Presence Of Niacin Research Articles

Abstract 1049: Pharmacological characterization of a novel potent nicotinamide phosphoribosyltransferase (NAMPT) inhibitor with robust in vivo efficacy and increased therapeutic index with niacin supplementation

Abstract Nicotinamide adenine dinucleotide (NAD+) is an important metabolite and cofactor for a number of cellular processes including genomic stability and epigenetic regulation. Nicotinamide phosphoribosyltransferase (NAMPT) is the rate limiting enzyme in NAD+ salvaging from nicotinamide. Many tumor cells have an increased need for NAD+ and are therefore highly sensitive to NAMPT inhibition. We have developed a selective and potent small molecule inhibitor, Cmpd1, which inhibits the NAMPT enzyme with sub-nanomolar potency. In cells, Cmpd1 treatment leads to an almost complete reduction of both NAD- and ATP-levels, followed by the induction of cell death. In order to identify sensitive cancer subtypes and associated biomarkers, we analyzed cell sensitivity to NAMPT inhibition in a panel of 240 cell lines. Small cell lung cancer and hematological malignancies were particularly sensitive to NAMPT inhibition. Overall, expression levels of NAMPT and NAD+ consuming enzymes correlated well with sensitivity to NAMPT inhibition. In order to investigate the effect of niacin on the antiproliferative effect of NAMPT inhibition across the cell panel, we further analyzed the cell sensitivity in the presence of niacin. Cells with a functional Preiss-Handler pathway can generate NAD+ from niacin, independent of NAMPT. We found that the antiproliferative effect of Cmpd1 was neutralized by niacin in 60% of the analyzed cells. The mRNA levels of nicotinate phosphoribosyltransferase 1 (NAPRT1), a central enzyme of the Preiss-Haendler pathway, predicted well the niacin rescue status of the cells. In vivo, niacin supplementation led to an at least 10-fold increase in the maximum tolerated dose of Cmpd1 in mice. Antitumor efficacy of Cmpd1 was abolished by niacin supplementation in xenografts derived from NAPRT1 expressing cells, but not in NAPRT1-deficient models. These data demonstrate that the therapeutic index of NAMPT inhibitors may be increased in NAPRT1-deficient tumors by niacin supplementation. Citation Format: Maria Quanz, Claudia Merz, Andreas Bernthaler, Stefan Kaulfuss, Anja Richter, Marcus Bauser, Andrea Haegebarth. Pharmacological characterization of a novel potent nicotinamide phosphoribosyltransferase (NAMPT) inhibitor with robust in vivo efficacy and increased therapeutic index with niacin supplementation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1049.

Method development and validation for pharmaceutical tablets analysis using transmission Raman spectroscopy

The objective of the study is to demonstrate the development and validation of a transmission Raman spectroscopic method using the ICH-Q2 Guidance as a template. Specifically, Raman spectroscopy was used to determine niacinamide content in tablet cores. A 3-level, 2-factor full factorial design was utilized to generate a partial least-squares model for active pharmaceutical ingredient quantification. Validation of the transmission Raman model was focused on figures of merit from three independent batches manufactured at pilot scale. The resultant model statistics were evaluated along with the linearity, accuracy, precision and robustness assessments. Method specificity was demonstrated by accurate determination of niacinamide in the presence of niacin (an expected related substance). The method was demonstrated as fit for purpose and had the desirable characteristics of very short analysis times (∼2.5s per tablet). The resulting method was used for routine content uniformity analysis of single dosage units in a stability study.

Micellar electrokinetic chromatographic determination of rosuvastatin in rabbit plasma and evaluation of its pharmacokinetics and interaction with niacin.

A specific, accurate, precise and reproducible micellar electrokinetic chromatographic method was developed for in vitro and in vivo estimation of rosuvastatin, a synthetic and potent HMG-CoA inhibitor, in rabbit plasma. Further, its pharmacokinetics in the presence of niacin, which could be co-administered for monitoring of severe hypercholestremia, was investigated. The assay procedures involved simple liquid-liquid extraction of rosuvastatin and internal standard, atorvastatin, from a small plasma volume directly into acetonitrile. The organic layer was separated and evaporated under a gentle stream of nitrogen. The residue was reconstituted in the mobile phase and injected electrokinetically into electropherosis system. The background electrolyte consisted of borate buffer (25.0 mm, pH 9.5), 10.0% organic modifier (5.0% methanol + 5.0% acetonitrile) and 25.0 mm sodium dodecyl sulfate at 20.0 kV applied voltage and 215.0 nm detection wavelength for the effective separation of rosuvastatin, niacin and atorvastatin.

Inhibition of Nicotinamide Phosphoribosyltransferase (NAMPT) Activity by Small Molecule GMX1778 Regulates Reactive Oxygen Species (ROS)-mediated Cytotoxicity in a p53- and Nicotinic Acid Phosphoribosyltransferase1 (NAPRT1)-dependent Manner

Cancer cells undergo mitosis more frequently than normal cells and thus have increased metabolic needs, which in turn lead to higher than normal reactive oxygen species (ROS) production. Higher ROS production increases cancer cell dependence on ROS scavenging systems to balance the increased ROS. Selectively modulating intracellular ROS in cancers by exploiting cancer dependence on ROS scavenging systems provides a useful therapeutic approach. Essential to developing these therapeutic strategies is to maintain physiologically low ROS levels in normal tissues while inducing ROS in cancer cells. GMX1778 is a specific inhibitor of nicotinamide phosphoribosyltransferase, a rate-limiting enzyme required for the regeneration of NAD(+) from nicotinamide. We show that GMX1778 increases intracellular ROS in cancer cells by elevating the superoxide level while decreasing the intracellular NAD(+) level. Notably, GMX1778 treatment does not induce ROS in normal cells. GMX1778-induced ROS can be diminished by adding nicotinic acid (NA) in a NA phosphoribosyltransferase 1 (NAPRT1)-dependent manner, but NAPRT1 is lost in a high frequency of glioblastomas, neuroblastomas, and sarcomas. In NAPRT1-deficient cancer cells, ROS induced by GMX1778 was not susceptible to treatment with NA. GMX1778-mediated ROS induction is p53-dependent, suggesting that the status of both p53 and NAPRT1 might affect tumor apoptosis, as determined by annexin-V staining. However, as determined by colony formation, GMX1778 long term cytotoxicity in cancer cells was only prevented by the addition of NA to NAPRT1-expressing cells. Exposure to GMX1778 may be a novel way of inducing ROS selectively in NAPRT1-negative tumors without inducing cytotoxic ROS in normal tissue.

Elevation of fasting morning glucose relative to hemoglobin A1c in normoglycemic patients treated with niacin and with statins

Niacin increases fasting glucose levels, and statins modestly increase the rate of new-onset diabetes. The clinical importance and mechanisms of these effects are not fully explored. On the basis of anecdotal observations, we hypothesized that elevated morning fasting glucose may be accompanied by relatively normal hemoglobin A1c (HbA1c) in patients treated with niacin and other lipid-modifying drugs. We conducted a retrospective cohort analysis to test this hypothesis. The Duke Lipid Clinic database (1994-2007) was screened for simultaneous determinations of fasting morning glucose and HbA1c, yielding 1483 data pairs among 554 subjects. Subjects with diabetes, by clinical diagnosis, medication, or any HbA1c ≥6.5%, or nondiabetes were analyzed separately. Repeated-measures linear regression featured glucose as dependent variable and included terms for HbA1c, drug(s), and their interaction. Regression lines for glucose on HbA1c had altered slopes in the presence of niacin and/or statin use in normoglycemic subjects. The corresponding interaction terms (drug and HbA1c) were significant (niacin P= .026, statin P= .013). Fibrate use had no effect (interaction P= .49). When modeled together, niacin and statin effects were independent. Regression curves in diabetic patients were not affected by lipid medications. Elevated fasting glucose may be accompanied by relatively normal HbA1c in niacin- and statin-treated patients. HbA1c reflects average daily glucose levels and is likely a better measure of the glycemic effect of lipid medications. Because our data were retrospective, confirmation from randomized trials is needed.

Two hypolipidemic agents, cholestyramine and niacin, affect the development and lipid content of Heliothis zea

AbstractTwo vertebrate hypolipidemic agents, cholestyramine and niacin, affected the growth and development of Heliothis zea as well as the quantity of acylglyceride or sterol present in the larva. As the concentration of cholestyramine in the diet increased to 6.0%: the number of larval molts increased from 5 or 6 to as many as 7 or 8, the time required for the onset of pupation increased from 11 or 12 to 20 days, and the number of adults that emerged decreased from at least 70 to 0%. The growth and development of the insect may have slowed, at least in part, because this agent reduced the quantity of sterol and glyceride in the tissues of the larva. Niacin also affected the growth and development of the insect. As the concentration of niacin in the diet increased to 5.0%: the number of larval molts increased by 1, the time required for the onset of pupation increased to 21 days, pupal weight decreased significantly, but adult emergence was normal. The growth and development of the insect may have slowed, at least in part, because this agent caused sterol to accumulate in the hemolymph of the larva. A water‐soluble component in the hemolymph also increased in the presence of niacin, but there was little or no change in the glyceride content. Further studies are warranted to determine the mode of action of these hypolipidemic agents in H. zea.

Sporulation-inducing factor in slime mould Physarum polycephalum.

THE highly synchronous sporulation of Physarum polycephalum is an attractive model of cell differentiation. Virtually all of the nuclei in a starved plasmodium proceed in step through the sporulation process in response to a well defined stimulus, light1–4. The regulatory mechanisms of this differentiation are unknown but several studies have been presented on the conditions necessary for sporulation. These have been reviewed by Sauer5, who concludes that two elements are necessary for sporulation, substrate and light. These must be applied sequentially. The substrate requirement is for starvation in the dark for at least 4 d in the presence of niacin and niacinamide4. The light requirement is for at least 4 h illumination by a 40 W fluorescent light. Sauer also cites unpublished results which suggest that the effect of illumination is a local one which cannot be transferred to an unilluminated, starved plasmodium or even from the illuminated half to the unilluminated half of the same plasmodium.

Synergistic Effect of IAA and Kinetin in Niacin Induced Root Inhibition During Early Seedling Growth

Niacin (nicotinic acid) was found to inhibit root-growth of the seedlings of Lactuca sativa var. Cabbage, Amaranthus oleracea and Lycopersicum esculentum var. S-120. The combined action of niacin and kinetin and niacin and indole acetic acid (IAA) were studied. It was found that kinetin and IAA both in presence of niacin (500 ppm) greatly enhenced the root-growth inhibition. Thus niacin showed a marked synergism with kinetin or IAA.