Nicotinamide In Patients Research Articles

Protocol of a randomized, double-blind, placebo-controlled, parallel-group, multicentre study of the efficacy and safety of nicotinamide in patients with Friedreich ataxia (NICOFA)

IntroductionCurrently, no treatment that delays with the progression of Friedreich ataxia is available. In the majority of patients Friedreich ataxia is caused by homozygous pathological expansion of GAA repeats in the first intron of the FXN gene. Nicotinamide acts as a histone deacetylase inhibitor. Dose escalation studies have shown, that short term treatment with dosages of up to 4 g/day increase the expression of FXN mRNA and frataxin protein up to the levels of asymptomatic heterozygous gene carriers. The long-term effects and the effects on clinical endpoints, activities of daily living and quality of life are unknown.MethodsThe aim of the NICOFA study is to investigate the efficacy and safety of nicotinamide for the treatment of Friedreich ataxia over 24 months. An open-label dose adjustment wash-in period with nicotinamide (phase A: weeks 1–4) to the individually highest tolerated dose of 2–4 g nicotinamide/day will be followed by a 2 (nicotinamide group): 1 (placebo group) randomization (phase B: weeks 5–104). In the nicotinamide group, patients will continue with their individually highest tolerated dose between 2 and 4 g/d per os once daily and the placebo group patients will be receiving matching placebo. Safety assessments will consist of monitoring and recording of all adverse events and serious adverse events, regular monitoring of haematology, blood chemistry and urine values, regular measurement of vital signs and the performance of physical examinations including cardiological signs. The primary outcome is the change in the Scale for the Assessment and Rating of Ataxia (SARA) over time as compared with placebo in patients with Friedreich ataxia based on the linear mixed effect model (LMEM) model. Secondary endpoints are measures of quality of life, functional motor and cognitive measures, clinician’s and patient’s global impression-change scales as well as the up-regulation of the frataxin protein level, safety and survival/death.PerspectiveThe NICOFA study represents one of the first attempts to assess the clinical efficacy of an epigenetic therapeutic intervention for this disease and will provide evidence of possible disease modifying effects of nicotinamide treatment in patients with Friedreich ataxia.Trial registrationEudraCT-No.: 2017-002163-17, ClinicalTrials.govNCT03761511.

Risk Stratification: Should All Actinic Keratoses in All Patients Be Treated?

Actinic keratoses (AKs) are foci of dysplastic keratinocytes in the epidermis. They are markers of both photodamage and risk of keratinocyte carcinoma (KC) formation. Individual AKs are thought to progress to KC uncommonly, although they arise from the same UV-induced mutations which give rise to KC. Thus, the rationale for treatment of AKs is to reduce the risk of KC formation since AKs are not dangerous in themselves. An estimated $1.68 billion is spent on treatment of AKs in the United States annually. Treatment of a region of skin (e.g., face, scalp, or forearms) to clear AKs is termed field treatment. Though field treatment of AKs and actinic damage has been associated with a reduction in cutaneous squamous cell carcinoma (CSCC), it is unclear to what degree treatment of individual lesions positively impacts health. The presence of AKs has been correlated with formation of KC, particularly CSCC. Field treatment can be accomplished by topical therapy [photodynamic therapy (PDT), topical 5-fluorouracil, ingenol mebutate, imiquimod, and/or sunscreen] or oral systemic therapy including nicotinamide or retinoids (i.e., acitretin, isotretinoin). Field treatments have been associated with a reduction in KC and therefore are likely cost-effective. However, there is a lack of data showing that treatment of individual AK lesions (usually accomplished via cryotherapy) reduces KC. Although cryotherapy is only associated with a 4% sustained clearance rate at 1 year, more than three times the amount of money is spent on cryotherapy as compared to topical therapy in Medicare patients. Field treatment is superior to cryotherapy for reduction of KC. However, it requires high patient compliance and increasingly entails high out-of-pocket expenses for patients. Since field-directed and systemic therapies of AKs reduce KC formation, allocation of resources should be directed toward these modalities. Efforts should be made to improve patient access to field treatments by increased reimbursement for photodynamic therapy (both standard and daylight), reduction of out-of-pocket expenses for topical treatments and retinoids, and increased use of nicotinamide in patients with field actinic damage.

Nicotinamide and phosphate homeostasis in chronic kidney disease.

Higher serum phosphate concentration is a central driver of the chronic kidney disease (CKD) mineral bone disorder (MBD). Although phosphate binders are commonly used to lower phosphate, they are minimally effective in CKD. Nicotinamide (vitamin B3) decreases intestinal phosphate transport in animals. Its efficacy and safety in CKD is uncertain. We review data differentiating nicotinamide from nicotinic acid (niacin) and compare the metabolism and side-effect profile of each. Several recent studies have tested the safety and efficacy of nicotinamide in patients with CKD and the general population. Available data on efficacy and safety, gaps in knowledge, and ongoing studies to address them are described. Nicotinamide is a novel potential tool to treat hyperphosphatemia in patients with CKD, but additional data on safety and efficacy are required before widespread clinical use.

Epigenetic and neurological effects and safety of high-dose nicotinamide in patients with Friedreich's ataxia: an exploratory, open-label, dose-escalation study

Friedreich's ataxia is a progressive degenerative disorder caused by deficiency of the frataxin protein. Expanded GAA repeats within intron 1 of the frataxin (FXN) gene lead to its heterochromatinisation and transcriptional silencing. Preclinical studies have shown that the histone deacetylase inhibitor nicotinamide (vitamin B3) can remodel the pathological heterochromatin and upregulate expression of FXN. We aimed to assess the epigenetic and neurological effects and safety of high-dose nicotinamide in patients with Friedreich's ataxia. In this exploratory, open-label, dose-escalation study in the UK, male and female patients (aged 18 years or older) with Friedreich's ataxia were given single doses (phase 1) and repeated daily doses of 2-8 g oral nicotinamide for 5 days (phase 2) and 8 weeks (phase 3). Doses were gradually escalated during phases 1 and 2, with individual maximum tolerated doses used in phase 3. The primary outcome was the upregulation of frataxin expression. We also assessed the safety and tolerability of nicotinamide, used chromatin immunoprecipitation to investigate changes in chromatin structure at the FXN gene locus, and assessed the effect of nicotinamide treatment on clinical scales for ataxia. This study is registered with ClinicalTrials.gov, number NCT01589809. Nicotinamide was generally well tolerated; the main adverse event was nausea, which in most cases was mild, dose-related, and resolved spontaneously or after dose reduction, use of antinausea drugs, or both. Phase 1 showed a dose-response relation for proportional change in frataxin protein concentration from baseline to 8 h post-dose, which increased with increasing dose (p=0·0004). Bayesian analysis predicted that 3·8 g would result in a 1·5-times increase and 7·5 g in a doubling of frataxin protein concentration. Phases 2 and 3 showed that daily dosing at 3·5-6 g resulted in a sustained and significant (p<0·0001) upregulation of frataxin expression, which was accompanied by a reduction in heterochromatin modifications at the FXN locus. Clinical measures showed no significant changes. Nicotinamide was associated with a sustained improvement in frataxin concentrations towards those seen in asymptomatic carriers during 8 weeks of daily dosing. Further investigation of the long-term clinical benefits of nicotinamide and its ability to ameliorate frataxin deficiency in Friedreich's ataxia is warranted. Ataxia UK, Ataxia Ireland, Association Suisse de l'Ataxie de Friedreich, Associazione Italiana per le Sindromi Atassiche, UK National Institute for Health Research, European Friedreich's Ataxia Consortium for Translational Studies, and Imperial Biomedical Research Centre.

Hypoxic radiosensitizers in radical radiotherapy for patients with bladder carcinoma

In animal models carbogen (normobaric 95% oxygen, 5% carbon dioxide) provides significant enhancement of local tumor control with fractionated radiotherapy. This approach to radiosensitization has been evaluated in the treatment of patients with bladder carcinoma using radical radiotherapy. Sixty-one patients with locally advanced bladder carcinoma were treated using a Phase II trial delivering radiotherapy to the bladder (50-55 Grays in 20 daily fractions over 4 weeks) with inhalation of carbogen alone in 30 patients and the addition of oral nicotinamide (80 mg/kg) prior to radiotherapy with carbogen in 31 patients. The results from these 61 patients were compared with those from two earlier attempts at hypoxic sensitization: the second Medical Research Council (MRC) hyperbaric oxygen trial in patients with bladder carcinoma and a Phase III trial of misonidazole with radiotherapy in patients with bladder carcinoma performed at Mount Vernon Hospital. Although there was no difference between the hyperbaric oxygen and misonidazole trials, when compared with the two earlier series there was a large, statistically significant difference in favor of those patients receiving carbogen with or without nicotinamide for local control (P = 0.00001), progression free survival (P = 0.001), and overall survival (P = 0.04). Although the advantage for the carbogen group may be explained in part by changes in radiotherapy practice over the period of the three studies the improvement in local control is sufficiently great to support the hypothesis that hypoxia is important in modifying the control of bladder carcinoma using radiation therapy. Further evaluation of accelerated radiotherapy, carbogen, and nicotinamide in patients with bladder carcinoma is needed in a Phase III trial.

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.

Effects of nicotinamide supplementation on human pancreatic islet function in tissue culture.

Nicotinamide currently attracts considerable interest as a compound that might prevent the development of human insulin-dependent diabetes mellitus. The present study investigated the direct actions of nicotinamide on human pancreatic beta-cells. For this purpose, islets were isolated from 11 adult cadaveric donors. The human islets were subsequently precultured in RPMI-1640 (5.6 mmol/L glucose) and 10% fetal calf serum for 3-4 days. The islets were cultured for another 6 days in the same medium in either the presence or absence of 10 mmol/L nicotinamide, and subsequently, islet function was examined. After culture, both groups of islets contained similar amounts of DNA, and DNA synthesis, determined by the tritiated thymidine incorporation rate, was unchanged. The insulin content both on a per islet basis and per DNA was similar in both groups as was the islet glucose oxidation rate. Insulin accumulation into the culture medium was sustained over the entire culture period and did not differ at any time point between the nicotinamide and the control group. Nicotinamide affected neither basal and glucose-stimulated insulin secretion nor (pro)insulin and total protein biosynthesis rates after culture. The insulin response to glucose of the human islets was about 5-fold. In conclusion, the present study shows that nicotinamide does not directly affect human beta-cell function or the cell replicatory rate. This would suggest that any potential beneficial effects observed after treatment with nicotinamide in patients with insulin-dependent diabetes mellitus may not necessarily reflect an action at the beta-cell level.

Methylation of Nicotinamide in Patients with Pernicious Anemia

SummaryAdministration of nicotinamide to four patients with pernicious anemia results in the urinary excretion of approximately 20% of the compound as the methylated derivative. The levels of N1-methylnicotin-amide are similar before and after therapy. The methylation of nicotinamide, under the conditions here employed, cannot be used as an index of the nutritional adequacy of vit. B12 or folic acid.