Naji Alamuddin

Bioactive products formed in humans from fish oils

Resolvins, maresins, and protectins can be formed from fish oils. These specialized pro-resolving mediators (SPMs) have been implicated in the resolution of inflammation. Synthetic versions of such SPMs exert anti-inflammatory effects in vitro and when administered to animal models. However, their importance as endogenous products formed in sufficient amounts to exert anti-inflammatory actions in vivo remains speculative. We biased our ability to detect SPMs formed in healthy volunteers by supplementing fish oil in doses shown previously to influence blood pressure and platelet aggregation under placebo-controlled conditions. Additionally, we sought to determine the relative formation of SPMs during an acute inflammatory response and its resolution, evoked in healthy volunteers by bacterial lipopolysaccharide (LPS). Bioactive lipids, enzymatic epoxyeicosatrienoic acids (EETs), and free radical-catalyzed prostanoids [isoprostanes (iPs)] formed from arachidonic acid and the fish oils, served as comparators. Despite the clear shift from ω-6 to ω-3 EETs and iPs, we failed to detect a consistent signal, in most cases, of SPM formation in urine or plasma in response to fish oil, and in all cases in response to LPS on a background of fish oil. Our results question the relevance of these SPMs to the putative anti-inflammatory effects of fish oils in humans.

Niacin and biosynthesis of PGD2 by platelet COX-1 in mice and humans

The clinical use of niacin to treat dyslipidemic conditions is limited by noxious side effects, most commonly facial flushing. In mice, niacin-induced flushing results from COX-1-dependent formation of PGD₂ and PGE₂ followed by COX-2-dependent production of PGE₂. Consistent with this, niacin-induced flushing in humans is attenuated when niacin is combined with an antagonist of the PGD₂ receptor DP1. NSAID-mediated suppression of COX-2-derived PGI₂ has negative cardiovascular consequences, yet little is known about the cardiovascular biology of PGD₂. Here, we show that PGD₂ biosynthesis is augmented during platelet activation in humans and, although vascular expression of DP1 is conserved between humans and mice, platelet DP1 is not present in mice. Despite this, DP1 deletion in mice augmented aneurysm formation and the hypertensive response to Ang II and accelerated atherogenesis and thrombogenesis. Furthermore, COX inhibitors in humans, as well as platelet depletion, COX-1 knockdown, and COX-2 deletion in mice, revealed that niacin evoked platelet COX-1-derived PGD₂ biosynthesis. Finally, ADP-induced spreading on fibrinogen was augmented by niacin in washed human platelets, coincident with increased thromboxane (Tx) formation. However, in platelet-rich plasma, where formation of both Tx and PGD₂ was increased, spreading was not as pronounced and was inhibited by DP1 activation. Thus, PGD₂, like PGI₂, may function as a homeostatic response to thrombogenic and hypertensive stimuli and may have particular relevance as a constraint on platelets during niacin therapy.

Association between weight bias internalization and metabolic syndrome among treatment-seeking individuals with obesity.

Weight stigma is a chronic stressor that may increase cardiometabolic risk. Some individuals with obesity self‐stigmatize (i.e., weight bias internalization, WBI). No study to date has examined whether WBI is associated with metabolic syndrome.

Comparative Impact on Prostanoid Biosynthesis of Celecoxib and the Novel Nonsteroidal Anti-Inflammatory Drug CG100649

Nonsteroidal anti‐inflammatory drugs (NSAIDs) elevate cardiovascular risk by disrupting cyclooxygenase‐2 (COX‐2)‐dependent biosynthesis of prostacyclin (PGI2). CG100649 is a novel NSAID proposed to inhibit both COX‐2 and carbonic anhydrase (CA)‐I/‐II. We compared its impact on prostanoid biosynthesis with that of celecoxib, an NSAID purposefully designed to selectively inhibit COX‐2. In a controlled, double‐blind randomized trial, single oral doses of 2 or 8 mg CG100649, 200 mg celecoxib, or placebo were well tolerated by healthy volunteers (n = 23). Both CG100649 and celecoxib had the effect of depressing urinary excretion of 2,3‐dinor‐6‐keto‐PGF1α (PGI‐M); the effect of CG100649 was dose‐dependent and more sustained (up to 240 h after the dose) than that of celecoxib. Neither CG100649 nor celecoxib significantly inhibited COX‐1‐dependent prostanoid formation. CA inhibition was not detected after administration of CG100649, despite its partitioning asymmetrically into erythrocytes. CG100649 and celecoxib are both relatively selective inhibitors of COX‐2, but they differ in duration of action. Whether they have similar impact on cardiovascular events remains to be determined.

Behavioral Treatment of the Patient with Obesity

Advisory panels encourage persons with obesity to lose 5% to 10% of body weight, which can be achieved with dietary change, increased physical activity, and behavioral therapy. Patients participate in weekly individual or group treatment sessions delivered in-person or by telephone. Large-scale trials have demonstrated the effectiveness of this approach, with resulting improvement in cardiovascular disease risk factors. Weight regain is common. Several strategies improve weight loss maintenance, including monthly or more frequent follow-up with an interventionist. Digitally-delivered approaches are promising because they have the potential to reach more individuals.

Lorcaserin plus lifestyle modification for weight loss maintenance: Rationale and design for a randomized controlled trial

BACKGROUND/AIMS Few studies have examined the efficacy of recently approved medications for chronic weight management in facilitating the maintenance of lost weight. This paper provides an overview of the design and rationale for a trial investigating whether lorcaserin, when combined with behavioral weight loss maintenance sessions (WLM), will facilitate the maintenance of losses of ≥5% of initial weight. METHODS In this two-phase trial, participants with obesity will enroll in a 14-week run-in diet program consisting of weekly group lifestyle modification sessions and a 1000-1200kcal/d meal replacement diet. Participants who complete this weight induction phase and lose at least 5% of initial weight will then be randomized to 52weeks of WLM plus lorcaserin or WLM plus placebo. We hypothesize that at 52weeks post randomization, participants assigned to WLM plus lorcaserin will achieve significantly better maintenance of the prior 5% weight loss. RESULTS We will recruit 182 adults with obesity to participate in the diet run-in, 136 of whom (75%) are expected to become eligible for the randomized controlled trial. Co-primary outcomes include the percentage of participants who maintain a loss of at least 5% of initial weight at week 52 and change in weight (kg) from randomization to week 52. CONCLUSIONS This two-phase design will allow us to determine the potential efficacy of chronic weight management using lorcaserin for maintaining initial losses of at least 5% body weight, induced by the use of a structured meal-replacement diet. This combined approach holds promise of achieving larger long-term weight losses. CLINICAL TRIAL REGISTRATION NCT02388568 on ClinicalTrials.gov.

A Randomized Trial of Lorcaserin and Lifestyle Counseling for Maintaining Weight Loss Achieved with a Low-Calorie Diet: Lorcaserin and Lifestyle for Weight Loss Maintenance

Improving the maintenance of lost weight remains a critical challenge, which can be addressed by long‐term behavioral and/or pharmacological interventions.

Management of Obesity

This review examines weight loss and accompanying improvements in obesity-related comorbidities produced by intensive lifestyle intervention, pharmacotherapy, and bariatric surgery. Obese individuals lose approximately 6 to 8 kg (approximately 6% to 8% of initial weight) with 6 months of participation in a high-intensity lifestyle intervention (≥ 14 treatment visits) consisting of diet, physical activity, and behavior therapy. Such losses reduce progression to type 2 diabetes in at-risk people and decrease blood pressure and triglyceride levels. All diets, regardless of macronutrient composition, can produce clinically meaningful weight loss (> 5%) if they induce a deficit ≥ 500 kcal/d. Physical activity of 150 to 180 min/wk yields modest short-term weight loss compared with diet but contributes to improvements in obesity-related conditions. Gradual weight regain is common after lifestyle intervention but can be prevented by continued participation in monthly weight loss maintenance sessions, as well as by high levels of physical activity (ie, 200 to 300 min/wk). Patients unable to reduce satisfactorily with lifestyle intervention may be candidates for pharmacotherapy, recommended as an adjunct. Five medications have been approved by the US Food and Drug Administration for chronic weight management, and each has its own risk/benefit profile. The addition of these medications to lifestyle intervention increases mean weight loss by 2.5 to 8.9 kg compared with placebo. Patients with severe obesity who are unable to reduce successfully with lifestyle intervention and pharmacotherapy are eligible for bariatric surgery, including Roux-en-Y gastric bypass, sleeve gastrectomy, or adjustable gastric banding. The first two procedures yield long-term (≥ 3 years) reductions of ≥ 20% of initial weight that are associated with decreases in morbidity and potentially mortality. Greater resources and dissemination efforts are needed to increase the availability of these three approaches for the millions of Americans who would benefit from them.

GCG100649, A Novel Cyclooxygenase-2 Inhibitor, Exhibits a Drug Disposition Profile in Healthy Volunteers Compatible With High Affinity to Carbonic Anhydrase-I/II: Preliminary Dose–Exposure Relationships to Define Clinical Development Strategies

CG100649, proposed as a dual inhibitor of cyclooxygenase (COX)‐2 and carbonic anhydrase (CA)‐I/‐II, is long‐lived in plasma and whole blood. The mean ± SD half‐lives were 131 ± 19 and 127 ± 33 hours, respectively, after administration of oral single doses of 2 or 8 mg CG100649 to healthy volunteers. The whole blood to plasma concentration ratio (78 ± 23) for CG100649 is linear over the dosing interval reflecting a biodistribution pattern consistent with other strong CA‐inhibitors (e.g., acetazolamide, methazolamide). A one compartment model with first order absorption and elimination described CG100649 concentration‐time profiles well. Estimates (%relative SD) between plasma and whole blood were in agreement for the absorption rate constant, 1.54 (58.6) and 1.43 (28.0) hour−1, respectively, but considerably different for clearance, 3.29 (10.4) and 0.04 (7.7) L/h/70 kg, and for volume of distribution, 559 (6.7) and 7.6 (2.4) L/70 kg, respectively. The extent to which these unique PK characteristics of CG100649 discriminate it from other COX‐2 inhibitors will be the subject of future investigation.

Short- and Long-Term Changes in Health-Related Quality of Life with Weight Loss: Results from a Randomized Controlled Trial: Health-Related Quality of Life and Weight Loss

The objective of this study was to determine the effects of weight loss and weight loss maintenance (WLM) on weight‐specific health‐related quality of life in a 66‐week trial.