Administration Of Nicotinamide Research Articles

The modification of human tumour blood flow using pentoxifylline, nicotinamide and carbogen

Aim: To assess the effect of combining oral nicotinamide, oral pentoxifylline and carbogen gas (2% CO2, 98% O2) breathing on human tumour red cell flux.Methods and materials: Microregional red blood cell flux was measured in accessible tumour nodules using laser Doppler microprobes in 11 patients with histologically proven malignancy. Patients received single oral doses of nicotinamide 40mgkg−1 and pentoxifylline 1200mg 2h before a 10-min period of carbogen gas breathing, corresponding to peak plasma concentrations of these drugs. Red cell flux in up to six microregions in each tumour was measured for 30min, recording pre-, during and post-carbogen breathing for 10min each.Results: Data from ten of the 11 patients could be assessed. The red cell flux in 48 microregions was analysed and the mean red cell flux was calculated. A mean relative increase in red cell flux of 1.18 (±0.09, 95% confidence interval (CI)) was observed after 6min of carbogen breathing, 2h after the administration of nicotinamide and pentoxifylline. This compares to relative increases of 1.4 (±0.39, 95%CI) after nicotinamide with carbogen and 1.15 (±0.10, 95%CI) after pentoxifylline with carbogen. These differences are not statistically significant (P>0.05). The increased red cell flux persisted after the cessation of carbogen gas breathing.Conclusions: A combination of pentoxifylline, nicotinamide and carbogen produces an increase in human tumour red cell flux, similar to that observed when each of the drugs are used alone with carbogen breathing.

RESPONSE TO THE LETTER BY DRS. FOGLI AND MORSIANI: CAN HEPATOCYTE GROWTH FACTOR HAVE AN EFFECT ON REGENERATION OF ISLET GRAFTS?

Hepatocyte growth factor (HGF) has been reported to induce proliferation of human fetal β cells as well as insulinotropic activity in vitro (1–4). The role of HGF and its receptor/c-met in normal pancreatic development and maturation in vivo has also been reported (5). These findings suggest that HGF may have an effect on regeneration of islet cells including the grafted one. Previously, we demonstrated that the administration of nicotinamide could ameliorate hyperglycemia in streptozotocin-induced diabetic rats receiving the marginal number of islet isografts (6). At 60 days after transplantation, the insulin content of the liver bearing the islet grafts in the recipients treated with nicotinamide increased four times as much as that of the original donor islets and the islet grafts appeared to become enlarged in size morphologically. The findings suggest that the treatment with nicotinamide may induce proliferation of β cells in the grafted islets. It remains undetermined whether HGF has the similar effect to nicotinamide. In our article that appeared in Transplantation on January 27, 2000 (7), the effect of HGF on amelioration of hyperglycemia in the streptozotocin-induced diabetic mice receiving the marginal number of islet isografts was examined. It was demonstrated that the short-term administration of HGF for 5 times on day 0, 2, 4, 6, and 8 after transplantation could produce amelioration of hyperglycemia within 2 weeks after transplantation. Morphologically, intact islet grafts could be easily seen in the liver of the recipients treated with HGF at 30 as well as 90 days after transplantation. However, there seemed no significant increase in size of grafted islets. These findings suggest that the major roles of HGF may include a protective effect on grafted islets and an effect on glucose metabolism as well as on insulin release rather than an effect on regeneration of islet grafts. Therefore, the point mentioned by Fogli is considered to be possible but unlikely in the current experimental model. However, it does not exclude the potential role of HGF in regeneration of islets. Recently, the success in clinical islet transplantation as a treatment of insulin dependent diabetes mellitus has been reported (8). The shortage of donor islets appears to be a major limiting factor for clinical transplantation. Therefore, it is essential to find a novel procedure to minimize the number of donor islets as well as to induce regeneration of islet grafts for successful clinical islet transplantation in future. Masahiko Nakano and Yohichi Yasunami

Oxidative changes in brain pyridine nucleotides and neuroprotection using nicotinamide

Pyridine nucleotides are critical during oxidative stress due to their roles in reductive reactions and energetics. The aim of the present study was to examine pyridine nucleotide changes in six brain regions of mice after an intracerebroventricular injection of the oxidative stress inducing agent, t-butyl hydroperoxide (t-BuOOH). A secondary aim was to investigate the correlation between NAD + levels and DNA fragmentation. Here, we demonstrate that t-BuOOH induced a rapid oxidation of NADPH and a slow depletion of NAD + in most brain regions. A slight increase in NADH also occurred in five brain regions. NAD + depletion was associated with increased DNA fragmentation. This suggests the initiation of a death cascade involving poly(ADP-ribose) polymerase (PARP), NAD +, ATP depletion and consequent cell death in brain tissue. PARP activity was accelerated in some brain regions after 20 min of oxidative stress. To counteract oxidative stress induced toxicity, NAD + levels were increased in the brain using an intraperitoneal injection of nicotinamide. A surplus of brain NAD + prevented DNA fragmentation in some brain regions. Nicotinamide administration also resulted in higher brain NADH, NADP + and NADPH levels in some regions. Their synthesis was further upregulated during oxidative stress. Nicotinamide as a precursor for NAD + may provide a useful therapeutic strategy in the treatment of neurodegeneration.

Effects of nicotinamide and carbogen on oxygenation in human tumor xenografts measured with luminescense based fiber-optic probes

Background and purpose: In head and neck cancer, addition of both carbogen breathing and nicotinamide to accelerated fractionated radiotherapy showed increased loco-regional control rates. An assay based on the measurement of changes in tumor pO 2 in response to oxygenation modification could be helpful for selecting patients for these new treatment approaches. Materials and methods: The fiber-optic oxygen-sensing device, OxyLite™, was used to measure changes in pO 2, at a single position in tumors, after treatment with nicotinamide and carbogen in three human xenograft tumor lines with different vascular architecture and hypoxic patterns. Pimonidazole was used as a marker of hypoxia and was analyzed with a digital image processing system. Results: At the position of pO 2 measurement, half of the tumors showed a local increase in pO 2 after nicotinamide administration. Steep increases in pO 2 were measured in most tumors during carbogen breathing although the increase was less pronounced in tumor areas with a low pre-treatment pO 2. A trend towards a faster local response to carbogen breathing for nicotinamide pre-treated tumors was found in all three lines. There were significant differences in hypoxic fractions, based on pimonidazole binding, between the three tumor lines. There was no correlation between hypoxic marker binding and the response to carbogen breathing. Conclusion: Temporal changes in local pO 2 can be measured with the OxyLite™. This system was used to quantitate the effects of oxygen modifying treatments. Rapid increases in pO 2 during carbogen breathing were observed in most tumor areas. The locally measured response to nicotinamide was smaller and more variable. Bio-reductive hypoxic cell marker binding in combination with OxyLite™ pO 2 determination gives spatial information about the distribution patterns of tumor hypoxia at the microscopic level together with the possibility to continuously measure changes in pO 2 in specific tumor areas.

Effects of nicotinamide and carbogen on tumour oxygenation, blood flow, energetics and blood glucose levels.

Both host carbogen (95% oxygen/5% carbon dioxide) breathing and nicotinamide administration enhance tumour radiotherapeutic response and are being re-evaluated in the clinic. Non-invasive magnetic resonance imaging (MRI) and 31P magnetic resonance spectroscopy (MRS) methods have been used to give information on the effects of nicotinamide alone and in combination with host carbogen breathing on transplanted rat GH3 prolactinomas. Gradient recalled echo (GRE) MRI, sensitive to blood oxygenation changes, and spin echo (SE) MRI, sensitive to perfusion/flow, showed large signal intensity increases with carbogen breathing. Nicotinamide, thought to act by suppressing the transient closure of small blood vessels that cause intermittent tumour hypoxia, induced a small increase in blood oxygenation but no detectable change in perfusion/flow. Carbogen combined with nicotinamide was no more effective than carbogen alone. Both carbogen and nicotinamide caused significant increases in the nucleoside triphosphate/inorganic phosphate (βNTP/P i) ratio, implying that the tumour cells normally receive sub-optimal substrate supply, and is consistent with either increased glycolysis and/or a switch to more oxidative metabolism. The most striking observation was the marked increase in blood glucose (twofold) induced by both nicotinamide and carbogen. Whether this may play a role in tumour radiosensitivity has yet to be determined. Copyright 2000 Cancer Research Campaign© 2000 Cancer Research Campaign

Metabolic Correction of Cerebral Radiation Syndrome

DNA strand breaks that occur after irradiation activate the repair enzyme adenosine diphosphoribosyl transferase, which consumes NAD as a substrate and causes depletion first of neuronal NAD and then of the ATP pool. This is considered to be the crucial link in the mechanism underlying the cerebral radiation syndrome (CRS). In this study, two ways to correct the CRS metabolically were examined: (a) prevention of depletion of NAD after irradiation by administration of the enzyme inhibitor nicotinamide and (b) shunting the NAD-dependent oxidative phosphorylation pathway of ATP resynthesis by administration of a substrate of NAD-independent oxidation, succinate. Cerebral lesions induced by radiation were modeled by irradiation of rats or rat brain homogenates with 150 Gy of X rays. The manifestations of CRS in rats (excitement, convulsions, etc.) closely resembled those seen after acute hypoxia. In brain homogenates, pyruvate tetrazolium-reductase activity decreased after irradiation and could be corrected by addition of NAD after irradiation. Succinate tetrazolium-reductase activity was not affected by irradiation. Oxygen consumption by brain homogenates after irradiation in vitro and in situ decreased, as did oxygen consumption by rats in vivo after cranio-caudal irradiation. Administration of nicotinamide or succinate prevented both the postirradiation decrease in respiration (in both rats in vivo and brain homogenates in vitro) and the development of cerebral radiation syndrome. These results help to clarify the mechanisms underlying CRS and its metabolic correction.

Protective effect of poly(ADP-ribose) synthetase inhibition on multiple organ failure after zymosan-induced peritonitis in the rat.

In the present study, we tested the hypothesis that peroxynitrite and subsequent activation of the nuclear enzyme poly(ADP-ribose) synthetase (PARS) play a role in the pathogenesis of multiple organ failure induced by peritoneal injection of zymosan in the rat. Animals were randomly divided into six groups (ten rats for each group). The first group was treated with ip administration of saline solution (0.9% NaCl) and served as the sham group. The second group was treated with ip administration of zymosan (500 mg/kg suspended in saline solution). In the third and fourth groups, rats received ip administration of 3-aminobenzamide (10 mg/kg) 1 and 6 hrs after zymosan or saline administration, respectively. In the fifth and sixth groups, rats received ip administration of nicotinamide (50 mg/kg) 1 and 6 hrs after zymosan or saline administration, respectively. After zymosan or saline injection, animals were monitored for 72 hrs to evaluate systemic toxicity (conjunctivitis, ruffled fur, diarrhea, and lethargy), loss of body weight, and mortality. A severe inflammatory response, characterized by peritoneal exudation, high plasma and peritoneal levels of nitrate/nitrite (the breakdown products of nitric oxide), and leukocyte infiltration into peritoneal exudate, was induced by zymosan administration. This inflammatory process coincided with the damage of lung, small intestine, and liver as assessed by histologic examination and by an increase of myeloperoxidase activity, which is indicative of neutrophil infiltration. Zymosan-treated rats showed signs of systemic illness, significant loss of body weight, and high mortality rates. Peritoneal administration of zymosan in the rat also induced a significant increase in the plasma levels of peroxynitrite as measured by the oxidation of the fluorescent dihydrorhodamine 123. Immunohistochemical examination demonstrated a marked increase in the immunoreactivity to nitrotyrosine, a specific "footprint" of peroxynitrite, in the lung of zymosan-shocked rats. In vivo treatment with ip administration of 3-aminobenzamide (10 mg/kg, 1 and 6 hrs after zymosan injection) or nicotinamide (50 mg/kg, 1 and 6 hrs after zymosan injection) significantly decreased mortality, inhibited the development of peritonitis, and reduced peroxynitrite formation. In addition, PARS inhibitors were effective in preventing the development of organ failure because tissue injury and neutrophil infiltration, by myeloperoxidase evaluation, were reduced in the lung, small intestine, and liver. In conclusion, the major findings of our study are that peroxynitrite and the consequent PARS activation exert a role in the development of multiple organ failure and that PARS inhibition is an effective anti-inflammatory therapeutic tool.

ARCON: accelerated radiotherapy with carbogen and nicotinamide in non small cell lung cancer: a phase I/II study by the EORTC

Background: Non small cell lung cancers (NSCLC) are rapidly proliferating tumours, which are characterized by the presence of extensive hypoxic components, especially in patients with advanced loco-regional disease. Previous studies suggest a deleterious impact of acute (perfusion-limited) hypoxia on the outcome of radiotherapy for these tumours.Aim: This pilot study was aimed at determining the feasibility and tumour response rates that can be achieved with an ARCON regime in patients with locally advanced, staged IIIA or B, NSCLC tumours.Methods: The phase I/II study included three steps: accelerated fractionation (AF) combined with carbogen (ten analysable patients), AF together with the daily administration of nicotinamide (n=11) and AF with both carbon and nicotinamide (n=14). Radiotherapy was based on a large daily dose per fraction (2.75 Gy up to 55 Gy in 4 weeks). Nicotinamide was administered at a dose of 6 g per patient per treatment day and carbogen was inhaled for 5 min before and during radiotherapy.Results: The incidence of grade 3+ acute toxicity during the irradiation did not exceed 10%, neither in the lung parenchyma nor in the mediastinum. No significant difference was found in loco-regional, radio-induced toxicity among the three study steps. Although a similar fraction of patients showed grade 2 or 3 emesis in all the steps, of the 25 patients entered in the two Nicotinamide containing steps 10 (40%) developed grade 2 or greater reactions which significantly detracted from their quality of life. There was no significant difference in tumour clearance rate among the three steps. The percentage of objective responses at 2 months was 60, 54 and 57% in steps 1, 2 and 3, respectively.Conclusion: The feasibility of this ARCON protocol, using 2.75 Gy doses per fraction over 4 weeks, is good as regards radiotherapy-related side effects but it appears necessary in future to reduce the dose of Nicotinamide to reduce the incidence of nausea and vomiting. There was no significant difference in time to progression among the three study steps.

A multi‐centre randomized trial of two different doses of nicotinamide in patients with recent‐onset Type 1 diabetes (the IMDIAB VI)

Background Intensive insulin therapy is the gold standard by which Type 1 diabetes is treated. In addition to this therapy, administration of nicotinamide (NA) can be beneficial. This concept is reinforced by the results of a recent meta-analysis of the use of NA in patients with recent-onset Type 1 diabetes. Methods In this study we compared two different doses of NA in 74 patients with duration of Type 1 diabetes <4 weeks (mean age 13 years). Patients were randomly allocated in blind to two treatment groups: 38 patients received a dose of 25 mg/kg (b.w.) of NA and 36 patients received a dose of 50 mg/kg (b.w.) of NA. Intensive insulin therapy was carried out in order to optimize metabolic control as soon as possible after diagnosis and to maintain blood glucose level as near to normal as possible. Response to therapy was monitored throughout the study by investigating the occurrence of clinical (complete) remission defined, according to the recommendations of the International Diabetes Immunotherapy Group, as restoration of normal fasting and post-prandial blood glucose without any insulin administration for more than 2 weeks. Moreover, the integrated measures of metabolic control (C-peptide, HbA1c and insulin dose) were analysed at 3- month intervals up to 1 year after diagnosis. Results There were no significant differences in the integrated measures of metabolic control between the two NA treated groups either at onset of the disease or at each 3-month interval up to 1 year after diagnosis, although there was a tendency toward higher insulin dosages in the 50 mg NA group. No significant differences were observed in the rate of clinical remission between the two groups. Conclusion We conclude that patients with recent-onset Type 1 diabetes treated with two different doses of NA, in addition to intensive insulin therapy, show similar residual beta-cell function 1 year later. Since both doses of NA are likely to be effective in reducing beta-cell dysfunction, the smaller dose of 25 mg/kg NA would be sufficient as a higher dose may induce insulin resistance. Copyright © 1999 John Wiley & Sons, Ltd.

Effect of nicotinamide administration on ethanol consumption and on liver and brain acetaldehyde oxidation rate, by UChB rats

The activities of liver and brain aldehyde dehydrogenase, an NAD(+) dependent enzyme, which controls acetaldehyde oxidation have been reported to play a role in voluntary ethanol consumption. It has been reported that nicotinamide administration to rats increases NAD(+) levels, that may increase acetaldehyde oxidation rates if basal NAD(+) levels are not saturating for the enzyme. In the present paper the effect of nicotinamide administration on voluntary ethanol consumption by genetically high ethanol consumer UChB rats and brain and liver mitochondrial acetaldehyde oxidation were studied. Administration of nicotinamide 250 or 500 mg/kg i.p. to UChB rats, produced a significant reduction in their voluntary ethanol consumption and increased brain acetaldehyde oxidation in brain but not liver homogenates.These results suggest that basal NAD(+) levels are not saturating for brain aldehyde dehydrogenase and that the reduction of ethanol consumption by UChB rats may be the consequence of a change in the brain redox state, rather than the local level of acetaldehyde.

Magnetic resonance imaging of perfusion in rat cerebral 9L tumor after nicotinamide administration

Purpose: To investigate the effect of nicotinamide on normal brain and 9L tumor blood flow in the rat using magnetic resonance imaging (MRI) and arterial spin tagging. Methods and Materials: Using MRI at 7 Tesla, measurements of blood perfusion were determined from two-dimensional maps of intracerebral 9L rat tumors and normal Fischer rat brains. The spatial and temporal influence of nicotinamide, 500 mg/kg i.p., on cerebral blood flow (CBF) was studied in normal brain and tumors between 5 and 21 days after tumor implantation. The MRI CBF measurements employed a variable tip-angle–gradient-recalled echo (VTA-GRE-CBF) readout of the magnetization of the tissue slice. The VTA-GRE-CBF required 8 minutes for a blood flow image with inplane resolution of 250 μm × 500 μm × 2 mm. Results: Normal brain blood flow decreased following the administration of nicotinamide. In contrast, tumor blood flow remained unaffected in the time following nicotinamide administration. Consequently, the blood flowing in the tumor relative to that in normal brain demonstrated a significant and selective increase in response to nicotinamide administration. Relative tumor blood flow increased at 10 minutes after nicotinamide injection compared with predrug levels and remained elevated for at least 1 hour. Conclusion: The results suggest that nicotinamide will not enhance radiosensitivity of brain tumors. The results support the use of nicotinamide to improve delivery of anticancer therapeutics through its ability to selectively increase tumor blood flow relative to that in normal brain.

Simultaneous determination of nicotinic acid and its metabolites in rat urine by micellar electrokinetic chromatography with photodiode array detection

Nicotinic acid, nicotinamide and their possible metabolites were successfully separated within 17 min by micellar electrokinetic chromatography using 50 m M borate buffer (pH 9.0) containing 150 m M sodium dodecyl sulfate as the running buffer. Calibration curves for all compounds showed good linearity in a range of 5 μg/ml and 250 μg/ml with good correlation. The present method did not require any clean-up procedures and made it possible to determine all metabolites without interference on a photodiode array detector. Urine samples collected from Wistar male rats were analyzed after high-dose oral or intravenous administration of nicotinic acid or nicotinamide. Metabolic pathways of nicotinic acid in male Wistar rats are also discussed.

Lack of perfusion enhancement after administration of nicotinamide and carbogen in patients with glioblastoma: a 99mTc-HMPAO SPECT study

Background: Nicotinamide (NAM) and carbogen both have been shown to enhance the radiation effect in rodent tumour models and are currently being tested in clinical trials. These agents have demonstrated to act against hypoxia and one of their underlying mechanisms could be an increase of tumour blood perfusion. Purpose: To analyse the effect of both agents on normal brain perfusion and tumour perfusion in patients with glioblastoma. Materials and methods: Nineteen patients with glioblastoma were studied with 99mtechnetium-hexamethylpropyleneamine oxime single photon emission computed tomography ( 99mTc-HMPAO SPECT) before and after administration of carbogen and/or NAM. Another six patients were studied with the same procedure but without any flow modulator and were used as controls. Results: Although the variations between patients were large, no significant enhancement in mean tumour and normal brain perfusion could be demonstrated with NAM or carbogen compared to the control patients. Also no consistent changes in the mean perfusion ratio between tumour and surrounding normal brain were found, suggesting an absence of a selective perfusion effect. Conclusions: No significant influence of carbogen and/or NAM on tumour perfusion and normal brain perfusion could be detected with SPECT in patients with glioblastoma.

Accelerated radiotherapy with carbogen and nicotinamide (ARCON) for laryngeal cancer

Background and purpose: Tumor hypoxia and tumor cell repopulation are known factors determining radiation response. Accelerated radiotherapy as a method to counteract cellular repopulation was combined with carbogen (95% O 2+5% CO 2) breathing and oral administration of nicotinamide as a means to improve tumor perfusion and oxygenation. The feasibility, toxicity and clinical effectiveness of this approach as a voice-preserving treatment for carcinoma of the larynx was assessed in a prospective study. Patients and methods: Sixty-two patients with stage III–IV laryngeal carcinoma were treated with a schedule of accelerated radiotherapy. The total radiation dose to the primary tumor was 64 Gy and that to the metastatic nodes was 68 Gy delivered in fractions of 2 Gy over 35–37 days. Radiotherapy was combined with carbogen breathing in the initial 11 patients and with both carbogen and nicotinamide administration in the subsequent 51 patients. Results: After a median follow-up of 24 months, the actuarial local control rate at 2 years was 92%. This is higher than any previous report in the literature for this category of patients. Five patients had a local tumor recurrence and underwent laryngectomy. There was one regional recurrence. Including salvage surgery the loco-regional control rate was 100%. Four patients developed distant metastases and died. The actuarial overall survival rate at 2 years was 85%. Toxicity was increased relative to conventional radiotherapy but was considered as acceptable. One patient underwent laryngectomy for radiation-induced cartilage necrosis. Conclusion: These preliminary results indicate that advanced laryngeal cancer can be controlled in a high proportion of patients when treated with accelerated radiotherapy combined with carbogen and nicotinamide. This approach offers excellent possibilities for larynx preservation.

A role of nicotinamide-induced increase in pancreatic β-cell mass on blood glucose control after discontinuation of the treatment in partially pancreatectomized OLETF rats

Otsuka Long–Evans Tokushima Fatty (OLETF) rat, a model of NIDDM, is normoglycemic at a young age. However, they become hyperglycemic, even at a young age as a result of a 70% pancreatectomy, which is associated with insufficient proliferation of β-cells. Administration of nicotinamide ameliorates the sustained hyperglycemia by increasing β-cell proliferation. In order to further understand its mode of action, we studied how long nicotinamide is effective, in terms of ameliorating hyperglycemia, as evidenced by an increase in β-cell mass, after its administration, in partially pancreatectomized OLETF rats. Male rats, 6 weeks of age, were allocated at random to two groups, 70% pancreatectomy (Px) and sham-pancreatectomy (sham). The Px group was divided into three subgroups, based on treatment with either nicotinamide (350 mg/kg), phlorizin (400 mg/kg) or saline, which continued until 4 weeks after surgery, and were sacrificed at 4, 6, or 8 weeks after surgery. A 70% Px resulted in sustained hyperglycemia in the saline-treated Px rats, which was ameliorated by administration of either phlorizin or nicotinamide, showing the non-fasting blood glucose levels reached to or near the levels found in the sham rats. After cessation of phlorizin injection, non-fasting blood glucose level increased rapidly, reaching the level of the saline-treated Px rats at the end of the experiment, whereas after cessation of nicotinamide injection, non-fasting blood glucose increased gradually to a level which was significantly lower than that observed in the saline-treated Px rats. An increased β-cell mass, 62.7±7.8% of total β-cell mass induced by nicotinamide at 4 weeks, decreased gradually, reaching the level of pretreatment, 30.3±4.0% 4 weeks after cessation of the treatment. The findings in this study suggest that ameliorated hyperglycemia as a result of proliferated β-cells during the administration of nicotinamide may results in slowing β-cell exhaustion (a majority of β-cell degranulation) once stopping injection, as compared with phlorizin treated group in this model rat.

Enhancement of brain choline levels by nicotinamide: mechanism of action

Following the subcutaneous (s.c.) administration of nicotinamide (10 mmol/kg), the brain and CSF levels of nicotinamide were increased to millimolar concentrations, but the concentrations of N-methylnicotinamide (NMN) in the CSF, and of NMN and NAD + in brain tissue were not significantly altered. Concomitantly, nicotinamide caused increases of the choline levels in the venous brain blood. In hippocampal slices, nicotinamide (1–10 mM) induced choline release in a calcium- and mepacrine-sensitive manner and, in [ 3H]choline-labelled slices, increased the levels of [ 3H]lyso-phosphatidylcholine and [ 3H]glycerophosphocholine. We conclude that nicotinamide enhances brain choline concentrations by mobilising choline from choline-containing phospholipids, presumably via activation of phospholipase A 2, while the formation of NMN does not contribute to this effect.

Effects of Nicotinamide on Xenotransplantation

ISLET transplantation from rodents is a useful model for developing potential approaches to both xenografts and allografts in humans. One of the major obstacles to pancreatic islet transplantation is the limited yield of islets from the donor pancreas. It is difficult to obtain a sufficient number of islets from one donor to reverse hyperglycemia in one recipient. Furthermore, a high rate of primary nonfunction (PNF) and early graft failure is observed in xenogeneic islet transplantation, making it difficult to test new immunosuppressor drugs. Some studies have demonstrated that nicotinamide (NA), an inhibitor of poly-ADPribose synthetase, might have protective effects on islet isografts and allografts. NA administration has been shown to produce a low rate of PNF, with fast normalization of glycemia and with a low number of transplanted islets. NA might have protective effects on other tissues. The purpose of this study was to analyze the effects of NA in a concordant model of islet xenotransplantation in relation to the graft survival, the rate of PNF, and the time for glycemia normalization.

Nicotinamide Counteracts Alcohol-Induced Impairment of Hepatic Protein Metabolism in Humans ,

We have recently shown that a large amount of wine (750 mL, ∼70 g of alcohol) markedly impairs postprandial hepatic protein metabolism in healthy subjects. This is probably due to the shift in the intracellular redox state (increased NADH/NAD+) induced by ethanol oxidation. If this hypothesis is true, the administration of nicotinamide (NAD+precursor) should provide NAD+in excess and thus correct the NADH/NAD+abnormalities and prevent the ethanol hepatotoxicity. Whole-body protein metabolism and the fractional secretory rates of hepatic (albumin, fibrinogen) and extra-hepatic (immunoglobulin G, IgG) plasma proteins were measured in the basal postabsorptive and in the absorptive states in 15 healthy subjects, that had been assigned to three groups matched for age and body mass index. During the absorptive state (intragastric meal), the three groups received water (control), 750 mL of wine, or 750 mL of wine + 1.25 g of nicotinamide, respectively. The redox state was estimated by determining the plasma lactate/pyruvate ratio. Compared with the basal state, wine alone increased the lactate/pyruvate ratio twofold and depressed the fractional secretory rates of albumin and fibrinogen (P< 0.01 vs. control and nicotinamide); nicotinamide reduced the effects of wine on the lactate/pyruvate ratio (P< 0.02 vs. wine alone) and prevented the reduction of albumin and fibrinogen secretory rates (P> 0.05 vs. control). These results indicate that nicotinamide counteracts the acute hepatotoxic effects of ethanol by ameliorating the redox state.

Inhibitory effect of nicotinamide on in vitro and in vivo production of tumor necrosis factor-α

Nicotinamide, a pellagra-preventive factor, has multiple functions such as inhibition of poly-ADP-ribose synthetase, inhibition of inducible nitric oxide synthase, free radical scavenging and suppression of major histocompatibility complex class II expression and ICAM-1 expression on endothelial cells. In addition to these, we have found an inhibitory effect of nicotinamide on production of tumor necrosis factor-α (TNF-α) in vitro and in vivo. Lipopolysaccharide (LPS)-induced in vitro TNF-α production by human peripheral blood mononuclear cells, measured by enzyme-linked immunosorbent assay (ELISA), was significantly inhibited with more than 1 × 10 −3 mol/l of nicotinamide, while interleukin-1-β was not inhibited and interleukin-6 was slightly inhibited even with 10 −2 mol/l. Oral administration of nicotinamide with more than 62.5 mg/kg also significantly inhibited LPS-induced serum TNF-α production measured by ELISA and bioassay in Balb c mice. Thus, nicotinamide has an inhibitory effect on TNF-α production that may be beneficial to TNF-α-mediated diseases.

Inhibitory effect of nicotinamide to paraquat toxicity and the reaction site on complex I.

The inhibitory effect and mechanism of action of nicotinamide to paraquat toxicity were studied in male Sprague-Dawley rats. Proteins of submitochondrial particles (SMP), especially of mol. wt. 25-30 kDa, in rat lungs were destroyed by paraquat radicals, and aggregated protein bands approximately 100 kDa were observed by polyacrylamide electrophoresis. The competitive inhibition effects were observed of nicotinamide on NADH oxidation by paraquat via SMP in rat lungs and the Ki was 9.3 mM. The inhibitory effects of nicotinamide on lipid peroxidation by paraquat with rat lung and liver SMP were verified. The times of occurrence of dyspnea and death in rats after paraquat exposure were delayed by nicotinamide administration. The activity of NADH: ubiquinone reaction of NADH:ubiquinone oxidoreductase (complex I) in rat lung was reduced 24 h after paraquat exposure, and was protected by nicotinamide. The activity of NADH:ferricyanide reaction of complex I was, however, reduced by administration not only of paraquat but also nicotinamide. These results imply that nicotinamide is inhibitory to paraquat toxicity. Nicotinamide, paraquat, and ferricyanide may react at overlapping sites on complex I.