Niacin Flush Research Articles

A-033 Development and Validation of a Liquid Chromatography Tandem Mass Spectrometry Bioanalytical Method for Prostaglandin D2 in Serum or Urine

Abstract Background Prostaglandin D2 (PGD2) is a major prostaglandin produced by the brain and by mast cells, and plays a role in vasodilation (“niacin flush”) and in the development of allergic diseases such as asthma and alopecia. We sought to develop a bioanalytical method for multiple specimen types for PGD2 for clinical use. Methods An analytical method was developed using a TX-4 HPLC system (Thermo-Fisher) with Agilent® 1200 pumps (Agilent Technologies, Inc.) and a Sciex® 5500 (Danaher) triple quadrupole mass spectrometer. Calibration curve based on purified PGD2 (Cayman) was prepared in depleted serum (Golden West Biologicals). Sample preparation consisted of an initial isotope dilution using a deuterated heavy isotope internal standard (PGD2-2H4) followed by solid phase extraction, evaporation and reconstitution using a second heavy isotope (PGD2-2H9). Double-isotope dilution allows discrimination between extraction loss and ion suppression as causes of decreased ion current. A reversed phase C18 analytical column was used with an acidified water/acetonitrile/methanol solvent gradient to achieve chromatographic separation of physiological PGD2 from related isobaric metabolites include Prostaglandin E2. Negative mode electrospray ionization (ESI) was used for detection in Multiple Reaction Monitoring (MRM) mode. Results Analytical range was 1–1000 pg/mL (up to 5000 pg/mL with dilution). Inter-assay precision ranged from 8.8% to 10.2% and inter-assay accuracy ranged from 95.7% to 103.3%. Reference intervals for adults was developed using residual serum and urine specimens. No interference was observed in the presence of hemolysis, icteric or lipemia. No difference in result was observed when using collection tubes containing EDTA, Heparin or gel barriers. Conclusion A bioanalytical method for PGD2 has been fully validated for clinical use.

Niasin Dislipidemi Riskini Azaltmada Potansiyel Bir Ajan Mıdır?

Cardiovascular diseases are the most common non-communicable diseases with the highest prevalence and mortality rate in the all around the world. There are some risk factors -such as modifiable and non-modifiable- which are effective on the development of these diseases. Modifiable risk factors are closely related to dyslipidemia, which forms the basis of cardiovascular diseases. Dyslipidemia is characterized by high triacylglycerol (TAG) and free fatty acids, decreased high density lipoprotein (HDL) level and function, increased low density lipoprotein (LDL) level and apolipoprotein B (Apo B) production. There is a relation between dyslipidemia with nutritional and physical activity behaviors. In particular, adherence to the Mediterranean diet and lifestyle behaviors instead of the Western diet can potentially decrease dyslipidemia risk. On the other hand, some of micronutrients such as niacin can potentially decrease dyslipidemia risk as a nutritional supplement. Niacin -which is a water-soluble, B group vitamin- can potentially decrease TAG, free fatty acids, Apo B, very low density lipoprotein (VLDL) and LDL levels and increase HDL and apolipoprotein A (Apo A) levels in plasma. Due to these potential beneficial effects, niacin acts a pharmacological agent to decrease both of dyslipidemia risk and symptoms. However, niacin is used more than tolerable upper intake level (35 mg/day) to show these potential effects (1-3 g). This situation may cause to ‘niacin flush’ symptom. In addition, there is a need for the studies which aim to determine the negative effects of high dose niacin intake on human’s health in long-term. In this review article, potential effects of the niacin on dyslipidemia are examined within the current literature.

Niacin skin flush and membrane polyunsaturated fatty acids in schizophrenia from the acute state to partial remission: a dynamic relationship

Despite the consistent finding of an attenuated niacin-induced flush response in schizophrenia, its long-term stability and relationship to the membrane polyunsaturated fatty acid (PUFA) levels remain unknown. We conducted niacin skin tests and measured the membrane PUFAs using gas chromatography among 46 schizophrenia inpatients and 37 healthy controls at the baseline and the 2-month follow-up. Attenuated flush responses were persistently observed in schizophrenia patients in both acute and partial remission states, whereas an increased flush response was found in the controls. A persistent decrease in both dihomo-gamma-linolenic acid and docosahexaenoic acid and an increased turnover of arachidonic acid (ARA) via endogenous biosynthesis were found in schizophrenia patients. A composite niacin flush score by combining those with a control-to-case ratio of >1.4 (i.e., scores at 5 min of 0.1 M, 0.01 M, and 0.001 M + 10 min of 0.01 M and 0.001 M + 15 min of 0.001 M) at the baseline was correlated positively with ARA levels among controls but not among schizophrenia patients, whereas the flush score at the 2-month follow-up was correlated positively with ARA levels among patients. The 2-month persistence of attenuated niacin-induced flush response in schizophrenia patients implies that the niacin skin test might tap a long-term vulnerability to schizophrenia beyond acute exacerbation.

Attenuated niacin-induced skin flush response in individuals with clinical high risk for psychosis

BackgroundImpaired sensitivity of the skin flush response to niacin is one of the most replicated findings in patients with schizophrenia. However, prior studies have usually focused on postonset psychosis, and...

Dysregulation of phospholipase and cyclooxygenase expression is involved in Schizophrenia.

BackgroundSchizophrenia (SZ) is a severe mental disease with highly heterogeneous clinical manifestations and pathological mechanisms. Schizophrenia is linked to abnormalities in cell membrane phospholipids and blunting of the niacin skin flush response, but the associations between these phenotypes and its molecular pathogenesis remain unclear. This study aimed to describe the PLA2/COX pathway, the key link between phospholipids and niacin flush, and to illustrate the pathogenic mechanisms in schizophrenia that mediate the above phenotypes.MethodsA total of 166 patients with schizophrenia and 54 healthy controls were recruited in this study and assigned to a discovery set and a validation set. We assessed the mRNA levels of 19 genes related to the PLA2/COX cascade in leukocytes by real-time PCR. Plasma IL-6 levels were measured with an ELISA kit. Genetic association analysis was performed on PLA2G4A and PTGS2 to investigate their potential relationship with blunted niacin-skin response in an independent sample set.FindingsSix of the 19 genes in the PLA2/COX pathway exhibited significant differences between schizophrenia and healthy controls. The disturbance of the pathway indicates the activation of arachidonic acid (AA) hydrolysis and metabolization, resulting in the abnormalities of membrane lipid homeostasis and immune function, further increasing the risk of schizophrenia. On the other hand, the active process of AA hydrolysis from cell membrane phospholipids and decreased transcription of CREB1, COX-2 and PTGER4 may explain the reported findings of a blunted niacin response in schizophrenia. The significant genetic associations between PLA2G4A and PTGS2 with the niacin-skin responses further support the inference.InterpretationThese results suggested that the activation of AA hydrolysis and the imbalance in COX-1 and COX-2 expression are involved in the pathogenesis of schizophrenia and blunting of the niacin flush response.FundingThis work was supported by the National Key R&D Program of China (2016YFC1306900, 2016YFC1306802); the National Natural Science Foundation of China (81971254, 81771440, 81901354); Interdisciplinary Program of Shanghai Jiao Tong University (ZH2018ZDA40, YG2019GD04, YG2016MS48); Grants of Shanghai Brain-Intelligence Project from STCSM (16JC1420500); Shanghai Key Laboratory of Psychotic Disorders (13DZ2260500); and Shanghai Municipal Science and Technology Major Project (2017SHZDZX01); China Postdoctoral Science Foundation (2018M642029, 2018M630442, 2019M661526, 2020T130407); Natural Science Foundation of Shanghai (20ZR1426700); and Startup Fund for Youngman Research at SJTU (19 × 100040033).

Cognition and autonomic function in schizophrenia: Inferior cognitive test performance in electrodermal and niacin skin flush non-responders

BackgroundPatients with schizophrenia suffer from a broad range of cognitive disturbances. The impact in terms of functional outcome is significant. There are also several reports of disturbed autonomic regulation in the disease. The present study examined cognitive function as well as psychophysiological parameters in patients with schizophrenia and healthy controls. MethodsTwenty-five patients and 14 controls were investigated with electrodermal activity (EDA), an oral niacin skin flush test and a comprehensive neurocognitive test program including the Wechsler battery (WAIS-R), Fingertapping Test, Trail Making Test, Verbal Fluency, Benton Visual Retention Test, Wisconsin Card Sorting Test and Rey Auditory Verbal Learning Test. ResultsThe patients generally had inferior test results compared to controls. Further analysis revealed that the EDA non-responding patient group explained this variation with significant lower test results than controls. On executive tests, EDA non-responders also performed significantly worse than EDA responding patients. The small group of niacin non-responding patients exhibited an even lower overall test performance. Delayed niacin flush also correlated inversely with psychomotor function and IQ in the patients. ConclusionThe findings support the hypothesis of a neurodevelopment disturbance affecting both autonomic function and higher cortical function in schizophrenia.

The impact of PLA2G4A and PTGS2 gene polymorphisms, and red blood cell PUFAs deficit on niacin skin flush response in schizophrenia patients

We investigated the etiology of the attenuated niacin skin flush response in schizophrenia patients. Skin response to topical niacin of 0.1M, 0.01M, 0.001M, and 0.0001M concentrations was rated using method of volumetric niacin response (VNR) and correlated to two functional A/G polymorphisms in genes: phospholipase A2 group IVA (BanI of the PLA2G4A), and rs689466 of the prostaglandin synthase-2 (PTGS2). We further tested the possible correlation between niacin response and fatty acid (FA) content of red blood cells (RBCs). We detected statistically significant but weak impact of both polymorphisms on niacin flush response in schizophrenia patients. The dosage of the G alleles of both polymorphisms was associated with higher VNR values, although each polymorphic variant accounted for only 1% of the overall flush response variability. Regarding FA content, both n−3 and n−6 polyunsaturated FAs (PUFAs) were significantly reduced in the patient group, but an association with niacin sensitivity was not detected.

A Genome-wide Quantitative Linkage Scan of Niacin Skin Flush Response in Families With Schizophrenia

Schizophrenia patients frequently display reduced niacin flush responses, and similar characteristics are also observed in their nonpsychotic relatives. This study aimed to identify loci influencing flush response to niacin in schizophrenia using genome-wide quantitative linkage scan. In a nationwide sample of families with at least 2 siblings affected with schizophrenia in each family, 115 families that had at least 2 affected siblings with information on the niacin skin test were subjected to quantitative trait loci linkage analysis, either involving affected individuals only or the whole family. Nonparametric linkage z (NPL-Z) scores were calculated for each of 386 microsatellite markers spaced at an average of 9-cM intervals. Niacin patches of 3 concentrations (0.001 M, 0.01, and 0.1 M) were applied to forearm skin, and the flush response was rated at 5, 10, and 15 minutes, respectively, with a 4-point scale. Determination of genome-wide empirical significance was implemented using 1000 simulated genome scans. One linkage peak attaining genome-wide significance was identified at chromosomal region 14q32.12 for 0.01 M concentration at 5 minutes (NPL-Z scores = 3.39, genome-wide empirical P = .03) in affected individuals, and the corresponding linkage signal remained strong (NPL-Z scores = 2.87) for the analyses of the whole family. This locus is distinct from the chromosomal region identified in the previous genome-wide scan for the diagnosis of schizophrenia, and the signal was higher than the peak linkage signal in that study. These findings indicate that there might be modifier or susceptibility-modifier genes at 14q32.12 for schizophrenia-related attenuation of flush response to niacin.

Mechanisms of Flushing Due to Niacin and Abolition of These Effects

There are many factors that increase the risk of cardiovascular disease, and a prominent factor among these is dyslipidemia. The following literature review focuses on the use of niacin therapy in order to treat dyslipidemia and how to control the associated "niacin flush." The associated studies gathered are reviews and randomized control trials. They were obtained by using electronic searches. Certain keywords took precedence, and articles focusing on niacin therapy were chosen. Recent research has found promising insight into more effective prevention of the niacin-mediated flush through a selective antagonist for the prostaglandin D2 receptor, laropiprant. Aspirin (or NSAIDs) also provide some prevention for flushing, although recent studies have shown that it is not as effective as laropiprant. There is a need for further research in order to come to a clear conclusion regarding combined therapies of aspirin and laropiprant pretreatment, as well as exact dosage requirements.

Niacin: An old drug rejuvenated

Niacin has long been used in the treatment of dyslipidemia and cardiovascular disease. Recent research on niacin has been focused on understanding the mechanism of action of niacin and preparation of safer niacin formulations. New findings indicate that niacin does the following: 1) it inhibits hepatic diacylglycerol acyltransferase 2, resulting in inhibition of triglyceride synthesis and decreased apolipoprotein B-containing lipoproteins; 2) it decreases the surface expression of hepatic adenosine triphosphate synthase beta-chain, leading to decreased holoparticle high-density lipoprotein catabolism and increased high-density lipoprotein levels; and 3) it increases redox potential in arterial endothelial cells, resulting in inhibition of redox-sensitive genes. Flushing, an adverse effect of niacin, results from niacin receptor GPR109A-mediated production of prostaglandin D2 and E2 via DP1 and EP2/4 receptors. DP1 receptor antagonist (laropiprant) attenuates the niacin flush. A reformulated preparation of extended-release niacin (Niaspan; Abbott, Abbott Park, IL) lowers flushing compared with an older Niaspan formulation. These advancements in niacin research have rejuvenated its use for the treatment of dyslipidemia and cardiovascular disease.

Nicotinic acid: recent developments

To review the recent progress in niacin research that is made in two major areas: new preparations to decrease flushing and niacin's mechanism of action. Flushing, an adverse effect of niacin, results from GPR109A-mediated production of prostaglandin D2 and E2 in Langerhans' cells which act on DP1 and EP2/4 receptors in dermal capillaries causing their vasodilatation. DP1 receptor antagonist (laropiprant) attenuates the niacin flush in animals and humans. A reformulated preparation of extended-release niacin lowers flushing compared with the extended-release niacin (Niaspan, Abbott Laboratories, Chicago, Illinois, USA). Aspirin pretreatment attenuates flushing from Niaspan. Recent data on niacin's mechanism of action indicate that it directly inhibits hepatic diacylglycerolacyl transferase 2 resulting in an inhibition of triglyceride synthesis and decreased apolipoprotein B-containing lipoproteins; niacin, by inhibiting the surface expression of hepatic ATP synthase beta chain, decreases the hepatic holoparticle high-density lipoprotein catabolism and raises high-density lipoprotein levels; and niacin increases redox potential in arterial endothelial cells resulting in the inhibition of redox-sensitive genes. Recent developments suggest that the niacin receptor GPR109A is involved in flushing, but it does not explain multiple actions of niacin. Actions of niacin on diacylglycerolacyl transferase 2, ATP synthase beta chain, and redox state may explain the multiple actions of niacin.

The high-affinity niacin receptor HM74A is decreased in the anterior cingulate cortex of individuals with schizophrenia

The pathway for de novo synthesis of the suite of niacin congeners, the kynurenine pathway, has been shown to be upregulated in prior studies of postmortem brain tissue from individuals with schizophrenia. The cause of the upregulation is unknown, but one factor may be a defect in feedback regulation via receptors responsive to niacin. A high-affinity and low-affinity receptor for niacin have been identified, HM74A and HM74, respectively. We used RT-QPCR and Western blots to quantify expression of HM74A and HM74 receptors in brain tissue obtained postmortem from patients with schizophrenia ( N = 12) or bipolar disorder ( N = 14) and from normal controls ( N = 14). Although the protein for the HM74 receptor was unchanged, the protein for HM74A was significantly decreased in the schizophrenia group, both when normalized to GAPDH protein or to HM74 as an internal control for degradation and gel-loading error (0.56-fold ± 0.36, p = 0.016 and 0.58-fold ± 0.19 the mean control value, p = 0.001, respectively). In contrast, the transcript for HM74A was significantly increased, revealing a striking dysregulation between gene transcription and final protein product. No significant differences in HM74A were found for the bipolar group relative to controls. These results are consistent with the blunted niacin flush response reported for individuals with schizophrenia and may be relevant to different rates of comorbid disease.

Mechanism of Action of Niacin

Nicotinic acid (niacin) has long been used for the treatment of lipid disorders and cardiovascular disease. Niacin favorably affects apolipoprotein (apo) B-containing lipoproteins (eg, very-low-density lipoprotein [VLDL], low-density lipoprotein [LDL], lipoprotein[a]) and increases apo A-I-containing lipoproteins (high-density lipoprotein [HDL]). Recently, new discoveries have enlarged our understanding of the mechanism of action of niacin and challenged older concepts. There are new data on (1) how niacin affects triglycerides (TGs) and apo B-containing lipoprotein metabolism in the liver, (2) how it affects apo A-I and HDL metabolism, (3) how it affects vascular anti-inflammatory events, (4) a specific niacin receptor in adipocytes and immune cells, (5) how niacin causes flushing, and (6) the characterization of a niacin transport system in liver and intestinal cells. New findings indicate that niacin directly and noncompetitively inhibits hepatocyte diacylglycerol acyltransferase-2, a key enzyme for TG synthesis. The inhibition of TG synthesis by niacin results in accelerated intracellular hepatic apo B degradation and the decreased secretion of VLDL and LDL particles. Previous kinetic studies in humans and recent in vitro cell culture findings indicate that niacin retards mainly the hepatic catabolism of apo A-I (vs apo A-II) but not scavenger receptor BI-mediated cholesterol esters. Decreased HDL-apo A-I catabolism by niacin explains the increases in HDL half-life and concentrations of lipoprotein A-I HDL subfractions, which augment reverse cholesterol transport. Initial data suggest that niacin, by inhibiting the hepatocyte surface expression of beta-chain adenosine triphosphate synthase (a recently reported HDL-apo A-I holoparticle receptor), inhibits the removal of HDL-apo A-I. Recent studies indicate that niacin increases vascular endothelial cell redox state, resulting in the inhibition of oxidative stress and vascular inflammatory genes, key cytokines involved in atherosclerosis. The niacin flush results from the stimulation of prostaglandins D(2) and E(2) by subcutaneous Langerhans cells via the G protein-coupled receptor 109A niacin receptor. Although decreased free fatty acid mobilization from adipose tissue via the G protein-coupled receptor 109A niacin receptor has been a widely suggested mechanism of niacin to decrease TGs, physiologically and clinically, this pathway may be only a minor factor in explaining the lipid effects of niacin.

Impaired Flush Response to Niacin Skin Patch Among Schizophrenia Patients and Their Nonpsychotic Relatives: The Effect of Genetic Loading

We previously reported familial aggregation in flush response to niacin skin patch among schizophrenia patients and their nonpsychotic relatives. However, little is known about whether this abnormal skin response is associated with genetic loading for schizophrenia. This study compared the niacin flush response in subjects from families with only one member affected with schizophrenia (simplex families) with those from families having a sib-pair with schizophrenia (multiplex families). Subjects were patients with schizophrenia and their nonpsychotic first-degree relatives from simplex families (176 probands, 260 parents, and 80 siblings) and multiplex families (311 probands, 180 parents, and 52 siblings) as well as 94 healthy controls. Niacin patches of 3 concentrations (0.001M, 0.01M, and 0.1M) were applied to forearm skin, and the flush response was rated at 5, 10, and 15 minutes, respectively, with a 4-point scale. More attenuated flush response to topical niacin was shown in schizophrenia probands and their relatives from multiplex families than in their counterparts from simplex families, and the differentiation was better revealed using 0.1M concentration of niacin than 0.01M or 0.001M. For the highest concentration of 0.1M and the longest time lag of 15 minutes, a subgroup of probands (23%), parents (27%), and siblings (19%) still exhibited nonflush response. Flush response to niacin skin patch is more impaired in schizophrenia patients and their relatives from families with higher genetic loading for schizophrenia, and this finding has implications for future genetic dissection of schizophrenia.

A study of the PEMT gene in schizophrenia

The phospholipid hypothesis of schizophrenia is becoming popular because of the findings from the niacin flush test, the treatment with polyunsaturated fatty acids (PUFAs), biochemical studies for the phospholipid metabolism pathway and genetic studies of phospholipase A2. The present study attempted to investigate the gene coding for phosphatidylethanolamine N-methyltransferase (PEMT), which is an important enzyme for the synthesis of membrane phospholipids. We recruited 271 Chinese parent-offspring trios of Han descent and detected 3 single nucleotide polymorphisms (SNPs) at the PEMT locus. The transmission disequilibrium test (TDT) showed allelic association for rs464396 (X2=9.4, P=0.002), but not for the other two. The 2-SNP haplotype analysis showed haplotypic association for both the rs936108-rs464396 haplotypes (X2=25.7, d.f.=3, P=0.00001) and the rs464396-rs4244593 haplotypes (X2=17.3, d.f.=3, P=0.0006). The 3-SNP haplotype analysis also showed a haplotypic association (X2=24.4, d.f.=7, P=0.0006). The present results suggest that the PEMT gene may contribute to the etiology of schizophrenia.

Negative correlation between cerebral inorganic phosphate and the volumetric niacin response in male patients with schizophrenia who have seriously and dangerously violently offended: A 31P magnetic resonance spectroscopy study

The aim of the study was to examine the association of arachidonic acid-related signal transduction with cerebral metabolism in patients with schizophrenia who have violently and dangerously offended while psychotic. Cerebral 31-phosphorus magnetic resonance spectroscopy was carried out in 11 male patients with schizophrenia who had violently offended (homicide, attempted murder, or wounding with intent to cause grievous bodily harm) while psychotic. Spectra were obtained from 70×70×70 mm 3 voxels using an image-selected in vivo spectroscopy pulse sequence. Niacin flush testing results were quantified as the volumetric niacin response. There was a strong, and negative, correlation between the volumetric niacin response and the metabolite concentration of inorganic phosphate expressed as a ratio of the total 31-phosphorus signal ( p<0.005). Our results suggest that patients with schizophrenia who have violently offended and have poor phospholipid-related signal transduction may have higher levels of cerebral energy metabolism.

Effect of drugs on high-density lipoprotein

The National Cholesterol Education Program Adult Treatment Panel III found evidence for raising high-density lipoprotein cholesterol (HDL-C) to reduce coronary artery disease (CAD) events supports use of HDL-C to help modify low-density lipoprotein cholesterol (LDL-C)−lowering goals, but not to establish new HDL-C−focused treatment recommendations. However, the HDL-C−raising clinical trials provide important lessons to help guide clinical management of dyslipidemic patients. The fibrate outcome trials demonstrate that these drugs reduce CAD events, but not death. Their greatest benefit is in patients with atherogenic dyslipidemia characterized by high triglycerides, small LDL particles, and low HDL-C. Unfortunately, there is no information on whether these drugs extend risk reduction when added to a statin. The niacin outcome trials also demonstrate a reduction in CAD events, both with niacin monotherapy and in combination with a statin. Unfortunately, most of the trials are too small to address the impact of niacin on mortality. In the clinic, statins are most useful for their LDL-C−lowering efficacy, although their modest HDL-C−raising effects can be important in CAD risk reduction. In most cases, other therapies will need to be added to a statin to augment HDL-C−raising, and the most effective drug for achieving this is niacin. The greatest challenge with the use of niacin is managing the vasodilatory side effects, but this can be effectively done in the majority of patients. Fibrates can also be added to a statin for management of atherogenic dyslipidemia. These drugs are among the most effective triglyceride-lowering drugs, and they also increase HDL-C levels, but not as much as niacin. The biggest concern with combining a fibrate with a statin is the enhanced risk of severe muscle toxicity, but this appears to be a problem unique to gemfibrozil, and not fenofibrate. In the research center, new approaches are under development for enhancing the availability of apolipoprotein A-I (ApoA-I) and nascent HDL particles to promote enhanced reverse cholesterol transport, increasing the production of transport molecules, in particular, ATP-binding cassette A-I, to facilitate delivery of cholesterol within the macrophage cell to the cell surface, where it can be taken up by nascent HDL particles for transport to the liver, and inhibiting the cholesteryl ester transport protein to promote retention of cholesteryl esters within the HDL core for delivery back to the liver. In addition, new insights into the role of prostaglandin D 2 in the niacin flush and discovery of the niacin receptor has led to a search for a more efficacious and “flushless” niacin.

Familial Aggregation in Skin Flush Response to Niacin Patch Among Schizophrenic Patients and Their Nonpsychotic Relatives

Though a reduced flush response to niacin has been found in schizophrenic patients, whether it is a vulnerability indicator to schizophrenia remains little known. We aimed to examine the familial aggregation in niacin flush response among schizophrenic patients and their nonpsychotic relatives. In a sample of 153 schizophrenia probands, 217 parents, 70 siblings, and 94 normal subjects, 3 concentrations (0.001 M, 0.01 M, and 0.1 M) of niacin were applied to the forearm skin and the flush response was rated at 5, 10, and 15 minutes, respectively, with a 4-point scale. Both the heritability for continuous flush scores and the recurrence risk ratios for binary non-flush response in the nonpsychotic relatives of schizophrenic patients were estimated, and ordinal logistic regression analyses of relatives' niacin response on probands' were further conducted to adjust for potential confounders. The greatest heritabilities ranged from 47% (0.01 M at 10 minutes) to 54% (0.1 M at 5 minutes). The risk ratios of 0.01 M at 10 minutes (ranging from 2.60 for using score 1 or less to 5.06 for using score 0 as non-flush) and 5 minutes (1.66 for using score 0 as non-flush) were significantly greater than one. Multiple ordinal logistic regression analyses further revealed that the association between probands and relatives in niacin flush response remained after adjustment for potential confounders, including age, sex, allergy, tobacco smoking, and coffee drinking. These findings provide support for the potential of niacin flush response as a vulnerability indicator to schizophrenia.

Nicotinic acid induces secretion of prostaglandin D 2 in human macrophages: An in vitro model of the niacin flush

Nicotinic acid is a safe, broad-spectrum lipid agent shown to prevent cardiovascular disease, yet its widespread use is limited by the prostaglandin D 2 (PGD 2) mediated niacin flush. Previous research suggests that nicotinic acid-induced PGD 2 secretion is mediated by the skin, but the exact cell type remains unclear. We hypothesized that macrophages are a source of nicotinic acid-induced PGD 2 secretion and performed a series of experiments to confirm this. Nicotinic acid (0.1–3 mM) induced PGD 2 secretion in cultured human macrophages, but not monocytes or endothelial cells. The PGD 2 secretion was dependent on the concentration of nicotinic acid and the time of exposure. Nicotinuric acid, but not nicotinamide, also induced PGD 2 secretion. Pre-incubation of the cells with aspirin (100 μM) entirely prevented the nicotinic acid effects on PGD 2 secretion. The PGD 2 secreting effects of nicotinic acid were additive to the effects of the calcium ionophore A23187 (6 μM), but were independent of extra cellular calcium. These findings, combined with recent in vivo work, provide evidence that macrophages play a significant role in mediating the niacin flush and may lead to better strategies to eliminate this limiting side effect.

Nicotinic Acid-Induced Secretion of Prostaglandin D2 by a Human Macrophage Cell Line: An In Vitro Model of the Niacin Flush

Nicotinic Acid-Induced Secretion of Prostaglandin D₂ by a Human Macrophage Cell Line: An <i>In Vitro</i> Model of the Niacin Flush