Three Doses of Vitamin D and Cognitive Outcomes in Older Women: A Double-Blind Randomized Controlled Trial.

Vitamin D may affect cognitive performance, but previous studies are either short term or observational. We conducted a randomized controlled trial of vitamin D supplementation on domain-specific cognitive measures in postmenopausal women. Overweight/obese women with serum 25-hydroxyvitamin D (25OHD) levels less than 30 ng/mL were recruited. Vitamin D3 supplementation (600, 2,000, or 4,000 IU/d) was randomly assigned in a double-blinded manner for 1 year. Serum 25-hydroxyvitamin D, osteocalcin (total and undercarboxylated), amyloid beta, parathyroid hormone, and estradiol were analyzed before and after supplementation. Cognitive tests were administered after treatment. The women (58 ± 6 years; body mass index, 30.0 ± 3.5 kg/m2) had a baseline serum 25-hydroxyvitamin D level of 22.6 ± 5.8 ng/mL that increased to 30.2 ± 5.6, 36.0 ± 4.9, and 40.8 ± 7.0 ng/mL in the 600, 2,000, and 4,000 IU/d groups, respectively (p < .001). Participants taking 2,000 IU/d compared to other doses performed better in learning and memory tests (p < .05), yet the 4,000 IU/d group had a slower reaction time compared to the 600 IU/d group. Multiple regression indicated that serum undercarboxylated osteocalcin predicted tasks associated with reaction time and executive function, whereas body mass index and parathyroid hormone negatively predicted reaction time and executive function (p ≤ .01). These data suggest that vitamin D has differential effects on domain-specific cognitive measures and that a higher dose may negatively affect reaction time.

Virtual screening to identify potent sepiapterin reductase inhibitors.

Sepiapterin reductase has been identified as a potential drug target for neuropathic and inflammatory pain. Virtual screening was executed against a publicly available x-ray crystal structure of sepiapterin reductase. A set of structurally diverse and potent sepiapterin reductase inhibitors was identified. This set of compounds with favorable ligand efficiency and lipophilic efficiency are tractable for further optimization. An SAR follow-up library was synthesized based on one of the virtual screening hits exploring SAR.

Pharmacological Assessment of Sepiapterin Reductase Inhibition on Tactile Response in the Rat.

There is an unmet medical need for nonopioid pain therapies in human populations; several pathways are under investigation for possible therapeutic intervention. Tetrahydrobiopterin (BH4) has received attention recently as a mediator of neuropathic pain. Recent reports have implicated sepiapterin reductase (SPR) in this pain pathway as a regulator of BH4 production. To evaluate the role of SPR inhibition on BH4 reduction, we developed analytical methods to monitor the relationship between the plasma concentration of test article and endogenous pterins and applied these in the rat spinal nerve ligation pain model. Sepiapterin is an endogenous substrate, which accumulates upon inhibition of SPR. In response to a potent inhibitor of SPR, plasma concentrations of sepiapterin increased proportionally with exposure. An indirect-effect pharmacokinetic/pharmacodynamic model was developed to describe the relationship between the plasma pharmacokinetics of test article and plasma sepiapterin levels in the rat, which was used to determine an in vivo SPR IC50 value. SPR inhibition and mechanical allodynia were assessed coordinately with pterin biomarkers in plasma and at the site of neuronal injury (i.e., dorsal root ganglion). Upon daily oral administration for 3 consecutive days, unbound plasma concentrations of test article exceeded the unbound in vivo rat SPR IC90 throughout the dose intervals, leading to a 60% reduction in BH4 in the dorsal root ganglion. Despite evidence for pharmacological modulation of the BH4 pathway, there was no significant effect on the tactile paw withdrawal threshold relative to vehicle-treated controls.

Metabolism, Excretion, and Mass Balance of Solithromycin in Humans.

Solithromycin, a novel macrolide and the first fluoroketolide, is being developed as a therapy for community-acquired bacterial pneumonia, with a distinct mechanism that provides activity against macrolide-resistant bacteria. The pharmacokinetics, metabolism, and excretion of solithromycin were studied in healthy male subjects after oral administration of a single 800-mg (∼100-µCi) dose of [14C]solithromycin. Solithromycin was well tolerated, and absorption from the solution occurred with a median time to peak concentration of 4.0 h. Solithromycin and the total radioactivity had similar profiles with no long-lived metabolites. The whole-blood total radioactivity was approximately 75% of the plasma total radioactivity. Recovery was essentially complete (mean, 90.6%), with 76.5% and 14.1% of the dose recovered in feces and urine, respectively. Unchanged solithromycin (CEM-101) was the predominant circulating radioactive component in plasma (77% of the total radioactivity area under the concentration-time curve [AUC]), with two minor plasma metabolites, CEM-214 and CEM-122 (N-acetyl-CEM-101), each accounting for approximately 5% of the total radioactivity. Urinary excretion was predominantly like that of the parent. Solithromycin was primarily eliminated in the feces after extensive metabolism via a complex metabolic pathway with CEM-262 as the major constituent (27.36% of the administered dose). Overall oxidative pathways, presumably carried out mostly by CYP3A4, represented the majority of the metabolism, with N-acetylation present to a lesser extent. No disproportionate human metabolites were observed.

Appetite and Gut Hormones Response to a Putative α-Glucosidase Inhibitor, Salacia Chinensis, in Overweight/Obese Adults: A Double Blind Randomized Controlled Trial.

Animal studies indicate Salacia reduces body weight, possibly due to its α-glucosidase inhibitor (α-GI) properties, but this has not been examined previously. In this study, a randomized, placebo-controlled, three-way cross-over design was used to evaluate whether Salacia Chinensis (SC) reduces appetite in healthy overweight/obese individuals (body mass index 28.8 ±3.6 kg/m²; 32 ± 12 years). Forty-eight participants were fasted overnight and consumed a dose of SC (300 or 500 mg) or placebo with a fixed breakfast meal at each visit. Appetite sensations, glycemic indices and gastrointestinal peptides were measured. Results indicated that SC had no effect on postprandial appetite. However, in women, hunger was reduced by SC compared to placebo at multiple time points (300 mg; p < 0.05), but not in men. Area under the curve (AUC) for serum glucose, insulin and amylin was attenuated with SC compared to placebo (p < 0.05). Glucagon like peptide-1 had two peaks after the meal, but the AUC did not differ between groups. The AUC of peak areas for peptide YY and ghrelin were greater for SC than placebo (p < 0.05). These findings indicate that Salacia decreases glycemic indices supporting its role as an α-GI, and affects certain gastrointestinal peptides suggesting it may be an appetite modulator.

Four Web-Based Interactive Endocrine Case Studies for Use in Undergraduate Medical Education.

INTRODUCTION: This resource is a collection of four case-based exercises intended to provide medical students with structured and focused opportunities to link basic science with clinical application. The cases are designed to help students self-evaluate their knowledge and develop a robust and well- integrated understanding of endocrine physiology and pathophysiology in the context of a representative range of endocrine disorders involving adrenal cortical, thyroid, and reproductive function. Although these cases were designed for, and used by, first-year students, they are also suitable for more advanced students. METHODS: Each case opens with a brief vignette containing a patient presentation and a history of present illness. The student first formulates a differential diagnosis and then sequentially narrows the differential by selecting from lists of diagnostic tests; correct answers with feedback are provided at each step. A diagnosis is ultimately required, and the student may be prompted to propose a treatment plan. RESULTS: End-of-course survey results from 128 first-year medical students suggest that the use of these interactive case studies was considered to be a worthwhile use of study time, and that knowledge gained in the correlate endocrine course was required to work through the cases. Students indicated that the levels of case and task complexity, along with feedback, were appropriate and helpful. DISCUSSION: These cases provide a resource for meeting the need for clinically relevant scenarios in the preclerkship years.

Crystal structures of human glycine receptor α3 bound to a novel class of analgesic potentiators.

Current therapies to treat persistent pain and neuropathic pain are limited by poor efficacy, side effects and risk of addiction. Here, we present a novel class of potent selective, central nervous system (CNS)-penetrant potentiators of glycine receptors (GlyRs), ligand-gated ion channels expressed in the CNS. AM-1488 increased the response to exogenous glycine in mouse spinal cord and significantly reversed mechanical allodynia induced by nerve injury in a mouse model of neuropathic pain. We obtained an X-ray crystal structure of human homopentameric GlyRα3 in complex with AM-3607, a potentiator of the same class with increased potency, and the agonist glycine, at 2.6-Å resolution. AM-3607 binds a novel allosteric site between subunits, which is adjacent to the orthosteric site where glycine binds. Our results provide new insights into the potentiation of cysteine-loop receptors by positive allosteric modulators and hold promise in structure-based design of GlyR modulators for the treatment of neuropathic pain.

Effects of disease salience and xenophobia on support for humanitarian aid.

This article examines how disease salience influences attitudes toward two types of humanitarian aid: sending foreign aid and housing refugees. Some have argued that disease salience increases levels of out-group prejudice through what is referred to as the behavioral immune system (BIS), and this increase in out-group prejudice works to shape policy attitudes. However, an alternative mechanism that may explain the effects of disease salience is contamination fear, which would suggest there is no group bias in the effects of disease threat. Existing work largely interprets opposition to policies that assist out-groups as evidence of out-group prejudice. We suggest it is necessary to separate measures of out-group animosity from opinions toward specific policies to determine whether increased out-group prejudice rather than fear of contamination is the mechanism by which disease salience impacts policy attitudes. Across two experiments, disease salience is shown to significantly decrease support for humanitarian aid, but only in the form of refugee support. Furthermore, there is converging evidence to suggest that any influence of disease salience on aid attitudes is not caused by a corresponding increase in xenophobia. We suggest that the mechanism by which disease threat influences policy attitudes is a general fear of contamination rather than xenophobia. These findings go against an important hypothesized mechanism of the BIS and have critical implications for the relationship between disease salience and attitudes toward transnational policies involving humanitarian aid.

Disrupted Nitric Oxide Metabolism from Type II Diabetes and Acute Exposure to Particulate Air Pollution.

Type II diabetes is an established cause of vascular impairment. Particulate air pollution is known to exacerbate cardiovascular and respiratory conditions, particularly in susceptible populations. This study set out to determine the impact of exposure to traffic pollution, with and without particle filtration, on vascular endothelial function in Type II diabetes. Endothelial production of nitric oxide (NO) has previously been linked to vascular health. Reactive hyperemia induces a significant increase in plasma nitrite, the proximal metabolite of NO, in healthy subjects, while diabetics have a lower and more variable level of response. Twenty type II diabetics and 20 controls (ages 46-70 years) were taken on a 1.5 hr roadway traffic air pollution exposure as passengers. We analyzed plasma nitrite, as a measure of vascular function, using forearm ischemia to elicit a reactive hyperemic response before and after exposure to one ride with and one without filtration of the particle components of pollution. Control subjects displayed a significant increase in plasma nitrite levels during reactive hyperemia. This response was no longer present following exposure to traffic air pollution, but did not vary with whether or not the particle phase was filtered out. Diabetics did not display an increase in nitrite levels following reactive hyperemia. This response was not altered following pollution exposure. These data suggest that components of acute traffic pollution exposure diminish vascular reactivity in non-diabetic individuals. It also confirms that type II diabetics have a preexisting diminished ability to appropriately respond to a vascular challenge, and that traffic pollution exposure does not cause a further measureable acute change in plasma nitrite levels in Type II diabetics.

Crystal structure of human glycine receptor-α3 bound to antagonist strychnine.

Neurotransmitter-gated ion channels of the Cys-loop receptor family are essential mediators of fast neurotransmission throughout the nervous system and are implicated in many neurological disorders. Available X-ray structures of prokaryotic and eukaryotic Cys-loop receptors provide tremendous insights into the binding of agonists, the subsequent opening of the ion channel, and the mechanism of channel activation. Yet the mechanism of inactivation by antagonists remains unknown. Here we present a 3.0 Å X-ray structure of the human glycine receptor-α3 homopentamer in complex with a high affinity, high-specificity antagonist, strychnine. Our structure allows us to explore in detail the molecular recognition of antagonists. Comparisons with previous structures reveal a mechanism for antagonist-induced inactivation of Cys-loop receptors, involving an expansion of the orthosteric binding site in the extracellular domain that is coupled to closure of the ion pore in the transmembrane domain.

Moderate weight loss in obese and overweight men preserves bone quality.

BACKGROUND: Weight loss (WL) negatively affects bone mineral density (BMD) in older populations and has specifically been shown in women. OBJECTIVE: In this prospective controlled trial, we examined variables of bone quality and endocrine changes after intentional WL in men. DESIGN: Thirty-eight overweight and obese [mean ± SD body mass index (in kg/m²): 31.9 ± 4.4; age: 58 ± 6 y] men were recruited to either WL through caloric restriction or weight maintenance (WM) for 6 mo. RESULTS: There was a -7.9 ± 4.4% and +0.2 ± 1.6% change in body weight in the WL and WM groups, respectively. There was a greater increase in femoral neck and total body BMD and bone mineral content (BMC) in the WM group than in the WL group (P-interaction effect < 0.05). In contrast, there was a trend for the tibia cortical thickness and area to decrease more in the WM group than in the WL group (P ≤ 0.08). There was a decrease in the periosteal circumference in both groups over time (P < 0.01) and no statistically significant changes in trabecular bone. Circulating total, free, and bioavailable estradiol decreased in the WL group compared with the WM group, and changes were different between groups (P < 0.05). Serum total and bioavailable testosterone increased in both groups (P < 0.01). Serum 25-hydroxyvitamin D increased to a similar extent in both groups (P < 0.05). CONCLUSIONS: Moderate WL in overweight and obese men did not decrease BMD at any anatomical site or alter cortical and trabecular bone and geometry. Also, despite increased BMD at some sites when maintaining excess body weight, cortical bone showed a trend in the opposite direction.

Pharmacokinetics and tolerability of the new second-generation nonnucleoside reverse- transcriptase inhibitor KM-023 in healthy subjects.

BACKGROUND: KM-023 is a new second-generation nonnucleoside reverse-transcriptase inhibitor that is under development for the treatment of human immunodeficiency virus (HIV) type 1 infection. OBJECTIVE: This study determined KM-023 tolerability and pharmacokinetic characteristics in healthy subjects. MATERIALS AND METHODS: A randomized, double-blinded, placebo-controlled, dose-escalation study was conducted in 80 healthy South Korean male volunteers. The subjects were allocated to single- or multiple-dose (once daily for 7 days) groups that received 75, 150, 300, or 600 mg drug or placebo in a 4:1 ratio. Safety and pharmacokinetic assessments were performed during the study. Plasma and urine concentrations were quantified using liquid chromatography-tandem mass spectrometry. RESULTS: The average maximum concentration (Cmax) and area under the concentration-time curve from time 0 to infinity (AUC∞) values of KM-023 for the 75-600 mg doses in the single-dose study ranged from 440.2 ng/mL to 1,245.4 ng/mL and 11,142.4 ng · h/mL to 33,705.6 ng · h/mL, respectively. Values of the mean Cmax at a steady state and AUC within the dosing interval ranged from 385.1 ng/mL to 1,096.7 ng/mL and 3,698.9 ng · h/mL to 10,232.6 ng · h/mL, respectively, following 75-600 mg doses in the multiple-dose study. Dose proportionality was not observed for KM-023. KM-023 showed a 0.6-fold accumulation after multiple doses in the 600 mg dose group. The mean half-life values ranged between 20.7 and 31.2 hours. KM-023 was generally well tolerated without serious adverse events. CONCLUSION: KM-023 demonstrated dose- and time-dependent nonlinear pharmacokinetic characteristics after single or multiple doses over a dose range (75-600 mg) in healthy subjects. KM-023 showed favorable tolerability in this study. This Phase I clinical trial information can be used to design further clinical studies appropriately to evaluate KM-023 in patients with HIV-1 infection.

Effect of intensive lifestyle intervention on sexual dysfunction in women with type 2 diabetes: results from an ancillary Look AHEAD study.

OBJECTIVE: Sexual dysfunction is a prevalent problem in obese women with type 2 diabetes. This study examined the effects of intensive lifestyle intervention (ILI) in these women. RESEARCH DESIGN AND METHODS: Look AHEAD is a 16-center, randomized, controlled trial evaluating the health effects of ILI compared with a control group (diabetes support and education [DSE]). The Look AHEAD Sexual Function Ancillary study included 375 female participants at five Look AHEAD sites. Participants completed the Female Sexual Function Inventory (FSFI) and Beck Depression Inventory (BDI), and assessments of weight and cardiovascular risk factors at baseline and 1 year were made. RESULTS: At baseline, 50% of the 229 participants who reported being sexually active met criteria for female sexual dysfunction (FSD); only BDI score was related to FSD. One-year weight losses were greater in the ILI group than in the DSE group (7.6 vs. 0.45 kg; P<0.001). Among women with FSD at baseline, those in the ILI group (N=60) compared with those in the DSE group (N=53) were significantly more likely to remain sexually active (83 vs. 64%; P<0.008), reported greater improvement in total FSFI scores and in most FSFI domains (P<0.05), and were more likely to experience remission of FSD (28 vs. 11%; P<0.04) at 1 year. No significant differences between ILI and DSE were seen in women who did not have FSD at baseline. CONCLUSIONS: Participation in ILI appeared to have beneficial effects on sexual functioning among obese women with diabetes, particularly in those who had FSD at baseline.

The effect of obesity on the relationship between serum parathyroid hormone and 25-hydroxyvitamin D in women.

CONTEXT: Obesity is associated with lower serum concentrations of 25-hydroxyvitamin D (25OHD) and higher intact PTH. The threshold of 25OHD needed to maximally suppress intact PTH has been suggested as a marker of optimal vitamin D status. OBJECTIVE: In this study, we hypothesized that whereas the obese have a higher serum PTH and lower 25OHD, suppression of serum PTH by 25OHD would be independent of body weight. DESIGN, SETTING, AND PARTICIPANTS: We performed a retrospective analysis on 383 women (ages 24-75 y) with a wide range of body weights (43-185 kg) who were stabilized to 1-1.2 g calcium/d for 1 month before blood draw. Body composition, serum PTH, 25OHD, calcium, and creatinine were measured. Locally weighted regression and smoothing scatterplots were used to depict the association between serum PTH and 25OHD. A nonlinear exponential model determined the point for near maximal suppression of PTH by 25OHD. RESULTS: The point for near maximal suppression of PTH by 25OHD for all women (body mass index, 31.4 ± 7.7 kg/m²) occurred at a 25OHD concentration of 21.7 ng/mL (95% confidence interval, 28-48 ng/mL). No point of maximal suppression was found for nonobese women, yet in the obese women (n = 207; body mass index, >30 kg/m²) suppression of PTH occurred at a 25OHD concentration of 11.1 ng/mL (95% confidence interval, 4.7-17.5 ng/mL). CONCLUSIONS: These results suggest that if PTH is suppressed at a lower serum 25OHD in the obese compared to the entire population, the lower average 25OHD concentrations in the obese may not have the same physiological significance as in the general population.

Vitamin D supplementation and calcium absorption during caloric restriction: a randomized double-blind trial.

BACKGROUND: Weight loss (WL) is associated with a decrease in calcium absorption and may be one mechanism that induces bone loss with weight reduction. OBJECTIVE: Because vitamin D supplementation has been shown to increase true fractional calcium absorption (TFCA), the goal of this study was to examine the effect of vitamin D during WL or weight maintenance (WM). DESIGN: A randomized, placebo-controlled, double-blind 6-wk study was conducted in 82 postmenopausal women [BMI (in kg/m(2); ±SD): 30.2 ± 3.7] with 25-hydroxyvitamin D [25(OH)D] concentrations <70 nmol/L during either WL or WM. All women were given 10 µg vitamin D(3)/d and 1.2 g Ca/d and either weekly vitamin D(3) (375 µg) or a placebo equivalent to 63 µg (2500 IU)/d and 10 µg (400 IU)/d, respectively. We measured TFCA with the use of dual-stable isotopes, 25(OH)D, parathyroid hormone, estradiol, calcitriol, and urinary calcium at baseline and 6 wk in weight loss and vitamin D(3)-supplementation (WL-D; n = 19), weight maintenance and vitamin D(3)-supplementation (WM-D; n = 20), weight loss and placebo (n = 22), and weight maintenance and placebo (n = 21) groups. RESULTS: WL groups lost 3.8 ± 1.1% of weight with no difference between vitamin D(3) supplementation and the placebo. The rise in serum 25(OH)D was greatest in the WL-D group (19.8 ± 14.5 nmol/L) compared with in WM-D (9.1 ± 10.3 nmol/L) and placebo groups (1.5 ± 10.9 nmol/L). TFCA increased with vitamin D(3) supplementation compared with placebo treatment (P < 0.01) and decreased during WL compared with WM. Serum 25(OH)D or 1,25-dihyroxyvitamin D did not correlate with TFCA. CONCLUSION: These data show that vitamin D supplementation increases TFCA and that WL decreases TFCA and suggest that, when calcium intake is 1.2 g/d, either 10 or 63 µg vitamin D/d is sufficient to maintain the calcium balance. This trial was registered at clinicaltrials.gov as NCT00473031.

Desensitization treatment for hypersensitivity reaction to octreotide in an acromegalic patient.

Octreotide is widely used as medical therapy for acromegaly. It is known to markedly reduce growth hormone levels, improve symptoms and reduce tumor size. Common side effects include gastrointestinal symptoms, hepatobiliary disorders, dizziness, headaches, bradycardia, hyperglycemia or hypoglycemia and thyroid dysfunction. Although urticaria, allergy/hypersensitivity reactions and anaphylaxis have been noted as possible adverse reactions, there is a lack of data showing a causal relationship between octreotide and hypersensitivity reactions and there is no information on management when continued use of this medication is essential. We now report a case of a 60 year old male with acromegaly who had presented with a cutaneous hypersensitivity reaction to octreotide. In addition he failed treatment with surgery, radiation, and dopamine agonist and could no longer afford to continue treatment with pegvisomant. The patient underwent desensitization treatment for his octreotide allergy and was able to resume treatment without any further side effects. We believe this case represents the first report of successful desensitization treatment for octreotide allergy in an acromegalic patient.

Development of a homogeneous AlphaLISA ubiquitination assay using ubiquitin binding matrices as universal components for the detection of ubiquitinated proteins.

The Ubiquitin Proteasome Pathway (UPP) has become a target rich pathway for therapeutic intervention as its role in pathogenic disease is better understood. In particular many E3 ligases within this pathway have been implicated in cancer, inflammation and metabolic diseases. It has been of great interest to develop biochemical assays to identify inhibitors of catalytic E3 ubiquitination activity as a means of abrogating the disease mechanism. Here we describe a homogeneous biochemical assay that utilizes native ubiquitin and Tandem-repeated Ubiquitin-Binding Entities (TUBEs) as a detection technology for ubiquitination activity. We developed a TUBEs based proximity AlphaLisa® assay for Mdm2, which is an E3 ligase that negatively regulates p53 tumor suppressor protein. We further demonstrate that this assay strategy or design can also be applied to the development of assays to detect autoubiquitination of other E3 ligases that are also of interest for therapeutic intervention. This article is part of a Special Issue entitled: Ubiquitin Drug Discovery and Diagnostics.

Multiple T-type Ca2+ current subtypes in electrophysiologically characterized hamster dorsal horn neurons: possible role in spinal sensory integration.

Whole cell patch-clamp recordings were used to investigate the contribution of transient, low-threshold calcium currents (I(T)) to firing properties of hamster spinal dorsal horn neurons. I(T) was widely, though not uniformly, expressed by cells in Rexed's laminae I-IV and correlated with the pattern of action potential discharge evoked under current-clamp conditions: I(T) in neurons responding to constant membrane depolarization with one or two action potentials was nearly threefold larger than I(T) in cells responding to the same activation with continuous firing. I(T) was evoked by depolarizing voltage ramps exceeding 46 mV/s and increased with ramp slope (240-2,400 mV/s). Bath application of 200 µM Ni(2+) depressed ramp-activated I(T). Phasic firing recorded in current clamp could only be activated by membrane depolarizations exceeding ∼43-46 mV/s and was blocked by Ni(2+) and mibefradil, suggesting I(T) as an underlying mechanism. Two components of I(T), "fast" and "slow," were isolated based on a difference in time constant of inactivation (12 ms and 177 ms, respectively). The amplitude of the fast subtype depended on the slope of membrane depolarization and was twice as great in burst-firing cells than in cells having a tonic discharge. Post hoc single-cell RT-PCR analyses suggested that the fast component is associated with the Ca(V)3.1 channel subtype. I(T) may enhance responses of phasic-firing dorsal horn neurons to rapid membrane depolarizations and contribute to an ability to discriminate between afferent sensory inputs that encode high- and low-frequency stimulus information.

Vildagliptin in the treatment of type 2 diabetes mellitus.

INTRODUCTION: Inhibition of dipeptidyl peptidase IV (DPP-4) augments glucose-dependent insulin release and is a new approach to the treatment of type 2 diabetes (T2DM). Vildagliptin is a new DPP-4 inhibitor approved in many countries for the treatment of T2DM. This review provides an overview of vildagliptin with emphasis on its pharmacology and clinical effectiveness. AREAS COVERED: Results of preclinical and several Phase II and III studies from 2004 - 2010 are discussed. EXPERT OPINION: Vildagliptin acts to inhibit the breakdown of glucagon-like peptide (GLP)-1, which in turn enhances the beta-cell response to glucose and inhibits glucagon secretion. It is an effective agent alone or in combination in patients with T2DM, resulting in modest improvements in HbA1c usually in the 0.5 - 1% range. Advantages include weight neutrality and a lesser incidence of hypoglycemia. Concerns remain regarding its use in renal disease and potential complications seen in animal models.