PubMed Health⌕ Search

Biomedical subjects

John K Lynch

Publications and source records attributed to John K Lynch.

13 recordsLinked to original sources
PubMed2006

Constrained 7-fluorocarboxychromone-4-aminopiperidine based Melanin-concentrating hormone receptor 1 antagonists: the effects of chirality on substituted indan-1-ylamines.

The incorporation of constrained tertiary amines into an existing class of N-benzyl-4-aminopiperidinyl chromone-based MCHr1 antagonists led to the identification of a series of chiral racemic compounds that displayed good to excellent functional potency, binding affinity, and selectivity over the hERG channel. Further separation of two distinct chiral racemic compounds into their corresponding pairs of enantiomers revealed a considerable selectivity for MCHr1 for one configuration, in addition to a striking difference in oral exposure between one pair of enantiomers in diet-induced obese mice. Oral administration of the most potent compound in this class in the same animal model led to significant reduction of fat mass in a semi-chronic model for weight loss.

Animals↗
PubMed2006

Optimization of chromone-2-carboxamide melanin concentrating hormone receptor 1 antagonists: assessment of potency, efficacy, and cardiovascular safety.

Evaluation of multiple structurally distinct series of melanin concentrating hormone receptor 1 antagonists in an anesthetized rat cardiovascualar assay led to the identification of a chromone-2-carboxamide series as having excellent safety against the chosen cardiovascular endpoints at high drug concentrations in the plasma and brain. Optimization of this series led to considerable improvements in affinity, functional potency, and pharmacokinetic profile. This led to the identification of a 7-fluorochromone-2-carboxamide (22) that was orally efficacious in a diet-induced obese mouse model, retained a favorable cardiovascular profile in rat, and demonstrated dramatic improvement in effects on mean arterial pressure in our dog cardiovascular model compared to other series reported by our group. However, this analogue also led to prolongation of the QT interval in the dog that was linked to affinity for hERG channel and unexpectedly potent functional blockade of this ion channel.

Acylation↗
PubMed2006

Effects of conjugated equine estrogen on stroke in the Women's Health Initiative.

BACKGROUND: The Women's Health Initiative (WHI) Estrogen Alone trial assessed the balance of benefits and risks of hormone use in healthy postmenopausal women. The trial was stopped prematurely because there was no benefit for coronary heart disease and an increased risk of stroke. This report provides a thorough analysis of the stroke finding using the final results from the completed trial database. METHODS AND RESULTS: The WHI Estrogen Alone hormone trial is a multicenter, double-blind, placebo-controlled, randomized clinical trial in 10,739 women aged 50 to 79 years who were given daily conjugated equine estrogen (CEE; 0.625 mg; n=5310) or placebo (n=5429). During an average follow-up of 7.1 years, there were 168 strokes in the CEE group and 127 in the placebo group; 80.3% of strokes were ischemic. For all stroke the intention-to-treat hazard ratio [HR] (95% CI) for CEE versus placebo was 1.37 (1.09 to 1.73). The HR (95% CI) was 1.55 (1.19 to 2.01) for ischemic stroke and 0.64 (0.35, 1.18) for hemorrhagic stroke. The HRs indicate excess risk of ischemic stroke was apparent in all categories of baseline stroke risk, including younger and more recently menopausal women and in women with prior or current use of statins or aspirin. CONCLUSIONS: CEE increases the risk of ischemic stroke in generally healthy postmenopausal women. The excess risk appeared to be present in all subgroups of women examined, including younger and more recently menopausal women. There was no convincing evidence to suggest that CEE had an effect on the risk of hemorrhagic stroke.

Aged↗
PubMed2006

Screening for cardiovascular safety: a structure-activity approach for guiding lead selection of melanin concentrating hormone receptor 1 antagonists.

An inactin-anesthetized rat cardiovascular (CV) assay was employed in a screening mode to triage multiple classes of melanin-concentrating hormone receptor 1 (MCHr1) antagonists. Lead identification was based on a compound profile producing high drug concentration in both plasma (>40 microM) and brain (>20 microg/g) with <15% change in cardiovascular endpoints. As a result of these stringent requirements, lead optimization activities on multiple classes of MCHr1 antagonists were terminated. After providing evidence that the cardiovascular liabilities were not a function of MCHr1 antagonism, continued screening identified the chromone-substituted aminopiperidine amides as a class of MCHr1 antagonists that demonstrated a safe cardiovascular profile at high drug concentrations in both plasma and brain. The high incidence of adverse cardiovascular effects associated with an array of MCHr1 antagonists of significant chemical diversity, combined with the stringent safety requirements for antiobesity drugs, highlight the importance of incorporating cardiovascular safety assessment early in the lead selection process.

Animals↗
PubMed2006

Pediatric stroke initiatives and preliminary studies: What is known and what is needed?

Cerebrovascular disorders are increasingly recognized as important causes of mortality and morbidity in the pediatric population. However, there have been no clinical trials performed to assess the safety and tolerability of acute interventions or secondary preventative treatments. In 2002, the International Pediatric Stroke Study was launched to create a network of investigators, with an interest in developing standards of practice, as well as design and implement the first-ever clinical trials in pediatric stroke. This article reviews existing studies in pediatric stroke epidemiology, risk factors, outcomes, as well as experience with antithrombotic trials in children. From there, current and future initiatives in the development of clinical trials in pediatric stroke are evaluated.

Child↗
PubMed2005

Aminopiperidine indazoles as orally efficacious melanin concentrating hormone receptor-1 antagonists.

The synthesis and biological evaluation of novel 3-amino indazole melanin concentrating hormone receptor-1 antagonists are reported, several of which demonstrated functional activity of less than 100nM. Compounds 19 and 28, two of the more potent compounds identified in this study, were characterized by high exposure in the brain and demonstrated robust efficacy when dosed in diet-induced obese mice.

Administration, Oral↗
PubMed2005

Discovery and characterization of aminopiperidinecoumarin melanin concentrating hormone receptor 1 antagonists.

4-(1-Benzo[1,3]dioxol-5-ylmethylpiperidine-4-ylmethyl)-6-chlorochromen-2-one (7) is a potent, orally bioavailable melanin concentrating hormone receptor 1 (MCHr1) antagonist that causes dose-dependent weight loss in diet-induced obese mice. Further evaluation of 7 in an anesthetized dog model of cardiovascular safety revealed adverse hemodynamic effects at a plasma concentration comparable to the minimally effective therapeutic concentration. These results highlight the need for scrutiny of the cardiovascular safety profile of MCHr1 antagonists.

Administration, Oral↗
PubMed2005

Pediatric stroke: what do we know and what do we need to know?

Stroke is a heterogeneous disorder and an important cause of mortality and chronic morbidity in children. Estimates of international incidence rates for childhood stroke have varied widely. Arterial ischemic stroke is reported to be more common than hemorrhagic stroke in children. The clinical presentation of stroke in children differs according to the child's age and stroke type and location. Several risk factors for ischemic and hemorrhagic stroke in children have been reported and include cardiac disorders, blood disorders, vasculopathies, viral infections, and arteriovenous malformations. Current treatment recommendations for stroke in children are based on small nonrandomized trials, adult stroke studies, case series, or consensus or individual expert opinion. Over half of children with stroke will develop lifelong cognitive or motor disability, and up to a third will have a recurrent stroke. International studies have provided important information on stroke in children, but major gaps in our knowledge of the disorder still exist. Currently, there is a need for prospective cohort studies in diverse populations, which utilize a consensus pediatric stroke classification system and a standard evaluation of risk factors and outcome, so that treatment and prevention strategies can be developed.

Age of Onset↗
PubMed2005

Perinatal arterial stroke: understanding mechanisms and outcomes.

Arterial ischemic infarction occurring around the time of birth is an increasingly recognized cause of neurological disability in children. The rate of arterial infarction in neonates is as high as the annual incidence of large-vessel ischemic stroke in adults. Factors contributing to this increased risk of stroke among neonates include complications that occur before, during, and after delivery. Maternal conditions that have been associated with perinatal stroke in the fetus include prothrombotic disorders, cocaine abuse, and placental complications such as chorioamnionitis and placental vasculopathy. In many cases, the placenta is suspected to be the underlying embolic source for perinatal stroke, although data on placental pathology is often lacking. During the delivery process, an infant may develop a cervical arterial dissection that leads to stroke. Several conditions in the neonatal period predispose to perinatal stroke including prothrombotic disorders, congenital heart disease, meningitis, and systemic infection. Perinatal stroke may present with neonatal seizures during the first weeks of life or may be asymptomatic until months later when the infant is first noted to have pathological handedness. The outcome of perinatal stroke is variable and depends on severity, anatomic localization, and other factors not yet well characterized. As many as 50% of infants with documented stroke recognized in the newborn period do not develop a hemiparesis. The incidence, clinical presentation, pathogenesis, risk factors, and outcome of this increasingly recognized disorder are reviewed.

Cerebral Arterial Diseases↗
PubMed2004

Comparison of MRI and CT for detection of acute intracerebral hemorrhage.

CONTEXT: Noncontrast computed tomography (CT) is the standard brain imaging study for the initial evaluation of patients with acute stroke symptoms. Multimodal magnetic resonance imaging (MRI) has been proposed as an alternative to CT in the emergency stroke setting. However, the accuracy of MRI relative to CT for the detection of hyperacute intracerebral hemorrhage has not been demonstrated. OBJECTIVE: To compare the accuracy of MRI and CT for detection of acute intracerebral hemorrhage in patients presenting with acute focal stroke symptoms. DESIGN, SETTING, AND PATIENTS: A prospective, multicenter study was performed at 2 stroke centers (UCLA Medical Center and Suburban Hospital, Bethesda, Md), between October 2000 and February 2003. Patients presenting with focal stroke symptoms within 6 hours of onset underwent brain MRI followed by noncontrast CT. MAIN OUTCOME MEASURES: Acute intracerebral hemorrhage and any intracerebral hemorrhage diagnosed on gradient recalled echo (GRE) MRI and CT scans by a consensus of 4 blinded readers. RESULTS: The study was stopped early, after 200 patients were enrolled, when it became apparent at the time of an unplanned interim analysis that MRI was detecting cases of hemorrhagic transformation not detected by CT. For the diagnosis of any hemorrhage, MRI was positive in 71 patients with CT positive in 29 (P<.001). For the diagnosis of acute hemorrhage, MRI and CT were equivalent (96% concordance). Acute hemorrhage was diagnosed in 25 patients on both MRI and CT. In 4 other patients, acute hemorrhage was present on MRI but not on the corresponding CT--each of these 4 cases was interpreted as hemorrhagic transformation of an ischemic infarct. In 3 patients, regions interpreted as acute hemorrhage on CT were interpreted as chronic hemorrhage on MRI. In 1 patient, subarachnoid hemorrhage was diagnosed on CT but not on MRI. In 49 patients, chronic hemorrhage, most often microbleeds, was visualized on MRI but not on CT. CONCLUSION: MRI may be as accurate as CT for the detection of acute hemorrhage in patients presenting with acute focal stroke symptoms and is more accurate than CT for the detection of chronic intracerebral hemorrhage.

Acute Disease↗
PubMed2004

Design and synthesis of novel cyanoguanidine ATP-sensitive potassium channel openers for the treatment of overactive bladder.

Thiourea derivatives were identified as glyburide-reversible potassium channel openers through high-throughput screening. Based on these findings, a number of novel cyanoguanidines were designed and synthesized, which hyperpolarized human bladder K(ATP) channels. These agents are potent full agonists in relaxing electrically-stimulated pig bladder strips. The synthesis, SAR and biological properties of these agents are discussed.

Adenosine Triphosphate↗
PubMed2004

Stroke in newborn infants.

The few days before and after birth are a time of special risk for stroke in both mother and infant, probably related to activation of coagulation mechanisms in this critical period. Arterial ischaemic stroke around the time of birth is recognised in about one in 4000 full-term infants, and may present with neurological and systemic signs in the newborn. Neonatal seizures are most commonly the clinical finding that triggers assessment. In other children, perinatal stroke is recognised only retrospectively, with emerging hemiparesis or seizures after the early months of life. Risk factors for perinatal stroke include hereditary or acquired thrombophilias and environmental factors. Perinatal stroke underlies an important share of congenital hemiplegic cerebral palsy, and probably some spastic quadriplegic cerebral palsy and seizure disorders. There is much to be learned about the natural history of perinatal stroke, and there are as yet no evidence-based strategies for prevention or treatment.

Brain Ischemia↗