradykinin is nephroprotective. Finally, evidence from animal models of nephropathy indicates that some of the beneficial effects of ACE inhibitors and vasopeptidase inhibitors are due to the action of bradykinin at B2 receptors. These data establish that stimulation of bradykinin B2 receptors is a target in diabetic nephropathy, and should provide impetus for the development of non-peptide, selective bradykinin B2 agonists.

Angiotensin II↗
PubMed2006

New targets in and potential treatments for cholesterol gallstone disease.

Gallstone disease is very common among American Indians and Hispanics, and approximately 20 million patients are treated for this disease annually in the US. Bile acid receptor (nuclear farnesoid X receptor; FXR) knockout mice fed a lithogenic diet are more susceptible to gallstone disease than wild-type mice. The C57L mouse is also susceptible to gallstone formation when fed a lithogenic diet, and in this model, the small-molecule FXR agonist GW-4064 prevents the precipitation of cholesterol. Bile acids (eg, P-muricholic acid) and their derivatives are also being developed as FXR agonists. Fatty acid bile acid conjugates have the potential to prevent and reverse cholesterol crystallization. Furthermore, agents that increase the expression of selected hepatocyte bile acid transporters may also be useful in the treatment of gall bladder disease.

Animals↗
PubMed2006

Australian neuroscience in 2006--highlights from the scientific meeting.

The annual meeting of the Australian Neuroscience Society (ANS) was held in Sydney, Australia, January 31-February 3, 2006. The main meeting was preceded by four satellite meetings. This report predominantly considers some of the drug targets highlighted at the ANS meeting, and at the Dementia, Ageing and Neurodegenerative Diseases Group (DANDIS) satellite. The targets considered are for neurodegeneration, stroke and neuroprotection. Also, various receptors, transporters and channels are considered as therapeutic targets in neuroscience.

Aging↗
PubMed2005

Cardiac chymase: pathophysiological role and therapeutic potential of chymase inhibitors.

On release from cardiac mast cells, alpha-chymase converts angiotensin I (Ang I) to Ang II. In addition to Ang II formation, alpha-chymase is capable of activating TGF-beta1 and IL-1beta, forming endothelins consisting of 31 amino acids, degrading endothelin-1, altering lipid metabolism, and degrading the extracellular matrix. Under physiological conditions the role of chymase in the mast cells of the heart is uncertain. In pathological situations, chymase may be secreted and have important effects on the heart. Thus, in animal models of cardiomyopathy, pressure overload, and myocardial infarction, there are increases in both chymase mRNA levels and chymase activity in the heart. In human diseased heart homogenates, alterations in chymase activity have also been reported. These findings have raised the possibility that inhibition of chymase may have a role in the therapy of cardiac disease. The selective chymase inhibitors developed to date include TY-51076, SUN-C8257, BCEAB, NK320, and TEI-E548. These have yet to be tested in humans, but promising results have been obtained in animal models of myocardial infarction, cardiomyopathy, and tachycardia-induced heart failure. It seems likely that orally active inhibitors of chymase could have a place in the treatment of cardiac diseases where injury-induced mast cell degranulation contributes to the pathology.

Animals↗
PubMed2005

BMS-354825: a novel drug with potential for the treatment of imatinib-resistant chronic myeloid leukaemia.

The BCR-ABL tyrosine kinase inhibitor imatinib has greatly improved the outcome for patients with chronic myeloid leukaemia (CML). Unfortunately, mutations causing resistance to imatinib are leading to relapses in some patients. In addition to inhibiting the wild-type BCR-ABL, BMS-354825 inhibited 14 of 15 BCR-ABL mutants. BMS-354825 treatment of immunodeficient mice prevented the progression of the disease in mice treated with the most clinical common imatinib-resistant mutant Met351Thr. The safety and efficacy of BMS-354825 is presently being evaluated in a phase I/II clinical trial in CML patients with imatinib resistance. The frequency of clinical use of BMS-3548125 in CML patients will depend on its efficacy/safety profile in clinical trial.

Animals↗
PubMed2005

Farnesoid X receptor agonism -- a new approach to the treatment of cholesterol gallstone disease.

Gallstone disease is very common among native Americans and Hispanics, and approximately 20 million patients are treated for this disease annually in the US. The nuclear farnesoid X receptor (FXR) is the receptor for bile acids, and GW4064 is a synthetic agonist at the FXR. FXR(-/-) mice fed a lithogenic diet (high fat, cholesterol and cholic acid) are more susceptible to gallstone disease than wild-type mice with the same mixed background, thus establishing that the ablation of FXR is associated with this disease. The C57L mouse is susceptible to gallstone formation. When C57L mice are fed a lithogenic diet for a week, the bile contains large aggregates of cholesterol precipitates, and two of five C57L mice had macroscopic cholesterol crystals. In contrast, when C57L mice were fed the lithogenic diet and administered GW4064 100 mg/kg/day by oral gavage, there was no precipitation of cholesterol. Treatment with this agent also increased bile salt and phospholipid concentration, and prevented gallbladder epithelium damage. As FXR agonism with GW4064 has been shown to be useful in a mouse model of cholesterol gallstone disease, it should undergo further development for the treatment of this condition.

Journal Article↗
PubMed2005

Ibutilide--recent molecular insights and accumulating evidence for use in atrial flutter and fibrillation.

Ibutilide is a 'pure' class III antiarrhythmic drug, used intravenously against atrial flutter and fibrillation. At a cellular level it exerts two main actions: induction of a persistent Na+ current sensitive to dihydropyridine Ca2+ channel blockers and potent inhibition of the cardiac rapid delayed rectifier K+ current, by binding within the channel pore cavity upon channel gating. Ibutilide has been shown to terminate atrial flutter and fibrillation in animal studies, with some risk of ventricular pro-arrhythmia. Experimental models of hypertrophy/heart failure show altered sensitivity to ibutilide, with increased dispersion of repolarisation and incidence of pro-arrhythmia. Patient trials show that ibutilide is effective at terminating atrial arrhythmias when given alone, and that it can increase effectiveness and reduce energy requirements of electrical cardioversion. The risk to patients of polymorphic ventricular tachycardia necessitates careful patient selection and monitoring during and after treatment. An ibutilide analogue, trecetilide, requires further investigation but may offer a less readily metabolised and pro-arrhythmic alternative to ibutilide.

Animals↗
PubMed2005

Berberine--a novel approach to cholesterol lowering.

Although low-density lipoprotein (LDL)-cholesterol lowering with the statins reduces the mortality and morbidity associated with coronary artery disease, considerable mortality and morbidity remains. Berberine upregulates the LDL receptor (LDLR) by a mechanism distinct from that of the statins, which involves stabilising the LDLR mRNA. In hamsters fed a high-fat and high-cholesterol diet for 2 weeks, the oral administration of berberine 100 mg/kg for 10 days reduced total serum cholesterol from approximately 4.8 to 2.7 mmol/l, and LDL-cholesterol from approximately 2.5 to 1.4 mmol/l. In subjects with hypercholesterolaemia, berberine hydrochloride (0.5 g b.i.d. for 3 months) reduced LDL-cholesterol (from 3.2 to 2.4 mmol/l) without any effect on high-density lipoprotein-cholesterol. Berberine also caused a reduction in triglyceride levels from 2.3 to 1.5 mmol/l. As berberine and statins both upregulate LDLR, their lipid-lowering profiles are similar. Thus, this mechanism is unlikely to make berberine an attractive alternative to statins for lipid lowering in most circumstances. However, the other effects of berberine (antihypertensive, inotropic and class III antiarrhythmic properties) may make it a useful agent in the treatment of cardiovascular disease.

Animals↗
PubMed2005

The nitrosterols--a step forward from the steroid anti-inflammatory drugs?

Nitric oxide (NO)-releasing non-steroidal anti-inflammatory drugs have been shown to have improved efficacy and lower toxicity than their parent agents, and are currently in clinical trials as anti-inflammatory agents. The same approach is now being taken with the glucocorticoids, and initial studies show that NO-releasing forms of prednisolone, flunisolide and hydrocortisone (the nitrosterols) are more potent anti-inflammatory agents than their parent molecules in animal models of acute and chronic inflammation. Experimental studies also suggest that the nitrosterols are less likely to cause the side effects associated with glucocorticoids. Thus, to date, the nitrosterols do seem to be a step forward from the steroid anti-inflammatory drugs. However, given that prolonged exposure to high concentrations of NO may be pro-inflammatory, further long-term studies are needed to determine whether the increased anti-inflammatory effects observed with short-term treatment with nitrosterols are maintained.

Animals↗
PubMed2005

New drugs being developed for the treatment of tuberculosis.

More than one-third of the world is infected with tuberculosis (TB) and 5000 people die of TB everyday. Of the many diarylquinolones shown to be effective at inhibiting the multiple-cycle growth of Mycobacterium tuberculosis, R-207910 was the most active and was chosen as the lead compound. In the non-established infection mouse TB model, a single dose of R-207910 50 mg/kg had a bacteriostatic effect, and a bactericidal effect was observed at 100 mg/kg. In the established infection mouse model, treatment was started 12-14 days after infection, and when added to the triple therapy of isoniazid, rifampin and pyrazinamide or substituted for any component of the triple therapy, R-207910 increased the effectiveness. As ethambutol is chemically simple, and only has modest potency in treating TB, it was considered to be amenable to optimisation by combinatorial chemistry, and from the analogues synthesised that inhibited the growth of M. tuberculosis, SQ-109 was eventually selected as the lead compound for further testing. In female mice infected with M. tuberculosis H37Rv by tail-vein injection, treatment with SQ-109 25 mg p.o. initiated 20 days later for 5 days/week for 4 weeks reduced the counts by 1.87 log units, which was slightly more than with ethambutol 100 mg (1.67 log units). These results indicate that exciting new drugs are under development for the treatment of TB.

Animals↗
PubMed2005

Is AMN-107 a step forward from imatinib in the treatment of chronic myeloid leukaemia?

The Philadelphia (Ph) chromosome was the first consistent chromosome abnormality identified in cancer. It is found in 90% of patients with chronic myeloid leukaemia (CML) and in a subset of patients with acute lymphoblastic leukaemia. The effectiveness of the Bcr-Abl kinase inhibitor imatinib in these conditions reduces with advancing disease and/or the development of resistance to imatinib. AMN-107 inhibited the proliferation of haematopoietic cells expressing the mutants in Ph+ CML and acute lymphoblastic leukaemia with concentrations causing 50% inhibition of approximately 12 nM, making it more potent than imatinib. AMN-107 was also effective against several imatinib-resistant Bcr-Abl mutants, but not T3151. In mice transduced with Bcr-Abl, AMN-107 reduced mortality and tumour burden. In mice transduced with the E255V imatinib-resistant mutant of Bcr-Abl, AMN-107 delayed the onset of leukaemia. As AMN-107 is more potent and more selective for Bcr-Abl than imatinib, it may represent a step forward in the treatment of CML, but further animal (and then clinical) studies are needed to test this.

Animals↗
PubMed2005

Rho-kinase inhibitors show promise in pulmonary hypertension.

In pulmonary arterial hypertension, it is necessary to obtain a vasodilation that is selective for the pulmonary circulation. Ras human orthologue (Rho)/Rho-kinase-mediated Ca2+ sensitisation plays a central role in mediating the sustained vasoconstriction and increased vasoreactivity in the rat hypoxic model of pulmonary hypertension. Rho-kinase inhibitors (Y-27632 and/or fasudil) have been shown to reduce pulmonary arterial pressure in three rat models of pulmonary hypertension. The first clinical study to report the effects of a Rho-kinase inhibitor in pulmonary hypertension enrolled nine patients with severe pulmonary hypertension. Fasudil hydrochloride 30 mg for 30 min i.v. caused a slight decrease in the mean pulmonary artery pressure and increase in the cardiac index but neither of these responses was significant. However, fasudil caused a significant decrease in pulmonary vascular resistance. Rho-kinase inhibitors may be useful in pulmonary hypertension, and should undergo further development for this indication.

Animals↗