Biotin alleviates hepatic and intestinal inflammation and apoptosis induced by high dietary carbohydrate in juvenile turbot (Scophthalmus maximus L.).

Excessive dietary carbohydrate commonly impairs the functions of liver and intestine in carnivorous fish. In the present study, a 10-week feeding trial was carried out to explore the regulation of biotin on the hepatic and intestinal inflammation and apoptosis in turbot (Scophthalmus maximus L.) fed with high carbohydrate diets. Three isonitrogenous and isolipidic experimental diets were designed as follows: the CC diet with 18.6% of carbohydrate and 0.04 mg/kg of biotin, the HC diet with 26.9% of carbohydrate and 0.05 mg/kg of biotin, and the HCB diet with 26.9% of carbohydrate and 1.62 mg/kg of biotin. Results showed that high dietary carbohydrate (HC diet) impaired the morphology of liver and intestine, however, inclusion of dietary biotin (HCB diet) normalized their morphology. Inflammation-related gene expression of nuclear factor κB p65 (nf-κb p65), tumor necrosis factor α (tnf-α), interleukin-1ß (il-1ß), il-6 and il-8, and the protein expression of NF-κB p65 in the liver and intestine were significantly up-regulated in the HC group compared to those in the CC group (P < 0.05), the HCB diet decreased their expression compared to the HC group (P < 0.05). The gene expression of il-10 and transforming growth factor-ß (tgf-ß) in the liver and intestine were significantly decreased in the HC group compared to the CC group (P < 0.05), and inclusion of dietary biotin increased the il-10 and tgf-ß expression in the liver and intestine (P < 0.05). Moreover, compared to the CC group, the HC group had a stronger degree of DNA fragmentation and more TUNEL-positive cells in the liver and intestine, and the HCB group had a slighter degree of DNA fragmentation and fewer TUNEL-positive cells compared to the HC group. Meanwhile, the gene expression of B-cell lymphoma protein-2-associated X protein (bax) and executor apoptosis-related cysteine peptidase 3 (caspase-3) were significantly up-regulated and the gene expression of B-cell lymphoma-2 (bcl-2) was significantly down-regulated both in the liver and intestine in the HC group compared with those in the CC group (P < 0.05). Inclusion of dietary biotin significantly decreased the bax and caspase-3 mRNA levels and increased bcl-2 mRNA level in the liver and intestine (P < 0.05). In conclusion, high dietary carbohydrate (26.9% vs 18.6%) induced inflammation and apoptosis in liver and intestine. Supplementation of biotin (1.62 mg/kg vs 0.05 mg/kg) in diet can alleviate the high-dietary-carbohydrate-induced hepatic and intestinal inflammation as well as inhibit apoptosis in turbot. The present study provides basic data for the application of biotin into feed, especially the high-carbohydrate feed for turbot.

Biotin-induced thyroid stimulating hormone aberrations in the setting of immunotherapy.

INTRODUCTION: Immune checkpoint inhibitors are associated with immune-mediated thyroid disease and other endocrinopathies. Biotin is an over-the-counter supplement known to interfere with lab assays, including thyroid function tests. Biotin-induced complications with lab monitoring during immunotherapy have not been previously reported. CASE REPORT: We present a case of a 68-year old woman with hypothyroidism after initiating immune checkpoint blockade therapy and abnormal laboratory monitoring values while concurrently taking biotin supplements.Management & outcome: The patient was initiated on levothyroxine with subsequent dose increases over a period of weeks with resolution of symptoms and normalization of free thyroxine levels. Thyroid stimulating hormone (TSH) levels appeared to remain elevated until biotin supplements were held and levels normalized. DISCUSSION: The purpose of this report is to provide the first known incidence of biotin complicating the routine monitoring of immune checkpoint inhibitors with elevated TSH levels and to alert providers to elicit accurate medication histories regarding over-the-counter supplements.

Dietary supplements in dermatology: A review of the evidence for zinc, biotin, vitamin D, nicotinamide, and Polypodium.

Dietary supplements are commonly recommended by dermatologists in the treatment of skin, hair, and nail disorders. This review of oral over-the-counter supplement use in dermatology summarizes current evidence for the use of zinc, biotin, vitamin D, nicotinamide, and Polypodium in the management of common dermatologic disorders. Evidence for the safety and efficacy of these supplements is limited. Very few large-scale randomized controlled trials exist for these over-the-counter supplements, particularly biotin and Polypodium. The lack of standardized dosing and standardized outcome measures makes comparison across existing studies challenging, and the lack of adverse events reporting in the majority of studies limits analysis of supplement safety. The most promising evidence exists for the use of nicotinamide in preventing nonmelanoma skin cancers. There is some evidence for the role of vitamin D in decreasing melanoma risk and progression in some individuals and for the photoprotective role of Polypodium, although additional high-quality studies are needed to determine appropriate dosing. Current evidence is insufficient to recommend the use of biotin or zinc supplements in dermatology. Large-scale randomized controlled trials investigating safety and efficacy are needed before widespread incorporation of these oral supplements into the general practice of dermatology.

Unusual Presentation of Denys-Drash Syndrome in a Girl with Undisclosed Consumption of Biotin

We describe a 46,XX girl with Denys-Drash syndrome, showing both kidney disease and genital abnormalities, in whom a misdiagnosis of hyperandrogenism was made. A 15 year-old girl was affected by neonatal nephrotic syndrome, progressing to end stage kidney failure. Hair loss and voice deepening were noted during puberty. Pelvic ultrasound and magnetic resonance imaging showed utero-tubaric agenesis, vaginal atresia and urogenital sinus, with inguinal gonads. Gonadotrophin and estradiol levels were normal, but testosterone was increased up to 285 ng/dL at Tanner stage 3. She underwent prophylactic gonadectomy. Histopathology reported fibrotic ovarian cortex containing numerous follicles in different maturation stages and rudimental remnants of Fallopian tubes. No features of gonadoblastoma were detected. Unexpectedly, testosterone levels were elevated four months after gonadectomy (157 ng/dL). Recent medical history revealed chronic daily comsumption of high dose biotin, as a therapeutic support for hair loss. Laboratory immunoassay instruments used streptavidin-biotin interaction to detect hormones and, in competitive immunoassays, high concentrations of biotin can result in false high results. Total testosterone, measured using liquid chromatography tandem mass spectrometry, was within reference intervals. Similar testosterone levels were detected on repeat immunoassay two weeks after biotin uptake interruption. Discordance between clinical presentation and biochemical results in patients taking biotin, should raise the suspicion of erroneous results. Improved communication among patients, health care providers, and laboratory professionals is required concerning the likelihood of biotin interference with immunoassays.

Neutralization of EP217609, a new dual-action FIIa/FXa anticoagulant, by its specific antidote avidin: a phase I study.

INTRODUCTION: EP217609 is a representative of a new class of synthetic parenteral anticoagulants with a dual mechanism of action. It combines in a single molecule a direct thrombin inhibitor and an indirect factor Xa inhibitor. EP217609 can be neutralized by a specific antidote avidin, which binds to the biotin moiety of EP217609. PURPOSE: The primary objective was to assess the neutralization of EP217609 by avidin in healthy subjects. Secondary objectives were to define the optimal avidin monomer/EP217609 molar ratio to achieve an adequate neutralization of EP217609 and to assess the safety and tolerability of EP217609 and avidin. METHODS: Healthy subjects (n = 36) were randomized to a 3 by 3 replicated Latin square design between 3 EP217609 doses (4, 8, 12 mg) and 3 avidin monomer/EP217609 molar ratios (1:1; 2:1; 3:1). EP217609 was administered as a single intravenous bolus, and avidin as a 30-min intravenous infusion, starting 90 min after EP217609 administration. RESULTS: Overall, EP217609 and avidin were well tolerated. One subject experienced a benign and transient typical pseudo-allergic reaction. The administration of EP217609 resulted in dose-dependent increases in pharmacodynamic markers. Avidin triggered a rapid and irreversible neutralization of EP217609 without rebound effect. Adequate neutralization of the anticoagulant activity was achieved with both 2:1 and 3:1 avidin monomer/EP217609 molar ratios. All safety parameters did not show any treatment-emergent clinically relevant changes or abnormalities in any dose group. CONCLUSIONS: These results will allow further investigation in patients requiring a neutralizable anticoagulant as those undergoing cardiac surgery. STUDY REGISTRATION: EudraCT number 2010-020216-10.

Intersections of pathways involving biotin and iron relative to therapeutic mechanisms for progressive multiple sclerosis.

While there are a variety of therapies for relapsing remitting multiple sclerosis (MS), there is a lack of treatments for progressive MS. An early study indicated that high dose biotin therapy has beneficial effects in approximately 12-15% of patients with progressive MS. The mechanisms behind the putative improvements seen with biotin therapy are not well understood, but have been postulated to include: 1) improving mitochondrial function which is impaired in MS, 2) increasing synthesis of lipids and cholesterol to facilitate remyelination, and 3) affecting gene expression. We suggest one reason that a greater percentage of patients with MS didn't respond to biotin therapy is the inaccessibility or lack of other nutrients, such as iron. In addition to biotin, iron (or heme) is necessary for energy production, biosynthesis of cholesterol and lipids, and for some protective mechanisms. Both biotin and iron are required for myelination during development, and by inference, remyelination. However, iron can also play a role in the pathology of MS. Increased deposition of iron can occur in some CNS structures possibly promoting oxidative damage while low iron levels can occur in other areas. Thus, the potential, detrimental effects of iron need to be considered together with the need for iron to support metabolic demands associated with repair and/or protective processes. We propose the optimal utilization of iron may be necessary to maximize the beneficial effects of biotin. This review will examine the interactions between biotin and iron in pathways that may have therapeutic or pathogenic implications for MS.

Conventional and pretargeted radioimmunotherapy using bismuth-213 to target and treat non-Hodgkin lymphomas expressing CD20: a preclinical model toward optimal consolidation therapy to eradicate minimal residual disease.

Radioimmunotherapy (RIT) with α-emitting radionuclides is an attractive approach for the treatment of minimal residual disease because the short path lengths and high energies of α-particles produce optimal cytotoxicity at small target sites while minimizing damage to surrounding normal tissues. Pretargeted RIT (PRIT) using antibody-streptavidin (Ab-SA) constructs and radiolabeled biotin allows rapid, specific localization of radioactivity at tumor sites, making it an optimal method to target α-emitters with short half-lives, such as bismuth-213 (²¹³Bi). Athymic mice bearing Ramos lymphoma xenografts received anti-CD20 1F5(scFv)(4)SA fusion protein (FP), followed by a dendrimeric clearing agent and [²¹³Bi]DOTA-biotin. After 90 minutes, tumor uptake for 1F5(scFv)4SA was 16.5% ± 7.0% injected dose per gram compared with 2.3% ± .9% injected dose per gram for the control FP. Mice treated with anti-CD20 PRIT and 600 µ Ci [²¹³Bi]DOTA-biotin exhibited marked tumor growth delays compared with controls (mean tumor volume .01 ± .02 vs. 203.38 ± 83.03 mm³ after 19 days, respectively). The median survival for the 1F5(scFv)4SA group was 90 days compared with 23 days for the control FP (P < .0001). Treatment was well tolerated, with no treatment-related mortalities. This study demonstrates the favorable biodistribution profile and excellent therapeutic efficacy attainable with ²¹³Bi-labeled anti-CD20 PRIT.

Biotin-directed assembly of targeted modular lipoplexes and their transfection of human hepatoma cells in vitro.

The asialoglycoprotein receptor, which is abundantly and near exclusively expressed on hepatocytes, has received much attention in the design of non-viral hepatotropic DNA delivery systems. Thus, asialoglycoproteins and hexopyranosyl ligands have been coupled to DNA-binding cationic polymers and liposomes in the assembly of complexes intended for uptake by liver parenchymal cells. The aim of the study was to construct a hepatocyte-targeted multimodular liposome-based transfecting complex, in which the biotin-streptavidin interaction provides the cohesive force between the ligand asialorosomucoid and the liposome bilayer, and to evaluate its transfection capabilities in the hepatocyte-derived human transformed cell line HepG2. Dibiotinylated asialoorosomucoid was attached to cationic liposomes constructed from 3beta[N-(N',N'-dimethylaminopropane)-carbamoyl] cholesterol (Chol-T):dioleoylphosphatidylethanolamine:biotinylcholesterylformylhydrazide (MSB1) (48:50:2 mole ratio) through streptavidin interposition. Liposome-pGL3 DNA interactions were studied by gel band shift and ethidium displacement assays. The cytotoxicity of assemblies was evaluated in the HepG2 cell line and transfection capabilities determined by measuring the activity of the transgene luciferase. Binding assays showed that all DNA was liposome associated at a DNA (negative):liposome (positive) charge ratio of 1:1. Accommodation of a streptavidin dibiotinylated asialoorosomucoid assembly was achieved at a DNA:liposome:streptavidin dibiotinylated asialoorosomucoid ratio of 1:4:9 (weight basis). Complexes showed optimal transfection activity at this ratio, which was reduced 10-fold by the presence of the competing ligand asialofetuin. The streptavidin-biotin interaction has been applied for the first time to the assembly of hepatocyte-targeted lipoplexes that display asialoorosomucoid and that are well tolerated by a human hepatoma cell line in which transfection is demonstrably achieved by receptor mediation. Favorable size and charge ratio characteristics suggest that this system may be suitable for in vivo application.

Radioimmunotherapy in advanced ovarian cancer: is there a role for pre-targeting with (90)Y-biotin?

OBJECTIVES: Despite recent advances in the management of ovarian cancer, this tumor remains the leading cause of death among gynecologic malignancies. Moreover, advanced ovarian carcinoma has a poor prognosis, thus requiring new therapeutic modalities. Previous studies have indicated a survival advantage for ovarian cancer patients (pts) treated with radioimmunotherapy (RIT). Pre-targeting RIT, based on the avidin-biotin system, has been the objective of previous studies performed by our group. PATIENTS AND METHODS: In the present study, the therapeutic efficacy and toxicity of RIT in 38 advanced ovarian cancer patients have been retrospectively evaluated. RIT was performed according to the following three-step protocol: biotinylated monoclonal antibodies (MoAb) and avidin were intraperitoneally (ip) injected (1st and 2nd step), and 12-18 h later (90)Y-labeled biotin either iv or ip was injected as 3rd step. Sixteen out of 38 patients were treated by intraperitoneal injection only, whereas other 22 pts received the combined treatment (ip + iv); the dose range was 10-100 mCi of (90)Y-biotin. RESULTS: Both of the two therapy regimens were well tolerated; no acute side effects were observed. Two patients (5%) showed temporary hematological grade III-IV toxicity. As regards to the therapeutic efficacy, in the ip group we observed 6% of objective tumor reduction, stabilization in 31% of pts, and progression in 50%. In the group of combined treatment, 9% of patients achieved objective responses, 32% showed stable disease, and 41% had a progression. CONCLUSIONS: These data show the excellent tolerability (maximum tolerated dose (MTD) has not been determined yet) and the potential therapeutic role of RIT in advanced ovarian cancer. Patients with minimal residual disease would probably take the best advantages of RIT with (90)Y-biotin (electrons). These data warrant further prospective studies.

Life-threatening eosinophilic pleuropericardial effusion related to vitamins B5 and H.

OBJECTIVE: To report a case of eosinophilic pleuropericarditis resulting from concomitant use of vitamins B5 and H. CASE SUMMARY: A 76-year-old white woman was admitted to the hospital because of chest pain and dyspnea related to pleurisy and a pericardial tamponade. This patient had no history of allergy and had been taking vitamins B5 and H for two months. Blood tests performed showed an inflammatory syndrome and a high eosinophil concentration (1200-1500 cells/mm3). Pleurocentesis and pericardiotomy yielded a sterile exudative fluid with an eosinophilic infiltrate. There were no nuclear antibodies and no rheumatic factor; screenings for viruses, parasites, bacteria, and malignant tumor were negative. A myelogram, biopsy of the iliac crest bone, and concentration of immunoglobulin E were also normal. After withdrawal of the vitamins, the patient recovered and the eosinophilia disappeared. DISCUSSION: Prolonged hypereosinophilia has marked predilection to damage specific organs, including the heart, but pleuropericardial effusion is uncommon. Drug-related pleuropericarditis usually occurs without an increased eosinophil count. Other drugs responsible for eosinophilic pleuropericarditis are cephalosporins, dantrolene, propylthiouracil, and nitrofurantoin. To our knowledge, this is the first case report of pleuropericarditis related to vitamins B5 and H. CONCLUSIONS: This case suggests that vitamins B5 and H may cause symptomatic, life-threatening, eosinophilic pleuropericarditis. Physicians prescribing these commonly used vitamins should be aware of this potential adverse reaction.

The effect of an acute dose of biotin at a post-implantation stage and its relation with female sex steriods in the rat.

An acute dose (10 mg/100 g body weight) of biotin at the post-implantation stage (day 14 and 15) inhibited the fetal and placental growth, and in few rats it also caused resorption of fetuses and placentae. The maintenance of pregnancy with normal fetal and placental growth was effected with estrogen therapy, but progesterone failed to correct the biotin-induced effect. The uterine and placental glycogen, RNA and protein levels, as well as, glucose-6-phosphate dehydrogenase activity in the ovary, liver and uterus showed a reduction following biotin treatment. Estrogen therapy under such conditions corrected these adverse effects of biotin overdose, while progesterone had no significant effects. The study suggests that the acute dose of biotin at an advance stage of pregnancy may cause adverse effects on the physiological regulation of gestation, possibly by creating deficiency of estrogen and gestagen. The possible role of estrogen in the fetal and placental growth and regulation of gestagen secretion is discussed.

The effect of an acute dose of biotin at the pre-implantation stage and its relation with female sex steroids in the rat.

An acute dose of biotin (10 mg/100 g body weight) in two subcutaneous injections when given to a rat on day 1 and 2 of pregnancy, caused resorption of fetuses and placentae. Pregnancies under such biotin-treated conditions were maintained by continued estrogen or progesterone therapy. Biotin-treated pregnant rats failed to maintain normal levels of uterine weight, glycogen and protein as well as hepatic protein concomitantly with the loss of pregnancy. Estrogen therapy under such conditions improved all the parameters in these organs including the placenta, but progesterone therapy did not. Glucose-6-phosphate dehydrogenase (G-6-PD) activity in ovary, adrenal, liver and uterus was also reduced following biotin-induced loss of pregnancy which had been improved by estrogen or progesterone therapy. Nevertheless, estrogen was superior to progesterone in stimulating the enzyme activity in these organs excepting the adrenal. As far as the tissue response to biotin, estrogen or progesterone in the nonpregnant rat is concerned, biotin and progesterone exerted a suppressing effect on uterine glycogen and protein and also on liver protein, while estrogen stimulated them. Similarly biotin and progesterone adversely affected G-6-PD activity in all the organs studied except the liver and adrenal. Estrogen stimulated the enzyme activity in all these organs but adrenal. The study suggests that the primary reason for an acute dose of biotin-induced loss of pregnancy is blockage of estrogen production, which probably regulates endogenous progesterone secretion. The associated metabolic derangements are probably secondary to estrogen deficiency and are discussed.