Design, synthesis and biological evaluation of indane derived GPR40 agoPAMs.

GPR40 (FFAR1 or FFA1) is a G protein-coupled receptor, primarily expressed in pancreatic islet β-cells and intestinal enteroendocrine cells. When activated by fatty acids, GPR40 elicits increased insulin secretion from islet β-cells only in the presence of elevated glucose levels. Towards this end, studies were undertaken towards discovering a novel GPR40 Agonist whose mode of action is via Positive Allosteric Modulation of the GPR40 receptor (AgoPAM).

Multivessel Spontaneous Coronary Artery Dissection: Amberen as a Possible Risk Factor.

Spontaneous coronary artery dissection (SCAD) is a rare phenomenon that causes acute, life-threatening myocardial infarction. Most notably occurring in the female population, certain risk factors have been implicated in SCAD including pregnancy, hormone therapy, stimulant drug use, connective tissue disorders and systemic inflammatory disorders. However, the effects of over-the-counter supplements have not been widely studied in SCAD.

Spontaneous Coronary Artery Dissection in a Patient with Undiagnosed Ehlers-Danlos Syndrome.

Spontaneous coronary artery dissection (SCAD) is a rare and deadly cause of acute myocardial infarction (MI). It remains greatly misdiagnosed and carries a high in-hospital mortality rate. Herein, we report a healthy 38-year-old female who presented to our institution for non-ST segment myocardial infarction, in which subsequent coronary angiogram revealed a type 2 spontaneous coronary artery dissection of the obtuse marginal branch with diffuse single-vessel disease of the circumflex artery.

Structure-Activity Relationship of Novel and Selective Biaryl-Chroman GPR40 AgoPAMs.

A series of biaryl chromans exhibiting potent and selective agonism for the GPR40 receptor with positive allosteric modulation of endogenous ligands (AgoPAM) were discovered as potential therapeutics for the treatment of type II diabetes. Optimization of physicochemical properties through modification of the pendant aryl rings resulted in the identification of compound , which possesses an improved metabolic profile while demonstrating sustained glucose lowering.

GPR40 partial agonists and AgoPAMs: Differentiating effects on glucose and hormonal secretions in the rodent.

GPR40 agonists are effective antidiabetic agents believed to lower glucose through direct effects on the beta cell to increase glucose stimulated insulin secretion. However, not all GPR40 agonists are the same. Partial agonists lower glucose through direct effects on the pancreas, whereas GPR40 AgoPAMs may incorporate additional therapeutic effects through increases in insulinotrophic incretins secreted by the gut.

GPR40 partial agonist MK-2305 lower fasting glucose in the Goto Kakizaki rat via suppression of endogenous glucose production.

GPR40 (FFA1) is a fatty acid receptor whose activation results in potent glucose lowering and insulinotropic effects in vivo. Several reports illustrate that GPR40 agonists exert glucose lowering in diabetic humans. To assess the mechanisms by which GPR40 partial agonists improve glucose homeostasis, we evaluated the effects of MK-2305, a potent and selective partial GPR40 agonist, in diabetic Goto Kakizaki rats.

Design and Synthesis of Novel, Selective GPR40 AgoPAMs.

GPR40 is a G-protein-coupled receptor expressed primarily in pancreatic islets and intestinal L-cells that has been a target of significant recent therapeutic interest for type II diabetes. Activation of GPR40 by partial agonists elicits insulin secretion only in the presence of elevated blood glucose levels, minimizing the risk of hypoglycemia. GPR40 agoPAMs have shown superior efficacy to partial agonists as assessed in a glucose tolerability test (GTT).

Recurrent myocardial infarctions in a young football player secondary to thrombophilia, associated with elevated factor VIII activity.

Myocardial infarction (MI) due to coronary atherosclerosis in young adults is uncommon; rare causes such as cocaine abuse, arterial dissection, and thromboembolism should be considered. A 21-year-old football player, and otherwise healthy African American man, developed chest pain during exercise while bench-pressing 400 lbs. Acute MI was diagnosed based on physical examination, electrocardiography findings, and elevated cardiac enzymes.

New-onset orthostatic intolerance following bariatric surgery.

Background: As bariatric surgery has become an increasingly popular treatment for obesity, we have seen an increasing number of patients present after bariatric surgery with new-onset syncope, near-syncope, and lightheadedness.

Methods: We retrospectively reviewed patients who had had bariatric surgery referred to our institution for evaluation of orthostatic intolerance. We reviewed history, physical examination, type of bariatric surgery procedure, and tilt table test results in these patients.

[Lymphocytic hypophysitis and hypothalamitis-case report].

Lymphocytic hypophysitis is an unusual disorder that nearly exclusively affects women. We present a case of 69 year-old female patient who developed the symptoms of diabetes insipidus and partial insufficiency of the anterior pituitary gland. Magnetic resonance imaging of the brain revealed a mass involving the sella and suprasellar region.

Successful radiofrequency catheter ablation of left lateral accessory pathway using transseptal approach during pregnancy.

Recurrent supraventricular tachycardia (SVT) associated with the Wolff-Parkinson-White syndrome during pregnancy may be difficult to manage, mainly due to concerns about the effects of pharmacotherapy on the fetus. We report on a 32 year old woman in her 22nd week of pregnancy with recurrent symptomatic SVT in which standard pharmacotherapy had been ineffectual, contraindicated or poorly tolerated and in whom we were able to perform a successful transseptal ablation of a left lateral accessory pathway.

Permanent cardiac pacing as primary therapy for neurocardiogenic (reflex) syncope.

Recurrent reflex (or neurocardiogenic) syncope is a common clinical problem. Pacemaker therapy has been advocated as a potential therapy in severe or drug refractory cases of reflex syncope, while others have suggested that it may provide a benefit if employed as a primary therapeutic modality. The following paper reviews the concepts behind pacemaker therapy for reflex syncope and the results of various clinical trials that have evaluated its potential utility as a primary therapeutic modality.

Treatment of postural orthostatic tachycardia syndrome and inappropriate sinus tachycardia.

Postural orthostatic tachycardia syndrome and inappropriate sinus tachycardia are two clinically different entities but with significant overlap of symptoms. Treatment by and large is medical; however, other modalities of treatment are being evaluated.

Syncope resulting from autonomic insufficiency syndromes associated with orthostatic intolerance.

The disorders of autonomic control associated with orthostatic intolerance are a diverse group that can result in syncope and near-syncope. A basic understanding of these disorders is essential to diagnosis and proper treatment. Ongoing studies should help to define better the spectrum of these disorders and to elaborate better diagnostic and treatment modalities.

Vasodepressor Syncope.

Neurocardiogenic syncope is a common disorder affecting various individuals of different ages with a wide variety of circumstances and comorbid conditions. Although a large amount of data is available regarding evaluation and treatment options, there is still sufficient latitude for the physician to exercise clinical judgment. We summarize current opinions on treatment here and also add some of our own bias regarding how to manage such patients.

Preliminary observations on the use of midodrine hydrochloride in the treatment of refractory neurocardiogenic syncope.

Recurrent episodes of neurocardiogenic syncope that occur without warning are a common cause of recurrent syncope that can be identified during head upright tilt table testing. While the use of beta blockers, theophyllines, fludrocortisone, disopyramide, and serotonin reuptake inhibitors can be useful in the prevention of episodes, some patients are either unresponsive to or poorly tolerant of these agents. We investigated the use of the peripheral alpha stimulating agent midodrine in preventing both tilt-induced and spontaneous neurocardiogenic syncope.

Cerebral syncope: loss of consciousness associated with cerebral vasoconstriction in the absence of systemic hypotension.

Transcranial Doppler (TCD) ultrasonography done during head-upright tilt induced neurocardiogenic syncope has demonstrated that cerebral vasoconstriction occurs concomitant with (or precedes) loss of consciousness. This article demonstrates evidence that cerebral blood flow changes alone (vasoconstriction), in the absence of systemic hypotension, may result in syncope. Five patients (4 men, 1 woman; mean age 41 +/- 17 years) with recurrent unexplained syncope were evaluated by use of an upright tilt table test for 45 minutes with or without an infusion of low dose isoproterenol.

Update on implantable cardioverter-defibrillators. New, safer devices have led to changes in indications.

The safety and efficacy of ICDs have improved significantly in the past few years. Recent evidence supports the value of these devices not only for secondary prevention of sudden cardiac death, but also for primary prevention in post-myocardial infarction patients with poor left ventricular function, unsustained ventricular tachycardia, and inducible ventricular tachycardia on electrophysiologic study. Transvenous defibrillation using the defibrillator case as the high-voltage electrode and a biphasic shock is currently the procedure of choice.

Catheter ablation for atrial flutter and fibrillation. An effective alternative to medical therapy.

Atrial flutter and atrial fibrillation are common arrhythmias that can be difficult to manage clinically. In many patients, these conditions are refractory to pharmacologic therapy because of drug failure or intolerance. Radiofrequency catheter ablation may be a reasonable alternative in patients with typical atrial flutter.

The postural orthostatic tachycardia syndrome: a neurocardiogenic variant identified during head-up tilt table testing.

Head upright tilt table testing has emerged as an accepted modality for identifying an individual's predisposition to episodes of autonomically mediated hypotension and bradycardia that are sufficiently profound so that transient loss of consciousness ensues (neurocardiogenic syncope). However it has also become apparent that less dramatic falls in blood pressure, while not sufficient to cause full syncope, may produce symptoms such as near syncope, vertigo, dizziness, and TIA-like episodes. We have identified a subgroup of individuals with a mild form of autonomic dysfunction with symptoms of postural tachycardia and lightheadedness, disabling fatigue, exercise intolerance, dizziness, and near syncope.