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Identification of Skin as a Major Site on Prostaglandin D2 Release Following Oral Administration of Niacin in Humans
Abstract
Oral administration of niacin (nicotinic acid) at pharmacologic doses that reduce serum colestrol levels induces intense flushing in humans. We have recently shown that the vasodilation following ingestion of niacin is due to the release of prostaglandin (PG) D2. However, the site from which PGD2 is released is not known. It has previously been shown that topical application of methylnicotinate causes local cutaneous erythema. Thus, we investigated whether topical methylnicotinate causes a release of PGD2 locally from skin and the possibility that skin may be a major contributor to the release of PGD2 when niacin is administered by mouth.
Topical administration of methylnicotinate (10⁻¹ M) to the forearms of human volunteers resulted in 58- to 122- times increases in levels of the PGD2 and 9α,11β-PGF2 were not found in blood drawn simultaneously from veins in the contralateral arm, indicating that the PGD2 was released from the site of methylnicotinate application. The release of PGD2 in response to topically applied methylnicotinate occurred in a dose-dependent manner over the concentration range of 10⁻³ to 10⁻¹ M. The release of PGD2 was not accompanied by a release of histamine, suggesting that the release of PGD2 was not from the mast cell. Following oral ingestion niacin, levels of PGD2 in superficial venous blood draining the skin were 14 to 1200 times higher than the level in arterial blood supplying the skin is a major site from which PGD2 is released following oral ingestion of niacin.
These studies thus indicate that the cutaneous vasodilation that occurs following oral administration of niacin is primarily due to a release of PGD2 from a niacin responsive cell that resides in the skin.
... These effects may be secondary to a reduced eicosanoid signaling. In addition, eicosanoid signaling abnormalities are viewed as the cause of the abnormally attenuated skin flush response to niacin [19][20][21], an abnormality that has been widely replicated among patients with schizophrenia [11,22,23]. To date, there have been no reports on plasma eicosanoid levels during niacin-induced skin flushing in patients with schizophrenia. ...
... Following the method of Morrow et al. [20] to elicit eicosanoid release, we inserted an indwelling catheter into the antecubital vein. Two inches distal to the catheter site, the forearm was encircled with an 8-in. ...
... Following thrombin activation of platelets, there was an increased 3 H-labeling in 12-HETE, 12-hydroxyheptadecatrienoic acid, and thromboxane B 2 [35]. Similarly, there are marked increase of vasodilatory eicosanoids after topical application of niacin solution [19,20]. ...
... The levels of PGD 2 and 9α,11β-PGF 2 (a stable metabolite of PGD 2 ) rise markedly in skin exudate or venous blood following oral or topical administration of niacin in humans (Eklund et al., 1979;Kobza Black et al., 1982;Morrow et al., 1992). Evidence favors PGD 2 as the predominant mediator of the flush response (Morrow et al., 1989). ...
... In mice, the flush response to niacin can be eliminated by knocking out genes for either the niacin receptor or COX-1, consistent with an exclusive and obligatory role for this pathway in niacin-evoked skin flushing (Benyó et al. 2005). Classical vasodilatory mediators, such as histamine, bradykinin, serotonin, and acetylcholine do undergo changes in their skin transudate levels after niacin challenge (Morrow et al., 1992;Plummer et al., 1977). However, Papaliodis et al. (2008) showed that niacin induced the release of serotonin from human platelets in vitro and elevated blood levels of serotonin after intraperitoneal injection of niacin in rats. ...
... Formation of AA is the rate-limiting step in the biosynthesis of the vasodilatory PGD 2 and E2 (PGE 2 ) (Murakami and Kudo 2004) These prostaglandins bind to specific prostanoid receptors on vascular smooth muscle within the skin. Activation of prostanoid receptors dilates cutaneous blood vessels (Lai et al., 2007), and a visible skin flush arises from the ensuing increased blood flow (Benyó et al., 2005;Maciejewski-Lenoir et al., 2006;Morrow et al., 1989Morrow et al., , 1992. ...
This paper reviews the potential role of arachidonic acid in the pathophysiology of schizophrenia. We discuss how abnormal levels of arachidonic acid may arise, and how dysregulation of signaling molecules derived from it have the potential to disrupt not only dopamine signaling, but numerous other physiological processes associated with the illness. Pharmacological doses of niacin stimulate the release of arachidonic acid; and arachidonic acid-derived molecules in turn dilate blood vessels in the skin. A blunted skin flush response to niacin is reliably observed among patients with schizophrenia. The niacin response abnormality may thus serve as a biomarker to identify a physiological subtype of schizophrenia associated with defective arachidonic acid-derived signaling. Keywords: Phospholipids / arachidonic acid / eicosanoids / niacin-induced flushing, endophenotype marker / schizophrenia Résumé – Signalisation des phospholipides, de l'arachidonate et de l'écosanoïde dans la schizophrénie. Cet article examine le rôle potentiel de l'acide arachidonique dans la physiopathologie de la schizophrénie. Il est discuté comment des niveaux anormaux d'acide arachidonique peuvent survenir, et comment la dérégulation des molécules de signalisation qui en découle est capable de perturber non seulement la signalisation de la dopamine, mais aussi de nombreux autres processus physiologiques associés avec cette maladie. Des doses pharmacologiques de niacine stimulent la libération d'acide arachidonique ; des molécules dérivées de l'acide arachidonique dilatent à leur tour les vaisseaux sanguins dans la peau. Une brusque rougeur de la peau en réponse à la niacine est observée de manière constante parmi les patients atteints de schizophrénie. La réponse anormale à la niacine peut donc servir de biomarqueur afin d'identifier un sous-type physiologique de la schizophrénie, associé à un système défectueux de signalisation des dérivés de l'acide arachidonique.
... Additionally, Morrow et al. [6], utilizing gas chromatography-mass spectrometry, detected very large increases in blood levels of PGD 2 and its metabolite 9a; 11b-PGF 2 following oral niacin. Topical niacin caused elevated PGD 2 levels in venous blood from niacinexposed limbs; whereas there was no detectable PGD 2 in venous blood from nonexposed limbs [7]. Additionally, PGD 2 levels in arterial blood remained unchanged even after oral niacin; these observations suggest that the PGD 2 was originating from the skin following topical as well as oral niacin challenge [7]. ...
... Topical niacin caused elevated PGD 2 levels in venous blood from niacinexposed limbs; whereas there was no detectable PGD 2 in venous blood from nonexposed limbs [7]. Additionally, PGD 2 levels in arterial blood remained unchanged even after oral niacin; these observations suggest that the PGD 2 was originating from the skin following topical as well as oral niacin challenge [7]. The cutaneous origin of vasodilatory prostaglandins has been more directly demonstrated by findings that exudate fluid from niacin-treated skin contains substantially elevated levels of arachidonic acid (AA, 20:4n-6), PGD 2 and PGE 2 , and PGF 2a [8,9]. ...
... The cutaneous origin of vasodilatory prostaglandins has been more directly demonstrated by findings that exudate fluid from niacin-treated skin contains substantially elevated levels of arachidonic acid (AA, 20:4n-6), PGD 2 and PGE 2 , and PGF 2a [8,9]. In contrast, the levels of histamine, bradykinin, serotonin, and acetylcholine in skin exudate fluid do not change appreciably in response to topical niacin [8,10], nor is there any appreciable change in blood levels of histamine following oral or topical niacin challenge [6,7]. ...
The skin flush response to niacin is selectively mediated by the release of vasodilatory prostaglandins from the skin. The normal skin flush response to niacin is attenuated in many individuals with schizophrenia (SCZ). This finding suggests abnormal prostaglandin signaling in SCZ. Since prostaglandins are derived from arachidonic acid (AA), the finding of an abnormal skin flush response is consistent with biochemical data suggesting relative depletion of AA, and other essential fatty acids (EFAs), in a substantial portion of people with SCZ. This paper will describe the mechanism of the skin flush response to niacin, and will review evidence that the response to niacin is abnormal in SCZ, that this abnormality is not related to psychotropic medications, and that it may be a marker of the EFA deficiency which has been documented to be present in many patients with SCZ.
... It has been long been argued, however, that an altered response to the B-vitamin niacin (nicotinic acid; NA) could form the basis of such a test for schizophrenia [2]- [4]. When administered orally at sufficient doses NA causes in the relaxation of smooth muscle cells in the wall of blood vessels resulting in skin erythema ("flushing") and, in some cases, significant hypotension [5]. NA has this effect by binding to rGPR109b, a G-protein coupled receptor present on Langerhan cells residing in the skin and mucosa, resulting in the release of free fatty acids from membrane phospholipid molecules via the activation of the enzyme phospholipase A2 (PLA2) [5] [6]. ...
... When administered orally at sufficient doses NA causes in the relaxation of smooth muscle cells in the wall of blood vessels resulting in skin erythema ("flushing") and, in some cases, significant hypotension [5]. NA has this effect by binding to rGPR109b, a G-protein coupled receptor present on Langerhan cells residing in the skin and mucosa, resulting in the release of free fatty acids from membrane phospholipid molecules via the activation of the enzyme phospholipase A2 (PLA2) [5] [6]. One type of fatty acid, arachidonic acid, is further metabolized by cyclooxygenase and prostaglandin D2 synthase to form prostaglandin D2 (PGD2). ...
... One type of fatty acid, arachidonic acid, is further metabolized by cyclooxygenase and prostaglandin D2 synthase to form prostaglandin D2 (PGD2). PGD2 then diffuses from the Langerhan cell and acts via a second receptor present of the capillary wall to produce vasodilatation [5]. It has been known for some time that patients with schizophrenia have a lesser or absent vasodilatatory response to oral NA assessed either visually or by measuring skin temperature [2] [3]. ...
MNA response applied methylnicotinate (MNA) results in an arachidonic acid and cyclooxyge-nase-dependent vasodilatatory response which is diminished in patients with schizophrenia. This observation has been suggested to form the basis of a diagnostic test for the illness although the potential utility of such a procedure is diminished since the underlying mechanism is unclear. In this study we sought to discover if reduced MNA response in schizophrenia is related to increased oxidative stress i.e. whether or not the two measures are negatively correlated with each other. MNA response was assessed visually in 17 patients with schizophrenia and 16 healthy controls and compared to the extent of oxidative stress in each participant assessed by quantifying the li-pid peroxidation product ethane in breath. Serum vitamin E, a lipid soluble antioxidant, concentrations was also assessed. While MNA response was correlated with breath ethane concentrations , the expected relationship between the two measures was not observed. Instead a positive relationship between them suggests that some patients with schizophrenia have impaired fatty acid utilization leading to both diminished lipid peroxidation and cyclo-oygenation. This was not related to vitamin E concentrations, however, suggesting that lipid soluble anti-oxidant availability did not underlie our findings. Our data shed further light on the mechanism of impaired MNA response in schizophrenia and support the notion that this occurs consequent to a change in lipid metabolism.
... Flushing is caused by vasodilation of small skin capillaries and can be mediated by different molecules, including histamine, bradykinin, serotonin, and prostaglandins. [8][9][10][11][12] Although the mechanism underlying DR-DMFinduced flushing is not well understood, certain features, such as a comparable clinical course and timing, suggested that it may be similar to the niacininduced mechanism of flushing. Flushing is a common side effect of niacin therapy, and it usually subsides with continued use. ...
... Flushing is a common side effect of niacin therapy, and it usually subsides with continued use. 13 Several studies have shown that niacin-induced flushing is mediated via prostaglandin (PG) release (including PGD 2 and PGE 2 ) from epidermal Langerhans cells 11,12,14,15 and keratinocytes. 16,17 If DR-DMF-induced flushing were mediated by PG, a known inhibitor of PG synthesis, aspirin (acetylsalicylic acid), would be expected to reduce the incidence and/or intensity of flushing. ...
... The flushing observed with DR-DMF may be mechanistically similar to the flushing response seen after the administration of niacin, which is mediated, at least in part, by PGD 2 . 11,12 Indeed, in the present study, plasma levels of 9α,11β-PGF 2 (a major metabolite of PGD 2 in plasma) somewhat mirrored the pattern of flushing symptoms in that they were elevated on day 1 in subjects treated with DR-DMF and decreased by day 4. In our study, histamine levels were not elevated after treatment with DR-DMF, suggesting that DR-DMF-induced flushing was not an allergic response. ...
Delayed-release dimethyl fumarate (DR-DMF) has cytoprotective and antiinflammatory properties and has recently been approved in the United States as an oral treatment for relapsing forms of multiple sclerosis. The most common adverse events associated with DR-DMF are flushing and gastrointestinal (GI) events, the incidences of which diminish over time.
The purpose of this study was to evaluate the tolerability and pharmacokinetic (PK) profile of DR-DMF with or without concomitant acetylsalicylic acid (aspirin), a cyclooxygenase inhibitor.
Healthy volunteers (N = 56) were randomized to receive different dosing regimens of DR-DMF or matching placebo with or without pretreatment with 325 mg aspirin for 4 days. Plasma levels of the active metabolite monomethyl fumarate were assessed on days 1 and 4. Flushing and GI events were assessed using patient-reported scales. Potential flushing mediators were explored.
DR-DMF showed a safety, tolerability, and PK profile consistent with previous clinical experience, with no evidence of accumulation. Pretreatment with aspirin had no effect on the primary PK parameters, AUC0-10h, or Cmax. Flushing severity, assessed by 2 subject-reported rating scales, was generally mild and was rated highest at the start of treatment. Pretreatment with aspirin reduced flushing incidence and intensity without affecting GI events or the PK profile of DR-DMF. In some DR-DMF-treated individuals, plasma concentrations of a prostaglandin D2 (PGD2) metabolite were increased.
In healthy volunteers, DR-DMF was well tolerated over 4 days of dosing, with a PK profile consistent with that previously reported and no evidence of accumulation. Aspirin pretreatment reduced the incidence and intensity of flushing without affecting GI events or the DR-DMF PK profile. Elevated levels of PGD2 in some DR-DMF-treated individuals suggest that flushing may be, at least in part, prostaglandin mediated. ClinicalTrials.gov identifier: ID: NCT01281111.
... Dilates intracranial vessels and contracts extracranial vessels; increases skin biosynthesis of prostaglandin D2; rises plasma content of 9a,11b-prostaglandin F2 [194][195][196] Psychiatric disorders Niacin Low dietary intakes in neuropsychiatric patients [197] Nam Positive correlation between vitamin levels and schizophrenia Chronic supplementation effective in maintaining a bipolar type II patient stable and calm [198] [199] ...
... Taking into account that plasma content of serotonin inversely correlates with headache onset, niacin acts, at the central level, by increasing Trp-dependent synthesis of serotonin, via feedback inhibition of the KP [194]. At the peripheral level, pharmacological doses of nicotinic acid increase skin biosynthesis of prostaglandin D2 [195] and the plasma content of its by-product 9a,11b-PGF2, in healthy volunteers [196]. ...
Niacin (also known as “vitamin B3” or “vitamin PP”) includes two vitamers (nicotinic acid and nicotinamide) giving rise to the coenzymatic forms nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). The two coenzymes are required for oxidative reactions crucial for energy production, but they are also substrates for enzymes involved in non-redox signaling pathways, thus regulating biological functions, including gene expression, cell cycle progression, DNA repair and cell death. In the central nervous system, vitamin B3 has long been recognized as a key mediator of neuronal development and survival. Here, we will overview available literature data on the neuroprotective role of niacin and its derivatives, especially focusing especially on its involvement in neurodegenerative diseases (Alzheimer’s, Parkinson’s, and Huntington’s diseases), as well as in other neuropathological conditions (ischemic and traumatic injuries, headache and psychiatric disorders).
... By inducing the production of prostaglandin D 2 (PGD 2 ) in the skin, Niacin causes lateral dilation and cutaneous blushing which leads to an increase in the levels of PGD 2 , 9α, 11β-PGF 2 and other metabolites in the plasma [91]. Administration of niacin at doses of 500 mg orally or topically in the form of methyl nicotinate significantly increases the release of prostaglandin D 2 in the skin and its metabolites in the plasma [91,92]. It is not entirely clear whether prostaglandin D 2 affects the intracranial arteries, however, since niacin aborts acute migraine attacks, it seems applicable. ...
... It is not entirely clear whether prostaglandin D 2 affects the intracranial arteries, however, since niacin aborts acute migraine attacks, it seems applicable. Bicknell and Prescott [92], demonstrated that niacin has an important role in the vasodilation of the cerebral and spinal vessels, so intravenous injection increases the rate of intracranial blood flow without any alteration in blood pressure. Unfortunately, there is not enough evidence for the effect of niacin on increasing the rate of blood flow. ...
Objective:
Migraine as a disabling neurovascular disease affects 6% of men and 18% of women worldwide. The deficiency of many nutrients including magnesium, niacin, riboflavin, cobalamin, coenzymes Q10, carnitine, α-lipoic acid and vitamin D is associated with migraine. Some researchers postulate that mitochondrial dysfunction and impaired antioxidant status can cause migraine. Also increase in homocysteine level can lead to migraine attacks; therefore, some Nutraceuticals play a vital role in migraine prevention. Thus, the aim of the current study was to review randomized controlled trials (RCT) assessing the effect of nutritional supplements on migraine patients.
Methods:
English articles in the following databases were searched: MEDLINE, AMED, EMBASE and Cochrane Library. In this manuscript, RCTs published during 1990-2017 were reviewed.
Results:
Evidences indicate that supplementation with magnesium, carnitine, riboflavin, niacin, CoQ10, vitamin D, Vitamin B12and alpha lipoic acid have prophylactic and therapeutic effects on migraine patients.
Conclusion:
Due to the possible side effects of pharmacological drugs and drug addictions, the use of nutrient compounds alone or in combination with routine cures have been proposed. However, further constructive studies are required.
... (PGD2) [271,270] which suggests the existence of an abnormal prostaglandin signaling. In addition, the flush response to niacin does not differ between medicated and unmedicated schizophrenics [338] and is also impaired in nonpsychotic first-degree relatives of schizophrenic patients [386], suggesting that the alteration in niacin sensibility is a genetic trait independent of medication status. ...
... prostaglandins) are critical to various signal transduction pathways [35]. The abnormal niacin response found in schizophrenic patients [159,393,345] might be due to decreased levels of arachidonic acid [101] or can result from abnormal activity of the enzymes responsible for the synthesis of PGD2, whose epidermic release is involved in the flushing response to niacin [271,270]. ...
... Fatty acid signaling abnormalities have also been reported in social phobia. Methylnicotinate, applied topically, can induce vasodilatation by means of stimulating the release of arachidonic acid (an omega-3 PUFA) from membrane phospholipids [45]. The free arachidonic acid is then metabolized to form prostaglandin D 2 which acts upon capillary endothelial cells to causes vasodilatation [45]. ...
... Methylnicotinate, applied topically, can induce vasodilatation by means of stimulating the release of arachidonic acid (an omega-3 PUFA) from membrane phospholipids [45]. The free arachidonic acid is then metabolized to form prostaglandin D 2 which acts upon capillary endothelial cells to causes vasodilatation [45]. Patients with social phobia were found to display a reduced maximal vasodilatatory response to methylnicotinate the extent of which was correlated with the severity of the patients' symptoms [46]. ...
... Morrow et al. (224) used gas chromatography-mass spectrometry to detect large levels of PGD 2 and its metabolite 9a,11 β-PGF 2 following oral niacin. However, (225,226) suggested that flushing is strictly related to PGE 2 . ...
Schizophrenia is a neuropsychiatric illness with no single definitive aetiology, making its treatment difficult. Antipsychotics are not fully effective because they treat psychosis rather than the cognitive or negative symptoms. Antipsychotics fail to alleviate symptoms when patients enter the chronic stage of illness. Topical application of niacin showed diminished skin flush in the majority of patients with schizophrenia compared to the general population who showed flushing. The niacin skin flush test is useful for identifying patients with schizophrenia at their ultra-high-risk stage, and understanding this pathology may introduce an effective treatment. This review aims to understand the pathology behind the diminished skin flush response, while linking it back to neurons and microglia. First, it suggests that there are altered proteins in the GPR109A-COX-prostaglandin pathway, inflammatory imbalance, and kinase signalling pathway, c-Jun N-terminal kinase (JNK), which are associated with diminished flush. Second, genes from the GPR109A-COX-prostaglandin pathway were matched against the 128-loci genome wide association study (GWAS) for schizophrenia using GeneCards, suggesting that G-coupled receptor-109A (GPR109A) may have a genetic mutation, resulting in diminished flush. This review also suggests that there may be increased pro-inflammatory mediators in the GPR109A-COX-prostaglandin pathway, which contributes to the diminished flush pathology. Increased levels of pro-inflammatory markers may induce microglial-activated neuronal death. Lastly, this review explores the role of JNK on pro-inflammatory mediators, proteins in the GPR109A-COX-prostaglandin pathway, microglial activation, and neuronal death. Inhibiting JNK may reverse the changes observed in the diminished flush response, which might make it a good therapeutic target.
... Third, a significantly reduced n-6 FAs may be attributed to the blunted niacin-induced skin flushing in a subgroup of SZ patients, which might be clinically useful in the diagnosis of schizophrenia (Morrow et al., 1989(Morrow et al., , 1992Ward et al., 1998;Puri et al., 2001;Benyó et al., 2005;Maciejewski-Lenoir et al., 2006;Tang et al., 2006;Lai et al., 2007;Messamore and Yao, 2016). While the cause of such blunted skin flushing in SZ is still unclear, our findings of a significant decreased arachidonic acid (20:4n6) as well as its precursors in FEANS patients may offer a possible explanation to the underlying mechanism that caused the blunted niacin-induced response in SZ. ...
Membrane phospholipid deficits have been well-documented in schizophrenia (SZ) patients. Free fatty acids (FFAs) partially come from the hydrolysis of membrane phospholipids and serve as the circulating pool of body fatty acids. These FFAs are involved in many important biochemical reactions such as membrane regeneration, oxidation and prostaglandin production which may have important implications in SZ pathology. Thus, we compared plasma FFA levels and profiles among healthy controls (HC), affective psychosis (AP) patients and first-episode antipsychotic-naïve schizophrenia (FEANS) patients. A significant reduction of total free fatty acids levels was observed in SZ patients. Specifically, significant reductions of 16:0, 18:2n6c and 20:4n6 levels were detected in FEANS patients but not in APs when compared with levels in HCs. Also, disrupted metabolism of fatty acids especially in saturated and n-6 fatty acid families were observed by comparing correlations between precursor and product fatty acid levels within each fatty acid family. These findings may suggest an increased demand of membrane regeneration, a homeostatic imbalance of fatty acid biosynthesis pathway and a potential indication of increased beta oxidation.
... Immediate release formulations of niacin are associated with a cutaneous flushing side-effect in humans, which has been previously attributed to the NA glycine conjugation pathway leading to the formation of nicotinuric acid [36]. However, recent evidence suggests that the parent compound NA, through its interaction with the GPR109A receptor, is the principal mediator of flushing [37][38][39][40][41]. Interactions of NA with GPR109A receptors on epidermal Langerhans cells lead to increases in cytosolic calcium, which enhances phospholipase A2 activity and expression of prostaglandin D 2 . ...
Nicotinic acid (NA) and nicotinamide (NAM) are biosynthetic precursors of nicotinamide adenine dinucleotide (NAD+) - a physiologically important coenzyme that maintains the redox state of cells. Mechanisms driving their entry into cells are not well understood. Here we evaluated the hepatic uptake mechanism(s) of NA and NAM using transporter-transfected cell systems and primary human hepatocytes. NA showed robust organic anion transporter (OAT)2-mediated transport with an uptake ratio (i.e., ratio of accumulation in transfect cells to wild-type cells) of 9.7±0.3, and a Michaelis-Menten constant (Km) of 13.5±3.3 µM. However, no transport was apparent via other major hepatic uptake and renal secretory transporters, including OAT1/3/4, organic anion transporting polypeptide (OATP)1B1/1B3/2B1, sodium-taurocholate co-transporting polypeptide, organ cation transporter 1/2/3. OAT2-specific transport of NA was inhibited by ketoprofen and indomethacin (known OAT2 inhibitors) in a concentration-dependent manner. Similarly, NA uptake into primary human hepatocytes showed pH- and concentration-dependence and was subject to inhibition by specific OAT2 inhibitors. Unlike NA, NAM was not transported by the hepatic and renal solute carriers upon assessment in transfected cells, although its uptake into human hepatocytes was significantly inhibited by excess unlabelled NAM and a pan-SLC inhibitor (rifamycin SV 1 mM). In conclusion, these studies demonstrate, for the first time, a specific transport mechanism for NA uptake in the human liver and suggest that OAT2 (SLC22A7) has a critical role in its physiological and pharmacological functions.
... [39] Known side effects of nicotinic acid include flushing, nausea and vomiting, hypotension, headaches and itch, [40] presumably due to its vasodilatory effects [41] and release of prostaglandin D2 and other eicosanoids from the skin. [42] These vasodilatory side effects are not generally observed with NAM. [43] In an attempt to combat this side effect profile of immediate release nicotinic acid, an extended release compound (ERN) was created in combination with laropiprant (LRPT), a prostaglandin inhibitor (ERN-LPRT). ...
Nicotinamide is a water‐soluble vitamin B3 derivative that has many roles in medicine. This review examines the role of nicotinamide in dermatology and its actions in preventing photoageing and skin cancers in humans. Nicotinamide prevents ultraviolet radiation (UV) from reducing ATP levels and inhibiting glycolysis, thus preventing the UV radiation‐induced energy crisis. This enhances DNA repair and reduces UV‐induced suppression of immunity. Randomised controlled clinical trials have also shown that nicotinamide reduces transepidermal water loss and the development of new non‐melanoma skin cancers in high‐risk humans. This review also examines nicotinamide's safety profile.
... Rahman M et al. reported that GPR109a is also expressed in brain microglia and exhibited neuroprotective effect in mice [7]. However, NA mediated activation of GPR109a in langerhans cells and keratinocytes induces expression of prostaglandin D2 (PGD2) and ultimately cutaneous flushing [8,9] by b-arrestin1 mediated signaling [10]. Thus, a G-protein bias agonist of GPR109a that exhibits minimal or no b-arrestin1 dependent signaling would be a better candidate to avoid the side effect of targeting GPR109a. ...
In this study, we presented rational designing and synthesis of coumarin-dihydroquinazolinone conjugates to evaluate their agonist activity at GPR109a receptor. Among the synthesized small molecule library, compound 10c displayed robust agonist action at GPR109a with EC50 < 11 nM. Homology model of human GPR109a protein was generated to realize the binding interaction of the active molecule with the active site of GPR109a. Further, the efficacy of active compound 10c was supported by in-vivo experiments which showed reduced body weight in diet induced obese mice model. Interestingly, compound 10c reduced leptin in blood plasma and total serum cholesterol. These results suggest that the coumarin-dihydroquinazolinone conjugate is a suitable scaffold to further expand the chemical diversity and make them potential niacin receptor 1 agonist.
... The most problematic of these is cutaneous flushing, which has been shown to result from signalling through the DP 1 receptor, triggered by the production of PGD 2 in Langerhans cells following activation of the niacin receptor. [10][11][12][13][14][15] In attempting to address these issues, a number of sustained-and extended-release formulations have been developed, each with markedly different pharmacokinetic properties. 2 Sustained-release preparations are not approved for clinical use and are only available as food supplements. Extended-release preparations offer a pharmacokinetic 'mid-ground' between sustained-release formulations and the short-acting immediate-release niacin, and these have proved successful clinical agents. ...
... Evidence indicates that a skin test using methyl nicotinate (niacin ester derivative) can suggest a possibly reduced AA level in the cell membranes through the mechanism by which niacin may act (via niacin receptors) on immune cells and mediate the synthesis of prostaglandins. This inflammatory response can cause skin vasodilatation and redor (flushing) which is about four times greater in healthy control subjects compared with schizophrenic patients (10)(11)(12)(13). Some studies also showed that skin flush response to niacin is more impaired in the relatives of schizophrenic patients indicating the genetic aspect of schizophrenia (14,15). ...
Background: Patients with schizophrenia have abnormal skin flush response to niacin. We aimed to evaluate the accuracy of niacin skin test in these patients. Objectives: We aimed to evaluate the accuracy of niacin skin test in these patients. Materials and Methods: This diagnostic trial with parallel-group design was conducted at the Noor university hospital in Isfahan (Iran) from January to September 2014. Participated Subjects were hospitalized schizophrenic adult and their first degree relatives, bipolar disorder patients and healthy controls (n = 25 in each group). Niacin skin test was performed using 0.5 mL of 0.1Mand 0.01Mdiluted methyl nicotinate solutions applied every 5 minutes for a total of 20 minutes and graded from 0 (no redness) to 3 (extreme redness). Sensitivity, specificity, and positive and negative predictive values were calculated. Results: The time point at which there was no further significant change in the skin response was 10 minutes after the test. At this set point, schizophrenic patients had lower response to each solutions compared to others (P < 0.001), but there was no difference between bipolar disorder patients and controls (P > 0.05). A grade of ≤1 skin response to the 0.01 M solution of methyl nicotinate would provide sensitivity, specificity, positive and negative predictive values of 80%, 93.3%, 80%, and 93.3%, respectively, in differentiating schizophrenic from other groups. Using 0.1 M solution provide lower sensitivity (32%) and negative predictive value (81.5%), but higher specificity (100%) and positive predictive value (100%). Conclusions: Niacin skin flush response is impaired in schizophrenic patients. This phenomenon may be used as a complementary diagnostic test in psychiatric workups.
... Evidence indicates that a skin test using methyl nicotinate (niacin ester derivative) can suggest a possibly reduced AA level in the cell membranes through the mechanism by which niacin may act (via niacin receptors) on immune cells and mediate the synthesis of prostaglandins. This inflammatory response can cause skin vasodilatation and redor (flushing) which is about four times greater in healthy control subjects compared with schizophrenic patients (10)(11)(12)(13). Some studies also showed that skin flush response to niacin is more impaired in the relatives of schizophrenic patients indicating the genetic aspect of schizophrenia (14,15). ...
Background
Diabetic patients are more susceptible to cutaneous fungal infections. The higher blood sugar levels cause increasing the cutaneous fungal infections in these patients. The main objective of this study was to find the frequency of fungal infections among cutaneous lesions of diabetic patients and to investigate azole antifungal agent susceptibility of the isolates.
Materials and Methods
In this study, type 1diabetes (n = 78) and type 2 diabetes (n = 44) comprised 47 cases (38.5%) with diabetic foot ulcers and 75 cases (61.5%) with skin and nail lesions were studied. Fungal infection was confirmed by direct examination and culture methods. Antifungal susceptibility testing by broth microdilution method was performed according to the CLSI M27-A and M38-A references.
Results
Out of 122 diabetic patients, thirty (24.5%) were affected with fungal infections. Frequency of fungal infection was 19.1% in patients with diabetic foot ulcer and 28% of patients with skin and nail lesions. Candida albicans and Aspergillus flavus were the most common species isolated from thirty patients with fungal infection, respectively. Susceptibility testing carried out on 18 representative isolates (13 C. albicans, five C. glabrata) revealed that 12 isolates (10 C. albicans and two C. glabrata isolates) (66.6%) were resistant (minimum inhibitory concentration [MIC] ≥64 mg/ml) to fluconazole (FCZ). Likewise, eight isolates (80%) of Aspergillus spp. were resistant (MIC ≥4 mg/ml), to itraconazole.
Conclusion
Our finding expands current knowledge about the frequency of fungal infections in diabetic patients. We noted the high prevalence of FCZ-resistant Candida spp., particularly in diabetic foot ulcers. More attention is important in diabetic centers about this neglected issue.
... 35 When niacin is administered orally in amounts of 500 mg or topically via a 6-inch patch of 10 -1 M aqueous methylnicotinate on the forearm, PGD2 is markedly released in the skin and its metabolite appears in high amounts in the plasma. 35,36 It is not known if PGD2 causes vasodilatation of the intracranial arteries, but niacin's ability to abort acute migraine headaches suggests that this might be what is occurring. 37 Old reports cited by Bicknell and Prescott, 38 demonstrate that niacin does indeed cause vasodilatation of the cerebral and spinal vessels, and that intravenous administration increases the rate of intracranial blood flow in human beings for 20-60 minutes without any significant change in blood pressure. ...
While on parental leave during November 2009, my clinical shift was spearheaded by one of my colleagues who recommended fairly significant doses of inositol hexaniacinate to treat a patient's depression. In January 2010, the patient returned for a visit on my clinical shift, and much to my surprise her long-standing depression had resolved. As a result, I conducted a search for articles describing the use of vitamin B3 for depression. Six articles were found to meet the inclusion criteria and were included in this review. There is evidence that niacin and niacinamide (in combination with tryptophan) might be effective for the treatment of depression. Hypothetical reasons for niacin's effectiveness include its vasodilatory properties, while the mechanisms responsible for the effectiveness of niacinamide involve its ability to inhibit tryptophan pyrrolase and possibly protect neurons from damage. The side effect profiles of niacin and the niacinamide-tryptophan combination are also discussed. Even though the mechanisms of action for niacin and niacinamide have not been substantiated from well conducted controlled clinical trials, these forms of vitamin B3 appear to have beneficial effects upon depression. It is imperative that properly designed controlled trials are developed in order to determine the true therapeutic effects and adverse effect profile of both preparations of vitamin B3 for depression.
... The poor tolerability and adverse effects of niacin, however, has limited its use in the CKD population. The most common adverse effect of niacin is skin flushing, which occurs in the majority of patients 115 . In addition, niacin can cause hepatotoxicity, hyperuricaemia, and hyperglycaemia 116,117 . ...
Normal HDL activity confers cardiovascular and overall protection by mediating reverse cholesterol transport and through its potent anti-inflammatory, antioxidant, and antithrombotic functions. Serum lipid profile, as well as various aspects of HDL metabolism, structure, and function can be profoundly altered in patients with nephrotic range proteinuria or chronic kidney disease (CKD). These abnormalities can, in turn, contribute to the progression of cardiovascular complications and various other comorbidities, such as foam cell formation, atherosclerosis, and/or glomerulosclerosis, in affected patients. The presence and severity of proteinuria and renal insufficiency, as well as dietary and drug regimens, pre-existing genetic disorders of lipid metabolism, and renal replacement therapies (including haemodialysis, peritoneal dialysis, and renal transplantation) determine the natural history of lipid disorders in patients with kidney disease. Despite the adverse effects associated with dysregulated reverse cholesterol transport and advances in our understanding of the underlying mechanisms, safe and effective therapeutic interventions are currently lacking. This Review provides an overview of HDL metabolism under normal conditions, and discusses the features, mechanisms, and consequences of HDL abnormalities in patients with nephrotic syndrome or advanced CKD.
... Furthermore, the reaction to niacin in a skin flush test was attenuated in HD patients compared to controls [20]. The vasodilation brought on by niacin is thought to be regulated by release of arachidonic acid from membranes and its subsequent conversion to Prostaglandin D2 [21,22]. Despite these early studies, little else is known about the actual levels of specific glycerophospholipids in HD or about their role in HD pathology. ...
Objective:
We analyzed glycerophospholipid profiles from brains of 11 month old wild-type (WT) and Q140/Q140 HD knock-in mice to assess potential changes in glycerophospholipid metabolism.
Methods:
Polar lipids from cerebellum, cortex, and striatum were extracted and analyzed by liquid chromatography and negative ion electrospray tandem mass spectrometry analysis (LC-MS/MS). Gene products involved in polar lipid metabolism were studied using western blotting, immuno-electron microscopy and qPCR.
Results:
Significant changes in numerous species of glycerophosphate (phosphatidic acid, PA) were found in striatum, cerebellum and cortex from Q140/Q140 HD mice compared to WT mice at 11 months. Changes in specific species could also be detected for other glycerophospholipids. Increases in species of lyso-PA (LPA) were measured in striatum of Q140/Q140 HD mice compared to WT. Protein levels for c-terminal binding protein 1 (CtBP1), a regulator of PA biosynthesis, were reduced in striatal synaptosomes from HD mice compared to wild-type at 6 and 12 months. Immunoreactivity for CtBP1 was detected on membranes of synaptic vesicles in striatal axon terminals in the globus pallidus.
Conclusions:
These novel results identify a potential site of molecular pathology caused by mutant Huntingtin that may impart early changes in HD.
... glandin D2 (PGD2) is markedly released in the skin and high amounts of its metabolite appear in the plasma. 22,23 It is not known if PGD2 causes vasodilatation of the intracranial blood vessels, but niacin's ability to abort acute migraine headaches suggests that this might be occurring. 24 Old reports cited by Bicknell and Prescott, 25 indicated that niacin causes vasodilatation of the cerebral and spinal vessels. ...
Dementia affects approximately 5 million people in the United States, and about 475,000 elderly Canadians. Dementia is a debilitating and often progressive illness. The most common type of dementia is Alzheimer' s disease, followed by vascular types. There is a need to investigate novel treatments because the current crop of medications have limited value. Niacin might be a worthwhile treatment to consider. Research has shown that the risks of incident AD increase when patients have insufficient intakes of niacin from diet or medical conditions that precipitate niacin deficiency. Clini-cal reports have documented therapeutic benefits when patients receive optimum daily doses of niacin. Preliminary trials evaluating the reduced form of nicotinamide adenine dinucleotide (NADH) found it a safe and effective treatment for AD. At present, research evaluating the therapeutic applications of niacin and/or NADH for dementia is at a standstill. However, niacinamide is being evaluated in a clinical trial to determine if it is safe and beneficial for patients with AD. Hopefully, the forthcoming results will encourage researchers and clinicians to study niacinamide further, and revisit the therapeu-tic potential of vitamin B 3 as a safe and an effective treatment for dementia.
... The flushing can be avoided or reduced in intensity by previous intake of aspirin. The vasodilatation following ingestion of nicotinic acid is due to the release of prostaglandin (PG) D 2 locally in the skin [3] from PGD2 responsive cells in the skin most probably macrophages [4]. ...
... Another study by Sakai et al. showed reduced mean levels of docosahexaenoic acid in erythrocyte membranes of HD patients versus controls [34]. In a small clinical study, Puri found an altered response of HD patients to a skin flush test in response to niacin, which suggested changes in fatty acid metabolism [35], since vasodilation in response to niacin is thought to depend on liberation of arachidonic acid from membranes and its conversion to Prostoglandin D2 [36,37]. Thus, physicians and scientists have long hypothesized that changes in membrane phospholipids might cause pathology in HD patients [38]. ...
The Huntington's disease gene encodes the protein huntingtin (Htt), a soluble protein that largely distributes to the cytoplasm where about half the protein is found in association with membranes. Early studies on Huntington's disease patients suggested changes in membrane phospholipids. Furthermore, changes in phospholipid biosynthetic enzymes have been found in HD cell models using genetic methods. Recent investigations prove that Htt associates with membranes by direct interactions with phospholipids in membranes. Htt contains at least two membrane binding domains, which may work in concert with each other, to target to the appropriate intracellular membranes for diverse functions. Htt has a particular affinity for a specific class of phospholipids called phosphatidylinositol phosphates; individual species of these phospholipids propagate signals promoting cell survival and regulating changes in morphology. Mutant Htt fragments can disrupt synthetic phospholipid bilayers and full-length mutant Htt shows increased binding to numerous phospholipids, supporting the idea that mutant Htt can introduce pathology at the level of phospholipid interactions. There is a great potential to develop therapeutic agents since numerous enzymes regulate the both the biosynthesis/metabolism of lipids and the post-translational modifications of Htt that direct membrane interactions. Understanding the relationship of Htt with membrane phospholipids, and the impact of mutant Htt on membrane-related functions and lipid metabolism, may help identify new modes of therapeutic intervention for Huntington's disease.
... uwalniany z fosfolipidów błonowych poprzez aktywację związanych z białkiem G receptorów (np. D2) i uaktywnienie PLA2. Doustne przyjęcie kwasu nikotynowego przez zdrowych ochotników prowadzi do zaczerwienienia twarzy i górnej połowy ciała, co wiąże się z rozszerzeniem drobnych naczyń krwionośnych, indukowanym głównie przez prostaglandynę D2 (PGD2) (Morrow i wsp. 1992). PGD2 rozszerza naczynia krwionośne w mechanizmie zwiększenia produkcji cAMP, co obserwuje się klinicznie jako rumień, a w bardziej zaawansowanych przypadkach obrzęk. Upośledzenie powstawania rumienia w odpowiedzi na aplikację kwasu nikotynowego może być pośrednim dowodem na zmniejszenie dostępności AA i dalej zmieniony skład fosfolipi ...
Polyunsaturated fatty acids (PUFA), particularly arachidonic, eicosapentaenoic, dokosahexaenoic acids are the key structural elements of neuronal membranes. They constitute about 15-30% of the dry brain weight and that fact is largely responsible for the unique physical and chemical features of the neuronal phospholipid bilayers which cover many intracellular organelle and take part in information exchange processes. PUFA’s concentration changes in brain phospholipids influence many key cellular processes: membrane fluidity, tertiary structure of receptor and transport proteins, receptor-ligand interactions and induce neurotransmission disturbances. Developing brain utilizes vast quantities of PUFA’s, which are essential for neuronal development, migration, synaptogenesis, synaptic plasticity and neurogenesis. PUFA’s are also substrates for eicosanoids production, which are very short-living and extremely reactive substances playing many biological as well as signaling functions. Phospholipids processing by phospholipases is also connected with second messenger signaling activity and transduction of information received by many groups of metabotropic receptors. PUFAs concentration and metabolism disturbances have been observed repeatedly in schizophrenic patients. These changes were most frequent and intense on early stages of the disease. The above mentioned disturbances along with the key role of PUFAs in neurodevelopment and brain maturation contributed to the formulation of membrane phospholipids composition (MPC) hypothesis of schizophrenia, which may constitute a biochemical foundation for neuroimaging and neuronal cytoarchitecture disturbances observed in that chronic and devastating disease. The paper discusses the role of PUFA in brain, their metabolism and lipid abnormalities observed in schizophrenia. The main assumptions of David Horrobin’s MPC hypothesis of schizophrenia are also presented.
... Niacin (nicotinic acid) can induce a visible skin flush response that is mediated by the release of vasodilatatory prostaglandins from the skin [Morrow et al., 1992]. Studies consistently found lowered incidence or intensity of flush response to niacin skin patch in individuals with schizophrenia [Messamore et al., 2003;Liu et al., 2007a]. ...
Taiwan Schizophrenia Linkage Study (TSLS) was initiated with a linkage strategy for locating multiple genes, each of small to moderate effect, and aimed to recruit a large enough sample of pairs of affected siblings and their families ascertained from a multisite study. With a sample of 607 families successfully recruited, a total of 2,242 individuals (1,207 affected and 1,035 unaffected) from 557 families were genotyped using 386 microsatellite markers spaced at an average of 9-cM intervals. Here the author reviews the establishment of TSLS and initial signal derived from linkage scan using the diagnosis of schizophrenia. Based on the limited success of the initial linkage analysis, a sufficient-component causal model is proposed to incorporate endophenotypes and genes for schizophrenia. Four types of candidate endophenotype measured in TSLS, including schizotypal personality, Continuous Performance Test, Wisconsin Card Sorting Test, and niacin skin flush test, are briefly described. The author discusses different strategies of linkage analysis incorporating these endophenotypes, including quantitative trait loci (QTL) linkage analysis, clustering-derived subgroups, ordered subset analysis (OSA), and latent classes for linkage scan. Then the author summarizes the linkage signals generated from seven studies of endophenotype-based linkage analysis using TSLS, including QTL scan of neurocognitive performance, QTL scan of niacin skin flush, the family cluster of attention deficit and execution deficit, OSA by schizophrenia-schizotypy factors, nested OSA by age at onset and neurocognitive performance, and the latent class of deficit schizophrenia for linkage analysis. The perspective of combining next-generation sequencing with linkage analysis of families is also discussed. © 2013 Wiley Periodicals, Inc.
... Most patients ( ف 70%) receiving niacin experience fl ushing and about 20% of niacin-treated subjects drop out of clinical trials for this reason ( 14,72 ). Morrow and colleagues fi rst noted that prostaglandin D 2 (PGD 2 ) played a central role in the fl ushing that constrains the use of niacin ( 73,74 ). In mice, niacin-induced fl ushing results from an early phase of COX-1-dependent formation of PGD 2 and prostaglandin E 2 (PGE 2 ) in Langerhans cells, followed by delayed COX-2-dependent production of PGE 2 by keratinocytes ( 10 ). ...
Niacin (nicotinic acid) has been used for decades as a lipid-lowering drug. The clinical use of niacin to treat dyslipidemic conditions is limited by its side effects. Niacin, along with fibrates, are the only approved drugs which elevates high density lipoprotein cholesterol (HDL-C) along with its effects on low density lipoprotein cholesterol (LDL-C) and triglycerides. Whether niacin has a beneficial role by lowering cardiovascular risk on the background of well-controlled LDL-C, has not been established. In fact, it remains unclear whether niacin confers any therapeutic benefit and if so, by which mechanism. The results of recent trials reject the hypothesis that simply raising HDL-C is cardio protective. However, in the case of the clinical trials, structural limitations of trial design complicate their interpretation. This is also true of the most recent HPS - THRIVE trial in which niacin is combined with an antagonist of the D prostanoid (DP) receptor. Human genetic studies have also questioned the relationship between cardiovascular benefit and HDL-C. It remains to be determined whether niacin has clinical utility in particular subgroups, such as statin intolerant patients with hypercholesterolemia and whether its effects are confounded by DP antagonism in HPS-THRIVE.
... patch of 100 mmol/L aqueous methylnicotinate on the forearm, PGD 2 is markedly released in the skin and its metabolite appears in high amounts in the plasma. 70,71 It is not known if PGD 2 causes vasodilatation of the intracranial arteries, but the ability of niacin to abort acute migraine headaches suggests that this could be what is occurring. 60 Old reports cited by Bicknell and Prescott 72 demonstrate that niacin does indeed cause vasodilatation of the cerebral and spinal vessels and that intravenous administration increases the rate of intracranial blood flow in humans for 20 to 60 minutes without any significant change in blood pressure. ...
Niacin is required for a host of critical redox and adenosine diphosphate-ribosylation reactions in metabolism. Niacin deficiency leads to the distinctive signs and symptoms of pellagra, but these can happen in an unpredictable progression and can be altered in patients with polymorphisms in any of the hundreds of niacin-dependent enzymes. The symptomatology of niacin deficiency is becoming a forgotten knowledge base, and niacin deficiency is likely underdiagnosed. Additionally, high levels of niacin and niacinamide have pharmacological effects distinct from their role as sources of vitamin B3, allowing a wide range of effects on processes such as blood flow and lipid metabolism, which can be used to treat or prevent a variety of disease processes.
Introduction:
Nicotinamide adenine dinucleotide (NAD+) is a coenzyme of the NAD+-dependent protein deacetylase sirtuin-1 (SIRT1). An increase in NAD+ concentration induces SIRT1 activation that results in various health benefits. Since nicotinamide mononucleotide (NMN) is a precursor of NAD+, NMN ingestion is expected to have multiple health benefits such as alleviation of aging, lifestyle-related and neurodegenerative diseases, through the activation of SIRT1. In this study, we aimed to determine the effects of daily NMN ingestion on plasma levels of NMN and NAD+.
Methods:
Healthy volunteers received 250 mg of NMN once a day in the morning (n = 11) for 12 weeks, and the plasma concentrations of NMN and NAD+ were measured monthly. Physiological and laboratory tests were performed within 2 h after lunch (at 2 pm) before and during NMN administration.
Results:
Oral administration of NMN increased the plasma concentrations of NMN and NAD+, and the postprandial serum insulin levels. The elevation levels of NMN and insulin varied widely among individuals. No adverse symptoms were observed in the participants.
Conclusions:
Oral administration of NMN elevates plasma levels of NMN and NAD+, and postprandial serum insulin levels.
Vit B3, also known as niacin or nicotinic acid, is a water-soluble member of the Vit B3 complex, a family of vitamins that includes nicotinamide and nicotinamide riboside. Niacin was first described by chemist Hugo Weidel in his studies of nicotine [1]. It was later extracted from liver tissue by biochemist Conrad Elvehjem in 1937, who later identified the active ingredient, then referred to as the “pellagra-preventing factor” and the “anti-blacktongue factor.” [2] Nowadays, niacin is referred to as Vit B3 because it was the third of the B vitamins to be discovered. Niacin cannot be directly converted to nicotinamide, but since both compounds are precursors of the coenzymes nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP) in vivo, the term Vit B3 is used as a blanket term for both [3].
Quantitation of urinary metabolites of histamine, prostaglandin D2 and leukotriene E4 can fill the gap in our current efforts to improve diagnosis and management of symptomatic patients with systemic mastocytosis, and/or mast cell activation syndrome, Additionally, patients symptomatic due to mast cell activation but who do not meet all the criteria for mast cell activation syndrome also can have elevated baseline mediator metabolites. Serum tryptase levels have been the workhorse in diagnosing these disorders, but it has several drawbacks including the need to obtain acute and baseline samples that require two visits to health care facilities and two venipunctures. Recently, increased baseline tryptase has been reported in hereditary alpha tryptasemia complicating diagnostic possibilities of an increased baseline tryptase level. Furthermore, no treatment can specifically be targeted at tryptase itself. In contrast, the finding of one or more elevated urinary levels of histamine, prostaglandin D2 and/or leukotriene E4 metabolites:1) greatly narrows diagnostic possibilities for causes of symptoms; 2) informs the practitioner what specific metabolic pathways are involved; 3) targets the treatment in a specific, direct fashion. As a bonus, baseline spot/random urine samples can be obtained by the patients themselves and repeated at exactly the correct time when symptoms occur.
Mast cell(MC)s leave evidence of their presence and activation. Aside from increased numbers of MCs in tissues this evidence includes detecting elevated serum levels of tryptase and by discovering increased excretion of urinary metabolites of prostaglandin D2, leukotriene C4, and/or histamine. The importance of measuring these non-tryptase mediator metabolites has largely gone unnoticed.
We reviewed the utility of quantitating urinary levels of MC mediator metabolites in systemic mastocytosis (SM) and MC activation disorders and
summarized the relative production of these mediators by MCs and other cell types.
Quantitation of urinary n-methyl histamine, 2,3 dinor 11βPGF2α and LTE4 offers a simple, noninvasive avenue to monitor their constitutive release as well as contemporaneous discharge during MC activation as well as supporting a diagnosis of SM. These increases can occur independently of or in addition to raised levels of tryptase. Quantitation of these mediator metabolites potentially offers targets for therapeutic intervention. Synthesis of PGD2, a product nearly exclusively of MCs, can be controlled with aspirin, histamine increase by H1 and H2 receptor blockade, and LTC4 by a 5-LO inhibitor or LT receptor antagonist. Although other sources are reported, the increase in MC numbers in SM supports this cell as the predominant origin of all three mediators.
Immediate contact reactions are a heterogeneous group of inflammatory conditions characterized by two main clinical presentations: contact urticaria (CoU) for patients presenting with wheals/angioedema, and protein contact dermatitis (PCD) for patients presenting with predominantly dermatitis/eczema. Generalized lesions or systemic symptoms are feasible also in the contact urticaria syndrome (CUS). This chapter summarizes the most important aspects regarding the mechanisms of these two conditions. Nonimmunological, immunological, and uncertain mechanisms have been proposed as possible pathogenic mechanisms in CoU, and an immunological mechanism involving a combination of type I and type IV allergic skin reactions has been proposed in PCD. Understanding the possible mechanisms will help our approach to the different clinical manifestations and diagnostic procedures performed to confirm the diagnosis.
Schizophrenia is a serious mental illness of unclear aetiology. The reduced ability of methylnicotinate to induce a topical vasodilatory response in patients with the disorder is well established. Methylnicotinate causes vasodilation via stimulating the release of prostaglandins (including prostaglandin D2) in the skin which in turn leads to relaxation of vascular smooth muscle. To determine whether the abnormality is likely to be due to decreased prostaglandin production, or decreased prostaglandin effect upon the vessels, topical methylnicotinate was applied to the forearms of patients with schizophrenia or healthy controls, followed by rating of the resulting erythema. The concentration of prostaglandin D2 and its metabolite 11β-prostaglandin F2α in the blood draining the arm was also measured. Although erythema was reduced in the patient group, the plasma concentration of the prostaglandins was unaltered. This data suggests the abnormality underlying the reduced potency of methylnicotinate to produce vasodilation in the disorder occurs downstream of prostaglandin synthesis possibly within the vasculature itself.
The membrane phospholipid hypothesis suggests that the primary abnormality in schizophrenia is in phospholipid biochemistry. This particularly applies to mechanisms regulating highly unsaturated fatty acid metabolism at the Sn2 position of phospholipid molecules. As a consequence there are abnormalities of neuronal membrane structure and cell signalling. These lead secondarily to disturbances in neurotransmitter and ion channel-related mechanisms. Two separate abnormalities of phospholipid metabolism are proposed. They are present throughout the body and can be detected in red blood cells and also in the skin during stimulation of arachidonic acid metabolism by niacin. One of them may also be identified by abnormal P50 gating. Novel therapies based on this concept have yielded good results in clinical trials with none of the usual side effects of either typical or atypical neuroleptics. The phospholipid concept offers a new approach to the problems of understanding and treating schizophrenia.
Atherosclerosis is an arterial disease associated with elevated plasma lipid levels and is a major cause of morbidity and mortality worldwide. Clinical trials have demonstrated that reduction of low-density lipoprotein cholesterol (LDL-C), as can be accomplished with HMG-CoA reductase inhibitors (statins), leads to a reduction in coronary events and mortality by about 25%. Conversely, epidemiological evidence indicates that high-density lipoprotein cholesterol (HDL-C) levels have an inverse correlation with risk of coronary artery disease. The beneficial effects of HDL have been attributed to its involvement in the movement of cholesterol from the periphery to the liver as well as to its apparent antioxidant and anti-inflammatory activities. Consequently, there is much interest in identifying therapeutic approaches to raising HDL that will be useful as a treatment for atherosclerosis and dyslipidemias. The properties and physiologic role of HDL, as well as approaches to increasing plasma HDL concentrations, will be summarized.
The basic reasons for considering the possibility that lipid abnormalities may be important in psychiatric disorders are reviewed in detail in Chapter 7. In brief, lipids are required for the normal structures of all neural membranes. Lipid structure is an important determinant of the final tertiary structure of membrane associated proteins such as receptors, ion channels, and adenosine triphophatases. The potential influence of apparently minor variations in lipid structure on membrane protein function is well illustrated by the work of Witt and Nielsen (1994). They demonstrated that the addition of two carbon atoms to a fatty acid (FA) chain, or the insertion of a double bond into a FA, could substantially change the amount of benzodiazepine bound to a receptor. This is likely to be a general principle: Relatively small changes in membrane lipid structure can lead to consequential changes in tertiary protein structure and therefore in the function of a wide variety of membranebound and membrane-associated proteins.
Nonimmunologic contact urticaria (NICU) and other nonimmunologic immediate contact reactions (NIICRs) of the skin comprise a group of inflammatory reactions that appear within minutes to an hour after contact with the eliciting substance and usually disappear within a few hours. These reactions can also be called immediate-type irritancy. NIICRs can be caused by chemicals or proteins and occur without previous immunologic sensitization in most exposed individuals, and they are the most common type of immediate contact reaction [38]. In contrast to NICU, immunologic contact urticaria requires previous sensitization (not necessarily through the dermal route) to the offending agent, usually a protein. Subsequent contact with the material can then elicit the clinical symptoms, which are essentially indistinguishable from their nonimmunologic counterpart.However, in practice, from both a clinical and a mechanistic perspective, it can sometimes be difficult to be convinced whether one is dealing with an immunologic or a nonimmunologic (or a combination of both) type of urticaria.
The utility of measuring histamine and prostaglandin metabolites in the urine of patients with mastocytosis has not been critically examined in a large series of patients. This study examined the relationship between the extent of increase in urinary excretion of 11β-prostaglandinF2α and N-methyl histamine, with serum tryptase, whole blood serotonin and bone marrow findings including morphology, percentage involvement, and abnormal mast cell phenotype.
This was a retrospective analysis of 90 patients who were continuously enrolled in study for period of 6 years (2008-2014). We recorded serum tryptase, whole blood serotonin, levels of urinary mast cell metabolites 11β-prostaglandinF2α, N-methyl histamine (NMH), and bone marrow findings.
Urinary mast cell metabolites 11β-prostaglandinF2α and N-methyl histamine correlated with levels of serum tryptase, mast cell burden in bone marrow, presence of mast cell aggregates and atypical mast cells on bone marrow biopsy. Whole blood serotonin did not have a significant correlation with the serum tryptase or mast cell burden in bone marrow. Urinary NMH was significantly different between c-kit D816V positive and negative patients while 11β-prostaglandinF2α was not. Urinary 11β-prostaglandinF2α 24 hour excretion greater than 3500 ng and NMH levels greater than 400 μg/ gm Cr corresponded with high degree of bone marrow biopsies positive for atypical mast cells, presence of aggregates and c-kit mutation.
Easily-obtained and quantified urinary metabolites of histamine (greater than twice the upper limit of normal) and prostaglandin D2 (greater than 3.5 times the upper limit of normal) correlate well with bone marrow findings of mastocytosis. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
Erythematotelangiectatic rosacea shares facial flushing features with those seen after niacin. This study was performed to test the hypothesis whether prostaglandin D2 (PGD2) receptor subtype 1 antagonist (MK-0524) will improve the symptoms of rosacea. The purpose of this study was to evaluate the effect of MK-0524 100 mg administered once daily for 4 weeks on the signs and symptoms of erythematotelangiectatic rosacea. Subjects received MK-0524 100 mg once-daily (n = 30) or placebo (n = 30) for 4 weeks. The primary pharmacodynamics endpoint was change in Clinician's Erythema Assessment (CEA) score from Baseline to Week 4. The Patient Self-Assessment (PSA) was a secondary endpoint. MK-0524 was generally well tolerated in this study For the primary endpoint of change in CEA score from Baseline to Week 4, the least-squares mean of change from Baseline to Visit 4/Week 4 was -3.7 and -3.4 for placebo and MK 0524 (100 mg), respectively. The least-squares mean difference (placebo minus MK-0524) with 90% confidence interval of change in CEA score from Baseline to Visit 4/Week 4 was estimated as -0.3 (-1.6, 1.0). For the secondary endpoints, the least-squares mean difference (placebo minus MK-0524) with 90% confidence interval of change from Baseline to Visit 4/Week 4 was estimated as -0.7 (-7.7, 6.4) for PSA total score, -4.5 (-14.2, 5.3) for PSA emotion score, -1.3 (-7.8, 5.3) for PSA symptoms score, and 3.6 (-4.3, 11.4) for PSA functioning score. MK-0524 administered once daily for 4 weeks was generally well tolerated in this population of subjects with rosacea. However, there were no clinically meaningful changes in the primary endpoint of CEA given that the response to MK-0524 could not be differentiated from that to placebo. There was also no clinically meaningful change in the secondary endpoint, PSA. A DP1 antagonist is not likely to be effective in rosacea.
Background:
Although niacin often has beneficial effects on the lipoprotein profile, flushing is an untoward effect associated with its use. Aspirin can only reduce the flushing response by 30-40%. Thus, the aim of the present study was to investigate the mechanisms of niacin-induced flushing, with and without aspirin, in normal, healthy individuals.
Methods:
Niacin-induced flushing was evaluated in 30 healthy individuals after oral administration of 1000 mg niacin alone or with 325 mg aspirin. Neurological, autonomic nervous system, and skin blood flow measurements (using laser Doppler on the glabrous and hairy skin of each participant) were made at various times after drug administration. In addition, the systemic release of 9α,11β-prostaglandin (PG) F(2) was determined. Flushing symptoms of redness, warmth, tingling, itching, and intensity were recorded using the modified Flushing ASsessment Tool (FAST).
Results:
After aspirin, the mean flushing scores for all symptoms decreased significantly; however, 36-53% of participants still had some degree of symptoms, even though aspirin completely blocked 11β-PGF(2) synthesis. Maximum skin blood flow (MaxSkBF) in both the glabrous and hairy forearm increased significantly after niacin, but decreased significantly after aspirin only in hairy skin. Regression analysis showed that, in glabrous skin, both PGF(2) and parasympathetic activity were significant predictors of MaxSkBF after niacin, contributing 26% and 14%, respectively (total R(2) = 40%).
Conclusions:
The present study indicates, for the first time, that the parasympathetic nervous system, in addition to PGD(2) , may play an important role in niacin-induced flushing. Changing the sympathetic/parasympathetic balance in favor of parasympathetic activation may be a good therapeutic target to reduce niacin-induced flushing.
Niacin (nicotinamide, nicotinic acid) interferes on homeostasis, DNA regulation, signaling and longevity. Nicotinic acid reduces synthesis of lipoproteins-apo-B and increases HDL. Its antilipemic action in liver produces: 1) inhibition of DGAT2, with decreased triacylglycerol synthesis, 2) downregulation of the b-chain of adenosine triphosphate synthase, leading to reduced HDL-apo-A-I catabolism. Nicotinic acid could increase redox potential in vascular endothelium. HM74A receptor activation in macrophages would be responsible for the release of prostaglandins, causing flushing in epidermis. HM74A agonists could assist in identifying antilipemic agents. Extended release niacin in combination with statin appears to protect cardiovascular system of patients with low HDL.
This chapter focuses on high-affinity niacin receptor GPR109A Agonists. Niacin (nicotinic acid) at high doses favorably modulates the human lipid profile by elevating high-density lipoprotein cholesterol (HDL-C) and decreasing low-density lipoprotein cholesterol (LDL-C) and lipoprotein a [Lp(a)]. Specifically, the ability of niacin to increase HDL-C (∼20%) is greater than any other drug in the market. As such niacin is considered a broad-spectrum lipid-lowering drug. With well-established animal models to evaluate vasodilation and free fatty acids (FFA) reduction, several compounds have been profiled in vivo and they indeed displayed improved TIs relative to niacin. In addition, these models appeared to correlate to humans as two candidates including both MK-0354 and INCB-19062 that showed excellent FFA reduction accompanied by minimal flushing in humans. It is conceivable that GPR109A is still involved in the vascular inflammation pathway related to the antiatherosclerotic effect of niacin. To further investigate the therapeutic potential of GPR109A agonists in cardiovascular diseases or metabolic disorders, it is necessary to further elucidate the mechanism of action of niacin and the pharmacology of GPR109A.
: Psychoactive drugs of fungal origin, psilocin, ibotenic acid, and muscimol among them have been proposed for recreational use and popularized since the 1960s, XX century. Despite their well-documented neurotoxicity, they reached reputation of being safe and nonaddictive. Scientific efforts to find any medical application for these hallucinogens in psychiatry, psychotherapy, and even for religious rituals support are highly controversial. Even if they show any healing potential, their usage in psychotherapy is in some cases inadequate and may additionally harm seriously suffering patients. Hallucinogens are thought to reduce cognitive functions. However, in case of indolealkylamines, such as psilocin, some recent findings suggest their ability to improve perception and mental skills, what would motivate the consumption of "magic mushrooms." The present article offers an opportunity to find out what are the main symptoms of intoxication with mushrooms containing psilocybin/psilocin, muscimol, and ibotenic acid. The progress in analytical methods for detection of them in fungal material, food, and body fluids is reviewed. Findings on the mechanisms of their biologic activity are summarized. Additionally, therapeutic potential of these fungal psychoactive compounds and health risk associated with their abuse are discussed.
The mechanism of topically applied methyl nicotinate–induced local cutaneous erythema was studied in normal human subjects. Aqueous methyl nicotinate (0, 0.1, 1.0, 10.0, and 100 mmol/L) was applied to the volar forearms in quadruplicate after oral pretreatments with 25 mg doxepin hydrochloride, 600 mg ibuprofen, 50 mg indomethacin, 975 mg aspirin, and lactose placebo. The cutaneous vascular response was monitored by laser Doppler velocimetry. Although doxepin did not affect the cutaneous vascular response to methyl nicotinate, indomethacin, ibuprofen, and aspirin significantly suppressed the response. Because indomethacin, ibuprofen, and aspirin have different chemical structures, the common property of inhibition of the response to methyl nicotinate may be assigned to their common pharmacologic action, i.e., inhibition of prostaglandin bioformation.
The chapter presents a study on quantification of 9α, 11β-prostaglandin F2 (9α, 11β -PGF2) by stable isotope dilution mass spectrometric assay. 9α, 11β -PGF2 has been found to be biologically active. Transformation of an eicosanoid formed directly from PGH2 to a biologically active metabolite is unique to PGD2. 9α, 11β -PGF2 has been found to contract human bronchial smooth muscle, contract coronary arteries, inhibit platelet aggregation, induce natruresis, and it is a pressor substance. The chapter offers information on developing a stable isotope dilution mass spectrometric assay for quantification of 9α, 11β -PGF2 in biological fluids. This chapter details the preparation of the deuterium-labeled 9α, 11β -PGF2 internal standard, the procedures employed for purification of 9α, 11β -PGF2 in biological fluids, and the analysis of 9α, 11β -PGF2 by gas chromatography-mass spectrometry (GC-MS). Specific examples are given demonstrating both the utility and the limitations of the assay. The chapter concludes by stating that the mass spectrometric assay that is developed provides a sensitive and accurate means for the analysis of 9α, 11β -PGF2 in a variety of biological fluids. However, special precautions must be taken to differentiate 9α, 11β -PGF2 from PGF2 compounds present in biological fluids that arise from noncyclooxygenase oxidation of arachidonic acid rather than from 11-ketoreductase metabolism of PGD2.
1. Pharmacologically active mediators of inflammation were obtained from suction bullae raised on normal and inflamed human abdominal skin. These contained a clear inflammatory exudate, which was analysed for known mediators of inflammation.
2. The exudates were examined for smooth muscle-contracting activity by a superfusion cascade bioassay, for prostaglandin F2α by radioimmunoassay and by Lipidex 5000 gel-partition chromatography for other prostaglandins and related compounds.
3. Tetrahydrofurfuryl nicotinate (Trafuril) was applied topically before and after systemic administration of aspirin. Trafuril alone caused a sustained inflammatory response within minutes of application, which was reduced by prior administration of aspirin (a known prostaglandin synthetase inhibitor).
4. Exudate from inflamed skin showed increased prostaglandin activity compared with exudate from contralateral non-inflamed skin. However, aspirin prevented this increase in prostaglandin activity. Analysis by thin-layer and gas—liquid chromatography further suggested that Trafuril-induced inflammation was mediated by certain prostaglandins and related compounds.
5. No evidence was obtained to suggest any change in histamine or bradykinin after Trafuril. We suggest that the response caused by Trafuril is mediated by increased synthesis of prostaglandins. Aspirin, by blocking prostaglandin synthesis, prevents or reduces the erythema.
Recent evidence suggests that neural transmitters, including neuropeptides, may modulate the release of mast cell mediators. Because neuropeptide Y (NPY) has recently been recognized as a putative cotransmitter in noradrenergic neurons, we studied the effect of NPY on purified rat peritoneal mast cells. NPY induced mast cell degranulation, as assessed by a dose-dependent increase in net release of beta-hexosaminidase. The concentration that produced 50% of the maximal effect, approximately 10 mumol/L, evoked a 40% +/- 3% release. As previously reported for other neuropeptides, release was fast with maximal release already achieved at 60 seconds. Release was at 4 degrees C. In contrast to its effects on mast cell degranulation, NPY had no effect on the generation of prostaglandin D2, the major mast cell cyclooxygenase product. By comparison, the calcium ionophore A23187, at doses (4 mumol/L) that evoked comparable release of beta-hexosaminidase, stimulated a net release of 37 +/- 9 ng of PGD2 per 10(6) mast cells. These results raise the possibility that NPY may act as a modulator between the autonomic nervous system and mast cells. The results also imply that with neuropeptide stimulation, the release of preformed and newly formed mast cell mediators are mediated through independent pathways.
Nicotinic acid (niacin) is a B which is also a potent hypolipidemic agent. However, intense flusing occurs following ingestion of harmacology doses of niacin which greatly limits its usefulness in treating hyperlipidemias. Previous studies have demonstrated that niacin-induced flusing can be substantially attenuated by pre-treatment with cyclooxygenase inhibitors, suggesting that the vasodilation is mediated by a prostaglandin. However, the prostaglandin that presumably mediates the flush has not bee conclusively determined. In this study we report the finding that ingestion of niacin evokes the release of markedly increased quantities of PGD2 in vivo in humans. PGD2 release was assessed by quantification of PGD2 metabolite, 9α 11β-PGF2, in plasma by gas chromatography mass spectrometry. Following ingestion of 500 mg of niacin in three normal volunteers, intense flushing occurred and plasma levels of 9α, 11β-PGF2 were found to increase dramatically by 800, 430, and 535-fold. Levels of 9α,11β-PGF2 reached a maximum between 12 and 45 min. after ingesting niacin and subsequently declined to near normal levels by 2-4 hours. Levels of 9α, 11β-PGF2 in plasma correlated with the intensity and duration of flushing that occurred in the 3 volunteers. Release of PGD2 was not accompanied by a release of histamine which was assessed by quantification of plasma levels of the histamine metabolit, Nτ-methylhistamine. The suggests that the origin of the PGD2 release is not the mast cell. Only a modest increase (approximately 2-fold) in the urinary excretion of the prostacyclin metabolite, 2,3-dinor-6-keto-PGF1α, occurred following ingestion of niacin and no increase in the excretion of the major urinary metabolite of PGE2 was found. These results indicate that the major vasodilatory PG released following ingestion of niacin is PGD2. The fact that markedly increased quantities of PGD2 are released suggests that PGD2 is the mediator of niacin-induced vasodilation in humans.
The cellular localization of glutathione-requiring PGD synthetase, which catalyzes the predominant formation of PGD2 in various peripheral tissues, was investigated in adult rats by immunoperoxidase-staining with a polyclonal antibody specific for this enzyme. Although the 25 N-terminal amino acid residues of synthetase are 56% identical and 76% similar to those of several rat glutathione S-transferase subunits, the antibody cross-reacted only with synthetase in dot blotting and was nearly completely inactive with all transferase isozymes thus far purified. In Western blotting after SDS-PAGE of crude extracts of rat spleen, the antibody showed a single positive band at the same position as that of the purified enzyme (Mr = 26,000). The positive immunocytochemical stain was found in a number of histiocytes and/or dendritic cells in spleen, thymus, and Peyer's patch of intestine. The immunostain was also observed in such cells in lamina propria of the villus in small intestine and colon, in submucosal layer of stomach, and in Kupffer cells in liver. Immunoelectron microscopy confirmed that immunoreactivity of this enzyme was distributed in cytoplasm of those cells. Such immunoreactive cells were not observed in brain, spinal cord, kidney, heart, testis, and skeletal muscle. These observations suggest that PGD2 is produced by glutathione-requiring PGD synthetase localized in these types of APC in various tissues and may play a critical role in dictating the progression of immune responses.
A stable isotope dilution assay has been developed for the quantification of prostaglandin D2 (PGD2) in plasma. Samples are analysed by capillary column gas chromatography/negative ion chemical ionisation mass spectrometry (GC/NICIMS). The method employs an internal standard of [2H6]PGD2, prepared biosynthetically by incubation of rat peritoneal mast cells with deuterated arachidonic acid. No PGD2 was detected in peripheral venous plasma samples obtained from 10 healthy male volunteers (detection limit = 5 pg ml-1). Following intravenous infusion of PGD2 at increasing incremental infusion rates ranging from 16-256 ng kg-1 min-1, a dose related increase in the plasma concentration of PGD2 was observed. Plasma levels at 128 ng kg-1 min-1 ranged from 724-1444 pg ml-1. The major circulating metabolites of PGD2, during infusion, were identified as 13,14-dihydro-15-oxo-PGF2 alpha and 15-oxo-PGF2 alpha.
Anti-IgE-dependent activation of rat and human mast cells resulted in the preferential generation of the cyclooxygenase products prostaglandin D2 (PGD2) and prostaglandin I2 (PGI2) in the rat and PGD2 in the human. The average net generation of PGD2, determined by gas chromatography-mass spectrometry, was 13.1 ng/10(6) purified rat mast cells and 39.5 ng/10(6) dispersed, enriched human mast cells. After IgE-dependent activation, there was a linear relationship between the net quantities of PGD2 generated and of histamine secreted from dispersed human pulmonary cells when the number of mast cells was varied but the total number of cells was held constant, indicating that it is the number of mast cells participating in IgE-dependent activation, rather than total mast cell number, that determines PGD2 generation. A linear relationship was also shown between PGD2 generation, determined by radioimmunoassay, and the release of the granule marker beta-hexosaminidase from purified rat mast cells on the dose-response portion of the plot of their response to anti-IgE challenge. With higher concentrations of anti-IgE, PGD2 generation from rat mast cells plateaued, whereas net percent beta-hexosaminidase release increased further. In kinetic studies of rat mast cells activated with anti-IgE, the onset (1 to 2 min) and time of maximum generation (5 to 10 min) for PGD2 were delayed relative to the onset (15 to 30 sec) and completion (1 to 2 min) of beta-hexosaminidase release. Thus, the extracellular appearance of PGD2 during IgE-dependent mast cell activation represents a response additional to the secretion of granule-associated mediators.
Nutritional Toxicology
- Dr Miller
- Hayes