A Mixed Micelle Formulation for Oral Delivery of Vitamin K.

PURPOSE: To develop a stable micellar formulation of vitamin K for oral delivery, because the commercial and clinically used formulation of vitamin K (Konakion® MM) destabilizes at gastric pH resulting in low bioavailability of this vitamin in neonates with cholestasis. METHODS: Mixed micelles composed of EPC, DSPE-PEG 2000 and glycocholic acid, with and without vitamin K, were prepared by a film hydration method. The influence of pH on the stability of the micelles was analyzed by dynamic light scattering (DLS). The critical micelle concentration (CMC) was determined by fluorescence spectroscopy using pyrene and the morphology was evaluated by transmission electron microscopy . Caco-2 cells were used to study the cytocompatibilty. RESULTS: Mixed micelles with mean diameters from 7.1 to 11.0 nm and a narrow size distribution (PDI < 0.2) were obtained after 3 membrane extrusion cycles. Konakion® MM formed aggregated particles at gastric pH, which was avoided through steric stabilization by introducing PEG. TEM showed that mixed micelles had a spherical size (diameter of around 10 nm) with a narrow size distribution in agreement with the DLS results. The loading capacities for vitamin K of mixed micelles with varying molar fractions of DSPE-PEG and EPC (from 0/100 to 50/50 (mol/mol)) were 10.8-5.0 w%, respectively. The mixed micelles showed good cytocompatibility at concentrations of glycocholic acid between 0.12 and 1.20 mM. CONCLUSIONS: Mixed micelles with superior stability to Konakion® MM at low pH were obtained by introducing DSPE-PEG 2000. These are therefore attractive oral formulations for vitamin K.

[Dental and oral surgical treatment of medication-induced bleeding patients: Audit of the national guideline in Hungary]. / A gyógyszer indukálta vérzékeny betegek fogorvosi, szájsebészeti ellátása: a 2015-ös hazai szakmai ajánlás alkalmazása és értékelése.

INTRODUCTION: In 2015 a new Hungarian guideline was published regarding dental treatment and management of anticoagulated patients in agreement of the Hungarian Association of Oral and Maxillofacial Surgeons and the Dental Implantology Association of Hungarian Dentists. AIM: The aim of the authors was to evaluate the efficiency and safety of local hemostatic measures recommended by the guideline in anticoagulated patients. METHOD: In these patients, postoperative bleeding episodes were examined after dental and oral surgical treatments, retrospectively. RESULTS: Overall 263 bleeding risk cases were treated; 138 patients with vitamin K antagonists, 97 patients with antiplatelet therapy and 6 patients with novel oral anticoagulants. Six patients (2.3%) had minor postoperative bleeding after the "one hour control", while one patient needed a night duty support (0.5%). In contrast, 86 patients who were treated in rural practices neglecting the guideline attended the night duty with postoperative bleeding (3 patients treated with vitamin K antagonists, 24 patients taking low molecular weight heparin, 30 patients receiving antiplatelet therapy and one patient on novel oral anticoagulant therapy. CONCLUSIONS: The Hungarian guideline can be applied safely, without increasing the risk of postoperative bleeding, however, rural dental practices are frequently unprepared for these treatments. Orv. hetil., 2016, 157(43), 1722-1728.

[Dental management of hemorrhage-prone patients]. / A vérzékeny betegek fogorvosi ellátása.

The authors present a proposal of dental treatment and management of anticoagulated patients and of patients on antiplatelet therapy, with the approval by the Hungarian Association of Oral and Maxillofacial Surgeons and by the Dental Implantology Association of Hungarian Dentists. This current guide was based on recent Hungarian and on several foreign national guidelines and considers significant publications from international literature.

Unusual case of soft palate and uvula haematoma in a patient on anticoagulant drugs.

A 91-year-old Caucasian man on warfarin for atrial fibrillation presented in view of sudden-onset haemoptysis with fresh bleeding with clots immediately after having eaten a piping-hot traditional cheesecake (pastizz) and burning the soft-palate of his mouth. The haemoptysis had resolved by the time that the patient had arrived to hospital. On examination, a 2 cm by 2 cm dark red, solitary mass could be seen just anterior to the uvula. This was not causing any pain or discomfort to the patient. Blood results were mostly unremarkable except for a raised international normalised ratio (INR) of 3.53. The patient was administered 5 mg vitamin K orally in attempt to lower the INR level and warfarin was subsequently omitted for 7 days. He was also prescribed oral steroids on discharge. The lesion resolved in 7 days and warfarin was restarted then with no further consequences.

Deliberate self-poisoning with long-acting anticoagulant rodenticides.

Long-acting anticoagulant rodenticides, also called superwarfarins, are known for their greater potency, longer half-life and delayed onset of symptoms. Cases of superwarfarin poisoning can pose a diagnostic and clinical challenge due to a wide array of presentations and prolonged severe coagulopathy requiring months of high-dose oral vitamin K therapy. The most common presentation of long-acting anticoagulant rodenticide poisoning is mucocutaneous bleeding, with other common presentations including haematuria, gingival bleeding, epistaxis and gastrointestinal bleeding. We discuss a case of deliberate self-poisoning with long-acting anticoagulant rodenticides presenting with haematuria and coagulation values above measurable limits. This case is important as it required immediate and maintenance therapy in order to prevent profound bleeding, as well as the evaluation of the patient's psychosocial factors to ensure medical compliance and to prevent refractory complications or repeated self-harm.

Prenatal exposure to phenytoin, facial development, and a possible role for vitamin K.

Ten patients with maxillonasal hypoplasia (Binder "syndrome"), who were prenatally exposed to phenytoin (usually in combination with other anticonvulsants), were identified retrospectively. In addition to their facial anomalies, 6 of the patients were radiographed neonatally and showed punctate calcification, characteristic of chondrodysplasia punctata. Evidence is presented that the facial abnormalities seen in these children are due to anticonvulsant-induced vitamin K deficiency, causing abnormal development of the cartilaginous nasal septum. We propose that early vitamin K supplementation of at-risk pregnancies may prevent the development of maxillonasal hypoplasia, which in some patients is severely disfiguring and causes great emotional distress. Correction of this facial defect requires surgical and dental treatment over a long period of time.

Interaction of dietary factors with oral anticoagulants: review and applications.

This article reviews the published original sources of information on interactions of oral anticoagulants with dietary factors, points out deficiencies in our knowledge of these interactions, and suggests applications for this information in the clinical setting. As with many drug-nutrient interactions, the original references include a few experimental studies and many case reports. Deciding which interactions of oral anticoagulants with dietary factors are clinically relevant and determining the appropriate dietary prescription concerning each interaction involves, in most cases, an educated opinion rather than a conclusion based on extensive research. Enough information exists on the vitamin K content of foods and the quantity of vitamin K that alters coagulation status from the therapeutic range to provide the patient with advice concerning a group of foods to avoid and a group of foods to limit to one serving per day. With respect to other dietary factors that may interact with oral anticoagulants, the patient should be cautioned concerning supplements of vitamins A, E, and C and alcohol used chronically or ingested in large quantities.

Warfarin resistance and enteral feedings.

Nutritional support via enteral feeding tubes may interfere with the response to medications by a number of mechanisms. A 31-year-old, white man was admitted after sustaining a gunshot wound to the chest and mandible. Subsequently, the patient developed pulmonary emboli documented by angiography. Attempts at anticoagulation with oral warfarin were unsuccessful while the patient was receiving 50-100 ml/hr of Osmolite through an Entriflex feeding tube and intermittent oral Ensure Plus supplements. Discontinuation of the Osmolite resulted in a prompt prolongation of the prothrombin time. The Ensure Plus was continued and adequate prothrombin times were achieved on 7.5 to 10 mg of warfarin daily. The total amount of vitamin K received from the enteral feedings ranged from 50 to 115 micrograms/day, which is less than the normal daily intake of 300 to 500 micrograms. Previous reports of warfarin resistance implicated older enteral feeding products with a much higher vitamin K content. Difficulty with anticoagulation may still be experienced with the newer formulations. It is unknown whether the vitamin K content or malabsorption of warfarin is the mechanism of resistance.

Absorption of vitamin K2 by dogs after oral administration of a soft gelatin capsule formulation containing a new emulsion-type vehicle.

This study has evaluated the performance of a newly developed vehicle for administration of a drug in a soft gelatin capsule. The absorption of vitamin K2 in dogs after oral administration of the vitamin in a soft gelatin capsule containing the newly developed vehicle was compared with absorption after administration of a control formulation prepared by encapsulating the contents of a commercially available vitamin K2 capsule (Glakay capsules 15 mg) in the same type of soft gelatin. Under non-fasted conditions the profile of the plasma concentration of vitamin K2 against time for the test formulation was comparable with that for the control formulation in non-fasted dogs. Under fasted conditions, however, both the maximum concentration (Cmax) and the area under the plot of concentration against time (AUC) were significantly smaller for the test formulation than for the control formulation. The Cmax and AUC for the test formulation were about 10 times larger for non-fasted dogs than for fasted dogs whereas values for the control formulation were about twice as large. These results suggest that both formulations might require the presence of food or digestive fluid components, or both, for better absorption of vitamin K2. It seems that although the performances of the test and control formulations were comparable in the presence of these components, the control formulation works better in their absence. It should be also noted that, in contrast with the results from the absorption tests, the dispersibility of the test vehicle in water was much better than that of the control vehicle. This suggests that dispersibility does not significantly affect vitamin K2 absorption. In conclusion, although the new vehicle did not perform better than the control vehicle in terms of vitamin K2 absorption, the performance of the control formulation was comparable for non-fasted dogs. Because the new vehicle contains considerably less surfactant than the vehicles currently used in soft gelatin capsules, it could be a safer alternative for use under non-fasted conditions.

Management of anticoagulation in patients with prosthetic heart valves undergoing oral and maxillofacial operations.

There is wide variation in the management of patients with mechanical prosthetic valves who are taking anticoagulants and who require non-cardiac surgery. In this paper, we outline a pragmatic, practical approach to the adjustment of anticoagulation in relation to both the degrees of surgical trauma during oral and maxillofacial surgery and the risk of thromboembolism associated with the prosthetic valve. For minor surgery, no adjustment of anticoagulation is undertaken if the International Normalized Ratio is less than 4.0, if local haemostatic methods and tranexamic acid mouthwashes are used. For major surgery, warfarin is stopped preoperatively and low-molecular-weight heparin is used. For emergency surgery, partial reversal of anticoagulation with low-dose parenteral vitamin K is obtained.

[The effect of vicasol and pelentan on the biopolymers of the periodontium]. / O vliianii vikasola i pelentana na sostoianie biopolimerov periodonta zubov.

Vitamin K (vikasol) and pelentan were examined for their effects of periodontal tissue levels of collagen, hexosamine-containing biopolymers and sialoglycoproteins. During tooth replantation in dogs, vitamin K was demonstrated to elevate the levels of collagen, hexosamine-containing polymers in periodontal tissue by 25.8, 19.9, and 36.1%, respectively, whereas pelentan lowered the above parameters.

Prolonged coagulopathy related to coumarin rodenticide in a young patient: superwarfarin poisoning.

Superwarfarins (brodifacoum, difenacoum, bromodialone and chlorphacinone) are anticoagulant rodenticides that were developed in 1970s to overcome resistance to warfarin in rats. A 26-year-old previously healthy man was admitted to the emergency department with epigastric pain, severe upper and lower gastrointestinal haemorrhage, gingival bleeding and melena. The patient stated that he had been healthy with no prior hospital admissions and no personal or family history of bleeding diathesis. The patient, who later admitted attempted suicide, stated that he had taken 400 g rodenticide including brodifacoum orally for five days prior to admission to hospital. He had oral mucosal bleeding, numerous bruises over the arms, legs and abdomen, and an abdominal tenderness, together with melena. Laboratory tests revealed a haemoglobin level of 12.3 g/dl, leucocyte count of 9.1 × 10(9) /l, haematocrit of 28% and platelet count of 280 × 10(9) /l. The prothrombin time (PT) was > 200 s (normal range 10.5-15.2 s) and the activated partial thromboplastin time (aPTT) was 91 s (normal range 20-45 s). The INR (International normalised ratio) was reported to be > 17 (normal range 0.8-1.2). The thrombin time and plasma fibrinogen levels were in the normal range. The results showed the presence of brodifacoum at a concentration of 61 ng/ml, detected by reversed-phase liquid chromatography.

Dientes natales: informe de un caso y revisión de la literatura / Natal teeth: report of a case and review of the literature

Cuando se encuentran dientes presentes al nacimiento es frecuente que los médicos pediatras interconsulten con el odontólogo, dichos dientes reciben el nombre de natales y neonatales de acuerdo con el momento en el cual hacen su aparición, si los dientes se encuentran presentes al nacimiento se les denomina natales y si aparecen durante el primer mes de vida se les llama neonatales. No es raro que los dientes natales y neonatales carezcan de raíz, y debido a su débil unión con eltejido gingival es posible que estos dientes puedan desalojarse y serbroncoaspirados o deglutidos por el menor durante la alimentación al seno materno. Si bien los dientes natales y neonatales no constituyen una entidad patológica per se, existen algunos síndromes genéticos que entre sus características se encuentran los dientes natales o neonatales.

When teeth are present at birth, pediatricians frequently seek the opinionof a dentist. These teeth are known as natal or neonatal depending onwhether they are present at birth or appear during the fi rst month oflife. It is not uncommon for natal and neonatal teeth to have no root,and due to their weak bond to the gingival tissue they can come looseand be breathed in or swallowed by the child during breast feeding.While natal and neonatal teeth are not a pathological entity per se,there are certain genetic syndromes whose features include natal orneonatal teeth.

The influence of bile acids on the oral bioavailability of vitamin K encapsulated in polymeric micelles.

The purpose of this study was to assess the ability of polymeric micelles to enable gastrointestinal absorption of the extremely hydrophobic compound vitamin K, by comparison of its absorption in bile duct ligated and sham operated rats. Hereto, vitamin K was encapsulated in micelles composed of mPEG(5000)-b-p(HPMAm-lac(2)), a thermosensitive block copolymer. Vitamin K plasma levels rose significantly upon gastric administration of 1 mg vitamin K encapsulated in polymeric micelles in sham operated rats, but not after bile duct ligation (AUC 4543 and 1.64 ng/mL/h respectively, p<0.01). Duodenal administration of polymeric micelles together with bile acids in bile duct ligated rats fully restored absorption. Dynamic light scattering time series showed a significant and dose dependent rise in micellar size in the presence of bile acids in vitro, indicating the gradual formation of mixed micelles during the first 3 h of incubation. The highest bile acid amounts (11 mM deoxycholic acid and 41 mM taurocholic acid) eventually caused aggregation of the loaded micelles after the formation of mixed micelles. These data suggest that the gastrointestinal absorption of encapsulated vitamin K from polymeric micelles is mediated by free bile and that uptake of intact micelles through pinocytosis is insignificant.

Canine intestinal contents vs. simulated media for the assessment of solubility of two weak bases in the human small intestinal contents.

PURPOSE: This study was conducted to assess the relative usefulness of canine intestinal contents and simulated media in the prediction of solubility of two weak bases (dipyridamole and ketoconazole) in fasted and fed human intestinal aspirates that were collected under conditions simulating those in bioavailability/bioequivalence studies. METHODS: After administration of 250 mL of water or 500 mL of Ensure plus [both containing 10 mg/mL polyethylene glycol (PEG) 4000 as nonabsorbable marker], intestinal aspirates were collected from the fourth part of the duodenum of 12 healthy adults and from the mid-jejunum of four Labradors. Pooled samples were analyzed for PEG, pH, buffer capacity, osmolality, surface tension, pepsin, total carbohydrates, total protein content, bile salts, phospholipids, and neutral lipids. The shake-flask method was used to measure the solubility of dipyridamole and ketoconazole in pooled human and canine intestinal contents and in fasted-state-simulating intestinal fluid (FaSSIF) and fed-state-simulating intestinal fluid (FeSSIF) containing various bile salts and pH-buffering agents. RESULTS: For both compounds, solubility in canine contents may be predictive of human intralumenal solubility in the fasting state but not in the fed state. The poor agreement of results in canine and human aspirates can be attributed to the higher bile salt content in canine bile. Solubility in FaSSIF containing a mixture of bile salts from crude bile predicted satisfactorily the intralumenal solubility of both drugs in the fasted state in humans. Solubility in FeSSIF, regardless of the identity of bile salts or of the buffering species, deviated from intralumenal values in the fed human aspirates by up to 40%. This was attributed to the lack of lipolytic products in FeSSIF, the higher bile salt content of FeSSIF, and the lower pH of FeSSIF. CONCLUSIONS: FaSSIF containing a mixture of bile salts from crude bile, and FeSSIF containing lipolytic products and, perhaps, having lower bile salt content but slightly higher pH, should be more useful than canine intestinal aspirates for predicting intralumenal solubilities in humans.

Difference in the metabolism of vitamin K between liver and bone in vitamin K-deficient rats.

The difference between vitamin K metabolism in the liver and that in the bone of vitamin K-deficient rats was examined. After 17 d administration of vitamin K-deficient food, vitamin K in the liver was almost depleted, and prothrombin time (PT) was prolonged. Serum total osteocalcin level was slightly decreased by vitamin K deficiency, whereas serum undercarboxylated osteocalcin level did not change. The level of menaquinone (MK)-4 as well as that of phylloquinone was decreased, but approximately 40 % of the initial level still existed in the femur after the 17 d period. A single-dose administration of vitamin K (250 nmol/kg body weight) markedly increased vitamin K level in the liver but not in the femur. These results suggest that the turnover of vitamin K in the bone is slower than that in the liver, and bone metabolism may be little affected by the short period of intake of vitamin K-deficient food. However, intake of a larger amount of vitamin K is required for its accumulation in the bone than in the liver. Furthermore, the counteracting effect of MK-7 on prolonged PT in vitamin K-deficient rats was found to be higher than phylloquinone or MK-4.

Diarrhea-associated over-anticoagulation in a patient taking warfarin: therapeutic role of cholestyramine.

We present a case of significant over-anticoagulation temporally associated with a bout of protracted diarrhea in a patient on warfarin therapy. Cholestyramine was utilized to interrupt the enterohepatic recycling of warfarin and for its antidiarrheal effects to prevent gastrointestinal vitamin K wasting. Cholestyramine enabled the use of very low doses of sc vitamin K1 (2 mg total) with subsequent attainment of a therapeutic International Normalized Ratio in 39 h.

Conversion of dietary phylloquinone to tissue menaquinone-4 in rats is not dependent on gut bacteria.

The ability of male rats to accumulate menaquinone-4 (MK-4) in tissues when fed a vitamin K-deficient diet supplemented with intraperitoneal phylloquinone (K) as the sole source of vitamin K for 14 d was assessed. In both conventionally housed controls and gnotobiotic rats, supplementation with the equivalent of 1500 microg vitamin K/kg diet increased (P < 0.001) tissue MK-4 concentrations above those of controls fed a vitamin K-deficient diet. MK-4 concentrations were approximately 5 ng/g (11 pmol/g) in liver, 14 ng/g in heart, 17 ng/g in kidney, 50 ng/g in brain and 250 ng/g in mandibular salivary glands of gnotobiotic rats. MK-4 concentrations in conventionally housed rats were higher than in gnotobiotic rats in heart (P < 0.01), brain (P < 0.01) and kidney (P < 0.05) but lower in salivary gland (P < 0.05). Cultures of a kidney-derived cell line (293) converted K to the expoxide of MK-4 in a manner that was dependent on both time of incubation and concentration of vitamin K in the media. A liver-derived cell line (H-35) was less active in carrying out this conversion. These data offer conclusive proof that the tissue-specific formation of MK-4 from K is a metabolic transformation that does not require bacterial transformation to menadione as an intermediate in the process.