Antivitamins B12 -Some Inaugural Milestones.

The recently delineated structure- and reactivity-based concept of antivitamins B12 has begun to bear fruit by the generation, and study, of a range of such B12 -dummies, either vitamin B12 -derived, or transition metal analogues that also represent potential antivitamins B12 or specific B12 -antimetabolites. As reviewed here, this has opened up new research avenues in organometallic B12 -chemistry and bioinorganic coordination chemistry. Exploratory studies with antivitamins B12 have, furthermore, revealed some of their potential, as pharmacologically interesting compounds, for inducing B12 -deficiency in a range of organisms, from hospital resistant bacteria to laboratory mice. The derived capacity of antivitamins B12 to induce functional B12 -deficiency in mammalian cells and organs also suggest their valuable potential as growth inhibitors of cancerous human and animal cells.

The Impact of Antiepileptic Drugs on Vitamin Levels in Epileptic Patients.

BACKGROUND: The impact of antiepileptics on serum vitamin levels is controversial and uncertain. With no clear conclusions on the impact of antiepileptics on serum levels of vitamins, there is a need for further clinical studies in order to ascertain the impact of old and newer antiepileptic drugs on serum levels of vitamins in epileptic patients, thus accomplishing a suitable usage of vitamins supplementation. OBJECTIVE: The intention of the present research is to confirm the hypothesis of whether or not vitamin levels are altered with antiepileptic drugs. The study also aims to reveal which vitamin levels are particularly more altered, are vitamin levels affected by gender and the type and number of antiepileptics used. METHODS: The present research was piloted in collaboration with the Department of Neurology in Qilu Hospital of Shandong University. A total of 63 serum samples of epileptic patients receiving antiepileptics as monotherapy or polytherapy were requested for analysis of nine vitamin serum levels. Total nine vitamins (B1, B2, B6, B9, B12, A, C, D and E) in epileptic patients receiving antiepileptic drugs were analyzed. The serum results of all vitamins were compiled and evaluated with SPSS. RESULTS: It was alarmingly found that serum levels of vitamin D were particularly very low in almost all (90%) epileptic patients in this study. Notably, serum levels of vitamin C and vitamin B1 were also below reference range in 72% and 46% epileptic patients, respectively. The remaining vitamins were almost in reference range for most of the patients. In our study, mean and frequency of vitamin D, C and B1 levels do not vary too much among different gender groups. The patients receiving newer antiepileptic drugs displayed a slightly increased serum vitamin D levels in comparison to the patients receiving older antiepileptic drugs. We found low vitamin D, C and B1 serum levels in patients who were on monotherapy as in comparison with patients on polytherapy. CONCLUSION: The most significant and surprising finding of this study revealed that serum vitamin D levels in particular were very low in almost all patients and in some patients' vitamin B1 serum levels were also below the reference range. More importantly, it is first time reported here that vitamin C serum levels were also below reference range in the majority of these Chinese epileptic patients. It is recommended that all these vitamins should be regularly monitored in addition to therapeutic drug monitoring of antiepileptic drugs. Additional clinical trials are required for further evaluation. It is also recommended that epileptic patients with low serum levels of these vitamins may be prescribed vitamins supplementations with antiepileptic drugs in order to control their seizures more effectively and efficiently.

Outcomes of Geriatric Trauma Patients on Preinjury Anticoagulation: A Multicenter Study.

Outpatient anticoagulation in the geriatric trauma patient is a challenging clinical problem. The aim of this study is to determine clinical outcomes associated with class of preinjury anticoagulants (PA) used by this population. This is a multicenter retrospective cohort study among four Level II trauma centers. A total of 1642 patients were evaluated; 684 patients were on anticoagulation and 958 patients were not. Patients on PA were compared with those who were not. Drug classes were divided into thromboxane A2 inhibitors, vitamin K factor-dependent inhibitors, antithrombin III activation, platelet P2Y12 inhibitors, and thrombin inhibitors. Multivariate regression was used to adjust for age, gender, race, mechanism of injury, and Injury Severity Score. No single or combination of anticoagulation agents had a significant association with mortality; however, there were positive trends toward increased mortality were noted for all antiplatelet groups involving thromboxane A2 inhibitors and platelet P2Y12 inhibitors classes. The likelihood of complications was significantly higher with platelet P2Y12 inhibitors adjusted odds ratio (aOR) 2.39 [95% confidence interval (CI) 1.32, 4.3]. The likelihood of blood transfusion was increased with vitamin K inhibitors aOR 2.89 (95% CI 1.3, 6.5), P2Y12 inhibitors aOR 2.76 (95% CI 1.12, 6.76), and combined thromboxane A2 and P2Y12 inhibitors aOR 2.89 (95% CI 1.13, 7.46). P2Y12 inhibitors were also more likely associated with traumatic brain injury aOR 2.16 (95% CI 1.01, 4.6). All classes of PA were associated with solid organ injury. There were no significant differences in the use of antiplatelet agents between patients with major indications for PA and those without major indications. Geriatric trauma patients on outpatient anticoagulants have a higher likelihood of developing complications, packed red blood cell transfusions, traumatic brain injury, and solid organ injury. Attention should be paid to patients on platelet P2Y12 inhibitors, vitamin K inhibitors, and thromboxane A2 inhibitor agents combined with platelet P2Y12 inhibitors. Opportunities exist to address the use of antiplatelet agents among patients without major indications to improve patient outcomes.

Antivitamins B12--A Structure- and Reactivity-Based Concept.

B12 -antimetabolites are compounds that counteract the physiological effects of vitamin B12 and related natural cobalamins. Presented here is a structure- and reactivity-based concept of the specific 'antivitamins B12 ': it refers to analogues of vitamin B12 that display high structural similarity to the vitamin and are 'locked chemically' to prevent their metabolic conversion into the crucial organometallic B12 -cofactors. Application of antivitamins B12 to healthy laboratory animals is, thus, expected to induce symptoms of B12 -deficiency. Antivitamins B12 may, hence, be helpful in elucidating still largely puzzling pathophysiological phenomena associated with B12 -deficiency, and also in recognizing physiological roles of B12 that probably still remain to be discovered.

Antivitamins for Medicinal Applications.

Antivitamins represent a broad class of compounds that counteract the essential effects of vitamins. The symptoms triggered by such antinutritional factors resemble those of vitamin deficiencies, but can be successfully reversed by treating patients with the intact vitamin. Despite being undesirable for healthy organisms, the toxicities of these compounds present considerable interest for biological and medicinal purposes. Indeed, antivitamins played fundamental roles in the development of pioneering antibiotic and antiproliferative drugs, such as prontosil and aminopterin. Their development and optimisation were made possible by the study, throughout the 20th century, of the vitamins' and antivitamins' functions in metabolic processes. However, even with this thorough knowledge, commercialised antivitamin-based drugs are still nowadays limited to antagonists of vitamins B9 and K. The antivitamin field thus still needs to be explored more intensely, in view of the outstanding therapeutic success exhibited by several antivitamin-based medicines. Here we summarise historical achievements and discuss critically recent developments, opportunities and potential limitations of the antivitamin approach, with a special focus on antivitamins K, B9 and B12 .

[Questions--answers on the use of rivaroxaban for the treatment of venous thromboembolic disease]. / Questions - réponses sur l'utilisation du rivaroxaban pour le traitement de la maladie thromboembolique veineuse.

Rivaroxaban is a direct oral anticoagulant targeting factor Xa. Efficacy and safety of rivaroxaban were evaluated through the phase 3 EINSTEIN program, consisting in three clinical trials regarding the treatment of deep vein thrombosis (EINSTEIN DVT), pulmonary embolism (EINSTEIN PE), and in secondary prevention after a first episode of venous thromboembolic disease (EISNTEIN EXT). Rivaroxaban was recently approved both by the European and the French Health agencies for the treatment of DVT and prevention of deep vein thrombosis recurrence. This report addresses the use of rivaroxaban in clinical practice in such indications.

Non-antioxidant properties of α-tocopherol reduce the anticancer activity of several protein kinase inhibitors in vitro.

The antioxidant properties of α-tocopherol have been proposed to play a beneficial chemopreventive role against cancer. However, emerging data also indicate that it may exert contrasting effects on the efficacy of chemotherapeutic treatments when given as dietary supplement, being in that case harmful for patients. This dual role of α-tocopherol and, in particular, its effects on the efficacy of anticancer drugs remains poorly documented. For this purpose, we studied here, using high throughput flow cytometry, the direct impact of α-tocopherol on apoptosis and cell cycle arrest induced by different cytotoxic agents on various models of cancer cell lines in vitro. Our results indicate that physiologically relevant concentrations of α-tocopherol strongly compromise the cytotoxic and cytostatic action of various protein kinase inhibitors (KI), while other classes of chemotherapeutic agents or apoptosis inducers are unaffected by this vitamin. Interestingly, these anti-chemotherapeutic effects of α-tocopherol appear to be unrelated to its antioxidant properties since a variety of other antioxidants were completely neutral toward KI-induced cell cycle arrest and cell death. In conclusion, our data suggest that dietary α-tocopherol could limit KI effects on tumour cells, and, by extent, that this could result in a reduction of the clinical efficacy of anti-cancer treatments based on KI molecules.

Management of special conditions in patients on vitamin K antagonists.

Physicians are occasionally faced with difficult situations in the management of vitamin K antagonists (VKA) due to the lack of sound data available in controlled studies on certain conditions. In this review we would like to address some special but frequent conditions that can be encountered in daily clinical practice. These include the use of VKA in hemodialysis, thromboembolism in patients with liver cirrhosis and the thromboembolic risk in patients who bleed in the course of treatment with VKA. Moreover, two other conditions were examined: what the best way of expressing prothrombin time would be in patients with liver disease and how to behave when a patient treated with VKA shows a subtherapeutic INR. These topics were discussed by a panel of experts during a workshop recently held in Milan by the Italian Federation of Centres for the Diagnosis of Thrombosis and the Surveillance of Antithrombotic Therapies (FCSA). The main aim of the workshop was to provide helpful and practical advice to physicians in the daily management of VKA.

Multivariate analysis of the relation between diet and warfarin dose.

PURPOSE: The vitamin K antagonist (VKA) warfarin is effective for the prevention of thromboembolisms. Maintenance doses differ greatly among patients and are known to be primarily determined by genetic polymorphisms. The relative impact of dietary vitamin K intake is still a matter of debate. We hypothesize that a multivariate model is more suitable for exploring the relation between dietary intake of vitamin K and warfarin dose than conventional uni- or bivariate analyses. METHODS: In a cross-sectional study, we interviewed 244 patients in the maintenance phase of warfarin therapy and detected polymorphisms in the VKORC1 and CYP2C9 genes. Dietary vitamin K intake was estimated from food frequency questionnaires. RESULTS: A univariate correlation analysis and the regression coefficient from the multivariate model showed a small but significant negative relation between vitamin K intake and warfarin dose. A loading plot of the partial least squares regression model illustrated this counter-intuitive observation, which might be explained by the latent structure between variables. The variation in warfarin dose could be divided into two significant latent variables, the so-called components. In component one, pharmacogenetics explained 52% of dose variation. Component two described health-related behavior (diet, physical activity and body weight) and explained 8% of dose variation. Here, vitamin K intake positively correlated with warfarin dose. DISCUSSION: This study highlights the importance of choosing a statistical method that reflects the complexity of data for interpretation of results from observational studies. The multivariate model appears to be well suited to describe the complex relationship between vitamin K intake and VKA dose.

Could geriatric characteristics explain the under-prescription of anticoagulation therapy for older patients admitted with atrial fibrillation? A retrospective observational study.

BACKGROUND: Anticoagulation therapy with anti-vitamin K (AVK; vitamin K antagonist) for the prevention of thromboembolism in patients with atrial fibrillation (AF) is based on information derived from numerous well constructed, randomized controlled trials. Despite this conclusive evidence of efficacy, several studies have shown that 'real world' use of AVK in patients with AF is suboptimal. Our hypothesis was that geriatric characteristics (functional impairment, cognitive disorders, malnutrition, risk for falls, depression) could be an explanation for the underprescription of AVK in older patients with AF. OBJECTIVE: To analyse the barriers to the prescription of AVK therapy, with special attention on geriatric characteristics. METHODS: This was a retrospective study of 768 consecutive geriatric patients admitted to an acute geriatric unit of an academic hospital between April 2006 and November 2008. Data from comprehensive geriatric assessments were collected from computerized medical charts. RESULTS: Analysis of data from the 768 medical charts showed that 111 patients (14%) presented with AF. Among the 111 patients (72% women), 45% were living in an institution before admission. These patients presented a high prevalence of geriatric syndromes: cognitive disorders 59%, malnutrition risk 59%, incontinence 35%, depression 37%, and falls 61%. Ninety percent of the patients had an Identification of Seniors At Risk (ISAR) questionnaire score ≥2, which indicates an increased risk of frailty and functional decline during hospitalization. The prevalence of conditions measured by the CHADS(2) (congestive heart failure, hypertension, age >75 years, diabetes mellitus and previous stroke or transient ischaemic attack [TIA]) clinical prediction scale was as follows: heart failure 19%, hypertension 79%, age >75 years 95%, diabetes 15% and stroke 24%. The mean ± SD number of daily classes of drugs received at admission was 7.1 ± 3.3 (median 7, range 0-20). Forty-nine percent of patients had not received any AVK treatment before admission. The level of functional dependence for basic and instrumental activities of daily living did not differ between patients receiving AVK before admission and those not receiving AVK. Similarly, the proportion of geriatric problems (cognitive, malnutrition, depression and falls) did not differ between these two groups. To determine whether the decision to administer AVK therapy before admission was influenced by the risk of an embolic stroke, determined by the presence of CHADS(2) conditions, we compared the proportions of patients who fulfilled those conditions in each group: again, no difference was found. CONCLUSIONS: Almost half of the patients presenting with AF did not receive any AVK therapy before admission. In this population, in which most patients had multiple impairments, no single impairment or geriatric characteristic was identified as a barrier to AVK use. It is possible that combinations of impairments and geriatric characteristics were barriers to the prescription of AVK therapy across the whole of this population. More research is needed to identify and clarify the relative importance of patient-, physician- and healthcare system-related barriers to the prescription of AVK therapy in older patients with AF.

Hypercalciuria and nephrolithiasis on long-term follow-up of pseudo-vitamin D deficiency rickets.

A case of pseudovitamin D deficiency (Vitamin D dependent rickets type I) is presented, who initially responded to physiological doses of calcitriol but developed nephrolithiasis and hypercalciuria around puberty. Hypercalciuria was corrected after stopping calcitriol. Pseudo vitamin D deficiency rickets also called vitamin D dependent rickets type I (VDDR 1) is an uncommon cause of rickets. Patients appear normal at birth and manifests with signs between the ages of two months to two years. Muscle weakness is prominent, radiographic features are striking and response to calciferols is complete. Hypercalciuria and nephrolithiasis are uncommon in the untreated disease but can develop due to overtreatment with calcitriol or oral calcium. Here we report a patient who developed hypercalciuria and nephrolithiasis around puberty while on maintenance dose of calcitriol and oral calcium.

Sevelamer reduces the efficacy of many other drugs.

(1) Sevelamer, a phosphate-binding polymer, is used to treat hyperphosphataemia in patients with chronic renal failure. Pharmacokinetic studies and some clinical reports have shown that sevelamer binds many drugs, including furosemide, ciclosporin and tacrolimus, thus making them less effective; (2) It is best to take sevelamer some time before or after other drugs.

High-dosage pyridoxine-induced auditory neuropathy and protection with coffee in mice.

Auditory neuropathy (AN) is a hearing disorder characterized by an abnormal auditory brainstem response (ABR). This study examined experimental AN model induced in mice following increased dosages of pyridoxine. Induced AN was examined for < or =10 weeks following the last pyridoxine treatment. To assess AN, we evaluated the ABR, auditory middle latency response (AMLR), otoacoustic emission (OAE), and histochemical morphology of the auditory nerve. Pyridoxine-treated mice exhibited an increase in the hearing threshold shift and delayed latency of both ABR and AMLR in proportion to pyridoxine dosage. Additionally, the extent of auditory nerve fiber loss increased in a dose-dependent manner following pyridoxine intoxication. Coffee or trigonelline treatment ameliorated the hearing threshold shift, delayed latency of the auditory evoked potential, and improved sensory fiber loss induced by pyridoxine intoxication. The present findings demonstrate that high-dose pyridoxine administration can be used to produce a new mouse model for AN, and coffee or trigonelline as a main active compound of coffee extract can potentially facilitate recovery from pyridoxine-induced auditory neuropathy.

[Hemorrhagic complications of anti-vitamin K]. / Complications hémorragiques des anti vitamine K: enquête de prévalence aux urgences du CHU de Grenoble.

Adverse events related to oral anticoagulants represent a major public health problem. Hemorrhagic episodes are the most frequent complications and can be life-threatening. A 10 month prospective survey on all cases treated with anti-vitamin K (AVK), and admitted to emergency room of CHU Grenoble, was conducted to identify the hemorrhagic adverse drug events (HADE). The evaluation support was a directive questionnaire and consisted of 3 parts: patient characteristics, patient's medicated treatment and the hemorrhagic event. 216 patients treated with AVK were identified and 68 of them presented a hemorrhagic adverse drug event. 60 patients older than 65 years out of 158, presented HADE (38%); versus 8 patients < or = 65 years out of 58 (RR = 2.75; p = 0.0007). Among the patients who have their INR > or = 5, 79% developed HADE versus 16% in the group who had their INR < 5 (< 0.0001). In the group of patients who had a change in drug therapy within the 7 days preceding their admission, 47% developed HADE versus 25% of patients whose treatment was not modified: Anti-microbial agents were the drug most frequently involved. The patient's knowledge of INR value and signs of excess AVK were significant. Concerning missed dose, 48 patients declared taking the missed dose with the next dose or when they remembered: 35% of them developed HADE (p = 0.49).

Anticoagulación preventiva: ejemplo de análisis de riesgo/beneficio / No disponible

No disponible

Correction of coagulopathy in warfarin associated cerebral hemorrhage.

PURPOSE OF REVIEW: Warfarin is the most commonly used oral anticoagulant. Intracranial hemorrhage is the most serious complication of anticoagulation and the anticoagulant effect of warfarin has to be urgently reversed in this situation. Traditional methods of reversal of the anticoagulant effect of warfarin involving the use of vitamin K and fresh frozen plasma are slow and relatively ineffective and there is a need for alternative treatment approaches. RECENT FINDINGS: Agents such as prothrombin complex conjugates and recombinant activated factor VII are being increasingly used to emergently correct warfarin-associated coagulopathy. Over the last decade, several small case series have suggested that these agents may lead to more rapid correction of the INR, however, improved clinical outcome is yet to be proven. A recent small prospective trial has also demonstrated the safety of a prothrombin complex conjugate and its efficacy in rapidly correcting an elevated INR in these patients. SUMMARY: There is a need for well designed randomized clinical trials aimed at evaluating the efficacy of these agents in improving the outcome of patients with anticoagulant associated intracranial hemorrhage.

How should we determine length of anticoagulation after proximal deep vein thrombosis of the lower limbs?

The current approach for deciding the duration of vitamin K antagonist (VKA) treatment after an episode of venous thrombo-embolism (VTE) is mainly based on the characteristic of the index event (3 months or longer in case of unknown/persistent risk factors, 3 months or less in case of removable causes). However, the length of anticoagulation should be tailored on the patient's risk for recurrent thrombosis as well as for bleeding, but such 'time for decision' is often unclear and the optimal duration of VKA remains debatable. The presence of persistent residual vein thrombosis and increased D-dimer levels after stopping therapy are predictors for recurrent deep vein thrombosis (DVT). Management strategies based on these parameters have been demonstrated to optimize the decision for VKA duration, as they establish the patient's intrinsic risk for recurrent events. This annotation discusses current practice and upcoming approaches regarding the length of VKA treatment after a first episode of DVT.

Algunos aspectos antinutritivos de los alimentos / Some anti-nutritive aspects of foods

En la composición del alimento, aparte de las sustancias nutritivas, se encuentran otras sustancias consideradas antinutritivas. El interés que existe por estas sustancias es que hacen disminuir el valor nutritivo del alimento y pueden resultar peligrosas para el consumidor cuando la dieta es a base de alimentos de origen vegetal. Constituyen un grupo muy variado desde el punto de vista de su estructura química, por lo que su clasificación se realiza en función de los grupos de nutrientes con los que interfiere. En el artículo se hace una revisión de los inhibidores enzimáticos que afectan a la utilización digestiva de proteínas y carbohidratos, de las sustancias que interfieren total o parcialmente la asimilación de minerales (sustancias bociógenas, ácido oxálico y ácido fítico), de las antivitaminas y de los compuestos con actividad polivalente (taninos y fibra). Estas sustancias actúan interfiriendo la utilización y función metabólica de nutrientes esenciales, en el tracto gastrointestinal, en los tejidos e incluso en el propio alimento; pero al encontrarse en pequeñas proporciones, es preciso consumir grandes cantidades durante mucho tiempo para producir efectos adversos. El tratamiento culinario inactiva muchas de estas productos antinutritivos, por lo que no suelen presentar un riesgo serio para la salud en los países desarrollados. Los alimentos de consumo habitual contienen diversas sustancias antinutritivas, y su presencia en el alimento se debe tener en cuenta cuando se ingieren dietas deficientes, en países subdesarrollados, conflictos bélicos o en individuos malnutridos (AU)