Amiodarone, an iodinated benzofuran derivative, introduced in 1960's as an anti-anginal agent, emerged as a potent anti-arrhythmic agent by 1970's and is currently one of the most commonly prescribed drugs in US for ventricular and atrial arrhythmias. Although amiodarone is considered a class III anti-arrhythmic agent, it also has class I, II, IV actions, making it a unique and effective anti-arrhythmic agent. Because of its minimal negative inotropic activity and very low rate of pro-arrhythmia, it is considered safe in treating arrhythmias in patients with Coronary Artery Disease and Left ventricular systolic dysfunction. Despite these advantages, long term oral therapy with amiodarone is limited by side effect profile involving various organs like thyroid, lung, heart, liver, skin etc. Though the side effects can be decreased significantly by keeping the maintenance dose at 200 to 300 mg/day, patients on amiodarone should be followed closely. Amiodarone interacts with medications such as Warfarin, Digoxin, Macrolides, Floroquinolones etc., which share Cytochrome P450 metabolic pathway. Hence reducing their doses prior to starting amiodarone is recommended. Amiodarone, a category D drug, is contraindicated in pregnant and breast feeding women. This review discusses the pharmacokinetics of amiodarone, its evolving clinical indications, management of toxicity and drug interactions. less...

Natural phenolic compounds play an important role in cancer prevention and treatment. Phenolic compounds from medicinal herbs and dietary plants include phenolic acids, flavonoids, tannins, stilbenes, curcuminoids, coumarins, lignans, quinones, and others. Various bioactivities of phenolic compounds are responsible for their chemopreventive properties (e.g., antioxidant, anticarcinogenic, or antimutagenic and anti-inflammatory effects) and also contribute to their inducing apoptosis by arresting cell cycle, regulating carcinogen metabolism and ontogenesis expression, inhibiting DNA binding and cell adhesion, migration, proliferation or differentiation, and blocking signaling pathways. This review covers the most recent literature to summarize structural categories and molecular anticancer mechanisms of phenolic compounds from medicinal herbs and dietary plants. less...

BACKGROUND: Warfarin has been widely used for the prevention and treatment of thromboembolism. Warfarin therapy depends on interaction between physiological, environmental, and genetic factors. Vitamin K epoxide reductase (VKORC1) and cytochrome P450 2C9 (CYP2C9) enzyme conjointly determine the warfarin maintenance dose. The prevalence of CYP2C9 and VKORC1 variants varies among ethnic groups. The purpose of the present study was to investigate the prevalence of CYP2C and VKORC1 in the Northern Thai population. MATERIAL AND METHOD: Patients with valvular heart disease who regularly took a steady maintenance warfarin dose for at least one month were recruited into the present study. Patients who had taken amiodarone or an anti-inflammatory drug were excluded Clinical data were obtained from medical records. Five milliliters of whole blood was drawn from each patient for gene analysis and prothrombin time with international normalized ratio (INR) measurement. RESULTS: From 242 patients, CYP2C9 *1/*1 was found in 230 patients (95%) and CYP2C9 *1/*3 was found in 12 patients (5%). Neither mutant CYP2C9*2 allele nor individuals homozygous for CYP2C9*3 were observed. Regarding VKORC1, haplotype AB was found in 83 patients (34.3%) and haplotype AA was found in 154 patients (63.6%). Haplotype BB (wild type) was found in five patients (2.1%). CONCLUSION: The prevalence of CYP2C9 *1/*1 is high while the prevalence of CYP2C9*2 and CYP2C9*3 is very low. VKORC1 haplotype AA is the most common among the Northern Thai population. Further study regarding pharmacogenetic and non-genetic factors to develop warfarin-dosing algorithm is warranted less...

PURPOSE: The case of a patient whose International Normalized Ratio (INR) increased with concurrent use of ophthalmic erythromycin and warfarin is reported. SUMMARY: A 77-year-old Caucasian woman began therapy with warfarin for thromboembolism prophylaxis secondary to atrial fibrillation (target INR, 2-3). Warfarin was prescribed by her cardiologist, and care was established with clinical pharmacists in an anticoagulation clinic. She was receiving a weekly maintenance dosage of 14 mg. She had a history of atrial fibrillation, hyperlipidemia, osteoarthritis, hypothyroidism, coronary artery disease, myocardial infarction, congestive heart failure, and breast cancer. In addition to warfarin, the patient had been receiving alprazolam, carvedilol, furosemide, levothyroxine sodium, lisinopril, nitroglycerin, potassium chloride, propoxyphene hydrochloride- acetaminophen, simvastatin, and trazodone. After receiving warfarin at the same weekly dosage for over four months, the patient's ophthalmologist prescribed erythromycin ophthalmic ointment for chronic bacterial conjunctivitis. Three weeks later, her INR was found to be 8.5. A total of four warfarin doses were withheld, and her weekly maintenance dosage of warfarin was subsequently decreased to 12 mg. Five weeks later, her INR was 1.5, and it was determined that the erythromycin ophthalmic ointment had been discontinued five days prior. Her weekly maintenance dosage of warfarin was increased to 16 mg. Rechallenge with erythromycin five days before her next INR measurement resulted in an INR of 4.2. A new weekly maintenance dosage of 13 mg was established, and her subsequent INRs were within normal range. CONCLUSION: An increase in INR values was reported after initiation of ophthalmic erythromycin in a patient receiving warfarin and recurred upon rechallenge with ophthalmic erythromycin. less...

BACKGROUND AND PURPOSE: Evidence of atrial tachycardia/atrial fibrillation (AT/AF) is often sought in patients with ischemic stroke or transient ischemic attack. We studied patients with previous thromboembolic events (TE) who were implanted with devices capable of continuous arrhythmia monitoring to comprehensively quantify the incidence and duration of newly detected AT/AF. METHODS: This study represents a subgroup analysis of the TRENDS trial, which included patients with clinical indications for pacemakers or defibrillators and >/=1 stroke risk factors (heart failure, hypertension, age 65 or older, diabetes, or previous TE). A history of AF was not required. All implanted devices were capable of continuously monitoring the cumulative time spent in AT/AF each day. This analysis focuses primarily on the incidence and duration of newly detected AT/AF (defined as >/=5 minutes of AT/AF on any day) in patients with previous TE, no documented history of AF, and no warfarin or antiarrhythmic drug use. RESULTS: A total of 319 patients had a history of TE and >/=1 day of device data. Patients with a documented history of AF (n=80), warfarin use (n=56), or antiarrhythmic drug use (n=20) were excluded from analysis. Of the remaining 163 patients, newly detected AT/AF was identified via the device in 45 patients (28%) over a mean follow-up of 1.1+/-0.7 years. AT/AF recurred infrequently, with only 12 patients experiencing AT/AF on >10% of follow-up days. CONCLUSIONS: Newly detected episodes of AT/AF were found via continuous monitoring in 28% of patients with previous TE. Most episodes would not have been detected by standard intermittent monitoring techniques. less...

BACKGROUND AND PURPOSE: Secondary expansion of hematoma after spontaneous intracerebral hemorrhage occurs frequently and early with the potential sequelae of functional deterioration or death. The aim of this topical review is to give a summary of current evidence- and experience-based options to avoid or attenuate hematoma expansion. Method-We reviewed the literature of the past 10 years on efforts to restrict spontaneous intracerebral hemorrhage expansion by searching Medline and adding related articles known to us. Based on evidence, current guidelines, and our own clinical practice, we have collected consistent and inconsistent pieces of data. These were differentiated according to surgical versus medical approaches, weighed and discussed with regard to expectable benefit, potential risk, and practicability. Finally, we have outlined promising future approaches. RESULTS: Although consistent evidence on the topic is generally limited, some important studies have provided data on risk factors predicting spontaneous intracerebral hemorrhage expansion implying ways of directing therapy toward these risk factors. Large trials have shed light on 4 major efforts to avoid hematoma expansion: surgical hematoma treatment, reduction of hypertension, reversal of coagulopathies or anticoagulants, and hemostatic therapy. The results were largely disappointing but provide insights for new trials. Future strategies include the combination of surgical and medical treatment and the use of neuroprotectants. CONCLUSIONS: Early restriction of intracerebral hemorrhage is of paramount importance because secondary volume expansion leads to outcome deterioration and death. Although there appear to be few indications for neurosurgical measures, nonsurgical measures such as reduction of hypertension and normalization of altered coagulation seem to be beneficial. However, the routine use of coagulation factors outside of warfarin-associated spontaneous intracerebral hemorrhage cannot generally be recommended at present. The same applies for future approaches such as combined medical-surgical approaches and neuroprotective therapies at this point. less...

Oral anticoagulation with warfarin is a widely used form of treatment for an increasing number of medical conditions. Nevertheless, appropriate therapeutic monitoring and dosage readjustments should be carried out in order to ensure its safety and efficacy. Although prothrombin time (usually expressed as International normalized ratio [INR]) is the most common warfarin response marker, clotting factors (namely factors II and X) are also indicated as alternative anticoagulant effect markers. In this paper, we examine the relationship between these warfarin response markers using information obtained from eighty 80 patients undergoing long-term warfarin therapy. Within the usual INR therapeutic range (2.0-3.5), a moderate inverse correlation between INR and both clotting factors II and X was observed. However, for INR values above 3.5, a non-proportional relationship were found between INR and both response markers. Therefore, it can be concluded that below critical clotting factor concentrations (20.6% and 15.6% of factors II and X activity, respectively), time required for clot formation becomes non-proportional and haemostasis will be jeopardised. less...

BACKGROUND: Warfarin is a widely used oral anticoagulant with broad within- and between-individual dose requirements. Warfarin concentrations can be monitored by assessing its pharmacologic effects on International Normalized Ratio (INR). However, this approach has not been applied in the routine clinical management of patients receiving warfarin therapy. We performed a plasma warfarin assay using high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) to determine if such an assay can be utilized in routine clinical practice. METHODS: We included a total of 105 patients with atrial fibrillation, and who were receiving warfarin for more than 1 yr. The plasma concentrations of total warfarin and 7-hydroxywarfarin were determined by HPLC-MS/MS (Waters, UK). We assessed the association between warfarin dose, concentration, and INR as well as the effects of these factors on warfarin concentrations. RESULTS: The mean maintenance dose of warfarin in 105 patients was 4.1 +/-1.3 mg/day (range, 1.7-8.0 mg/day) and their mean plasma warfarin concentration was 1.3+/-0.5 mg/L. We defined a concentration range of 0.6-2.6 mg/L (corresponding to the 2.5th to 97.5th percentile range of the Plasma warfarin levels in the 74 patients showing INR within target range) as the therapeutic range for warfarin. The correlation of warfarin dose with warfarin concentration (r(2)=0.259, P<0.001) was higher than that with INR (r(2)=0.029, P=0.072). CONCLUSIONS: There was a significant correlation between warfarin dose and plasma warfarin concentrations in Korean patients with atrial fibrillation. Hence, plasma warfarin monitoring can help determine dose adjustments and improve our understanding of individual patient response to warfarin treatment. less...

Satisfactory results have not yet been obtained in therapy for secondary prevention in ischemic stroke patients with antiphospholipid syndrome (APS). We therefore compared single antiplatelet therapy and a combination of antiplatelet and anticoagulation therapy for secondary prevention in ischemic stroke patients with APS.The subjects were 20 ischemic stroke patients with antiphospholipid antibody, 13 with primary antiphospholipid syndrome and 7 with SLE-related antiphospholipid syndrome. Diagnosis of APS was based on the 2006 Sydney criteria. Eligible patients were randomly assigned to either single antiplatelet therapy (aspirin 100 mg) or a combination of antiplatelet and anticoagulation therapy (target INR: 2.0-3.0; mean 2.4+/-0.3) for the secondary prevention of stroke according to a double-blind protocol. There was no significant difference between the two groups in age, gender, NIH Stroke Scale on admission, mRS at discharge, or rate of hypertension, diabetes mellitus, hyperlipidemia, or cardiac disease. We obtained Kaplan-Meier survival curves for each treatment. The primary outcome was the occurrence of stroke. The mean follow-up time was 3.9+/-2.0 years. The cumulative incidence of stroke in patients with single antiplatelet treatment was statistically significantly higher than that in patients receiving the combination of antiplatelet and anticoagulation therapy (log-rank test, p-value=0.026). The incidence of hemorrhagic complications was similar in the two groups. The recent APASS study did not show any difference in effectiveness for secondary prevention between single antiplatelet (aspirin) and single anticoagulant (warfarin) therapy. Our results indicate that combination therapy may be more effective in APS-related ischemic stroke. less...

Study design:Systematic review.Objective:To conduct a systematic review of the effectiveness of interventions used to prevent and treat heterotopic ossification (HO) after spinal cord injury (SCI).Setting:St Joseph's Parkwood Hospital, London, Ontario, Canada.Methods:MEDLINE, CINAHL, EMBASE and PsycINFO databases were searched for articles addressing the treatment of HO after SCI. Studies were selected by two reviewers and were only included for analysis if at least 50% of the subjects had an SCI, there were at least three SCI subjects and if the study subjects participated in a treatment or intervention. Study quality was assessed by two independent reviewers using the Downs and Black evaluation tool for all studies, as well as the PEDro assessment scale for randomized control trials only. Levels of evidence were assigned using a modified Sackett scale.Results:A total of 13 studies met the inclusion criteria. The selected articles were divided into prevention or treatment of post-SCI HO. Nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin, and pulse low-intensity electrogmagnetic field (PLIMF) therapy were reviewed as prophylactic measures. Bisphosphonates, radiotherapy and excision were reviewed as treatments of post-SCI HO.Conclusions:Pharmacological treatments of HO after SCI had the highest level of research evidence supporting their use. Of these, NSAIDs showed greatest efficacy in the prevention of HO when administered early after an SCI, whereas bisphosphonates were the intervention with strongest supportive evidence once HO had developed. Of the non-pharmacological interventions, PLIMF was supported by the highest level of evidence; however, more research is needed to fully understand its role.Spinal Cord advance online publication, 5 January 2010; doi:10.1038/sc.2009.175. less...