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 ß-cells and intestinal enteroendocrine cells. When activated by fatty acids, GPR40 elicits increased insulin secretion from islet ß-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). Efforts were made to identify a suitable GPR40 AgoPAM tool molecule to investigate mechanism of action and de-risk liver toxicity of GPR40 AgoPAMs due to reactive acyl-glucuronide (AG) metabolites.

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. After a thorough evaluation, the patient was found to have underlying Ehlers-Danlos Syndrome that was previously undiagnosed. The patient was medically treated with dual antiplatelet therapy and statin and discharged with strict follow-up. This case is a good example of a rare and life-threatening disease process that was observed in a patient who was found to have Ehlers-Danlos Syndrome that was previously unknown.

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. We have a case of acute multivessel type 2 SCAD involving the obtuse marginal artery and posterior descending artery that may have been secondary to Amberen, an over-the-counter supplement used to relieve symptoms of menopause. This is a rare case of multivessel SCAD possibly caused by an over-the-counter supplement not previously known to trigger this disease process.

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. There were 14 women and one man with mean age 42 +/- 6 years, preoperative body mass index was 49.3 +/- 6.0 kg/m(2), and mean postoperative weight loss was 55.9 kg. Mean onset of symptoms was 5.2 +/- 3.9 months after surgery. Presenting symptoms were lightheadedness in 15 (100%), near-syncope in 11 (73%), and syncope in nine (60%). All but one patient had a positive tilt table test with eight (53%) having a neurocardiogenic response, three (20%) having a dysautonomic response, and (20%) having a postural tachycardia response. The likely mechanism of orthostatic intolerance is autonomic insufficiency in combination with reverse course of obesity-related hypertension. The majority of the patients (12 out of 15) responded to standard therapy for autonomic insufficiency. CONCLUSION: Some patients may develop significant orthostatic intolerance due to autonomic insufficiency following bariatric surgery, and awareness of the potential association between bariatric surgery and new orthostatic intolerance is important for providing timely care.

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 AP5, which possesses an improved metabolic profile while demonstrating sustained glucose lowering.

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. MK-2305 decreased fasting glucose after acute and chronic treatment. MK-2305-mediated changes in glucose were coupled with increases in plasma insulin during hyperglycemia and glucose challenges but not during fasting, when glucose was normalized. To determine the mechanism(s) mediating these changes in glucose metabolism, we measured the absolute contribution of precursors to glucose production in the presence or absence of MK-2305. MK-2305 treatment resulted in decreased endogenous glucose production (EGP) driven primarily through changes in gluconeogenesis from substrates entering at the TCA cycle. The decrease in EGP was not likely due to a direct effect on the liver, as isolated perfused liver studies showed no effect of MK-2305 ex vivo and GPR40 is not expressed in the liver. Taken together, our results suggest MK-2305 treatment increases glucose stimulated insulin secretion (GSIS), resulting in changes to hepatic substrate handling that improve glucose homeostasis in the diabetic state. Importantly, these data extend our understanding of the underlying mechanisms by which GPR40 partial agonists reduce hyperglycemia.

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). Herein, we report the discovery and optimization of a series of potent, selective GPR40 agoPAMs. Compound 24 demonstrated sustained glucose lowering in a chronic study of Goto Kakizaki rats, showing no signs of tachyphylaxis for this mechanism.

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. Here we describe how GPR40 AgoPAMs stimulate both insulin and incretin secretion in vivo over time in diabetic GK rats. We also describe effects of AgoPAMs in vivo to lower glucose and body weight beyond what is seen with partial GPR40 agonists in both the acute and chronic setting. Further comparisons of the glucose lowering profile of AgoPAMs suggest these compounds may possess greater glucose control even in the presence of elevated glucagon secretion, an unexpected feature observed with both acute and chronic treatment with AgoPAMs. Together these studies highlight the complexity of GPR40 pharmacology and the potential additional benefits AgoPAMs may possess above partial agonists for the diabetic patient.

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.

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. Coronary arteriography showed a thrombus occluding the proximal left anterior descending artery (LAD). Aggressive antiplatelet therapy with aspirin, clopidogrel, and eptifibatide was pursued, in addition to standard post-MI care. This led to the successful resolution of symptoms and dissolution of the thrombus, demonstrated by repeat coronary arteriography. Five months later, he presented with similar symptoms during exercise after lifting heavy weights, and was found to have another acute MI. Coronary arteriography again showed a thrombus occluding the LAD. No evidence of coronary artery dissection or vasospasm was found. Only mild atherosclerotic plaque burden was observed on both occasions by intravascular ultrasound. A bare metal stent was placed at the site as it was thought this site had acted as a nidus for small plaque rupture and thrombus formation. Elevated serum factor VIII activity at 205% (reference range 60%-140%) was found, a rare cause of hypercoagulability. Further workup revealed a patent foramen ovale during a Valsalva maneuver by transesophageal echocardiography. Both events occurred during weight lifting, which can transiently increase right heart pressure in a similar way to the Valsalva maneuver. In light of all the findings, we concluded that an exercise-related increase in factor VIII activity led to coronary arterial thrombosis in the presence of a small ruptured plaque. Alternatively, venous clots may have traversed the patent foramen ovale and occluded the LAD. In addition to continuing aggressive risk factor modification, anticoagulation therapy with warfarin was initiated with close follow-up.

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.