Influence of CYP2C9 polymorphism on the fall in International Normalized Ratio in patients interrupting warfarin therapy before elective surgery.

BACKGROUND: Patients on warfarin are normally required to stop treatment for a fixed number of days prior to an invasive procedure. However, the anticoagulant activity of warfarin subsides at different rates among different patients. OBJECTIVES: The aim of this study was to investigate the potential influence of CYP2C9 polymorphism on the variable rate of fall in the International Normalized Ratio (INR) in patients withdrawing from warfarin treatment prior to elective surgery. PATIENTS/METHODS: One hundred and fifty-two patients aged 43-93 years were recruited. Demographic data on age, height, weight, gender, daily warfarin dose, indication for anticoagulation therapy, medical diagnosis, surgical operation planned and concomitant medication were recorded. A blood sample was taken for later CYP2C9 genotyping. RESULTS: For patients with two CYP2C9 variant alleles (CYP2C9*2*2 or CYP2C9*2*3), the odds of having an INR of ≥ 1.5 before the planned day of surgery were 8.64 times greater (95% confidence interval [CI] 2.25-33.25) than for other patients. Multiple regression analysis revealed that the rate of fall in the INR was reduced in the presence of two CYP2C9 variant alleles, as well as increasing patient age, weight and number of comorbidities, and increased with increasing initial INR (F5,132  = 242.9, P < 0.0001), all of which accounted for ~ 90% of the interindividual variability in the fall in INR. CONCLUSION: A genotype-guided protocol to tailor warfarin withdrawal according to an individual patient's CYP2C9 genotype could reduce cancellation or delays of planned procedures, and could also be beneficial when transitioning patients from warfarin to one of the new oral anticoagulants.

The influence of slope and peatland vegetation type on riverine dissolved organic carbon and water colour at different scales.

Peatlands are important sources of fluvial carbon. Previous research has shown that riverine dissolved organic carbon (DOC) concentrations are largely controlled by soil type. However, there has been little work to establish the controls of riverine DOC within blanket peatlands that have not undergone major disturbance from drainage or burning. A total of 119 peatland catchments were sampled for riverine DOC and water colour across three drainage basins during six repeated sampling campaigns. The topographic characteristics of each catchment were determined from digital elevation models. The dominant vegetation cover was mapped using 0.5m resolution colour infrared aerial images, with ground-truthed validation revealing 82% accuracy. Forward and backward stepwise regression modelling showed that mean slope was a strong (and negative) determinant of DOC and water colour in blanket peatland river waters. There was a weak role for plant functional type in determining DOC and water colour. At the basin scale, there were major differences between the models depending on the basin. The dominance of topographic predictors of DOC found in our study, combined with a weaker role of vegetation type, paves the way for developing improved planning tools for water companies operating in peatland catchments. Using topographic data and aerial imagery it will be possible to predict which tributaries will typically yield lower DOC concentrations and which are therefore more suitable and cost-effective as raw water intakes.

Decreased thalamic blood flow in obsessive-compulsive disorder patients responding to fluvoxamine.

Functional imaging studies have pointed to a role of the orbitofrontal cortex (OFC), striatum and thalamus in the pathophysiology of obsessive-compulsive disorder (OCD). Effective treatment has been found to change brain activity within this circuitry. The aim of the present study was to explore possible differential effects of OCD responders and non-responders to drug treatment on the regional cerebral blood flow (rCBF). Measurements of rCBF were carried out in 15 out of 22 patients with OCD who completed an open-label trial with fluvoxamine. Patients were studied with 99mTc-HMPAO single photon emission computed tomography (SPECT) before and after 12 weeks of treatment. In addition, structural magnetic resonance imaging was obtained on all patients. Regions of interest comprised the OFC, caudate nucleus, putamen and thalamus. Seven patients responded to treatment. Levels of rCBF decreased significantly in the left caudate nucleus and the left and right putamen in both responders and non-responders to treatment. In responders, but not in non-responders, a significant decrease in rCBF was found in the right thalamus. Pre-treatment cerebellar and whole brain HMPAO uptake was significantly higher in responders to treatment compared with non-responders. We suggest that the thalamus plays a central role in the response to drug treatment.

Dietary vitamin K influences intra-individual variability in anticoagulant response to warfarin.

The relationship between dietary intake of vitamin K, fat, plasma vitamin K concentrations and anticoagulation response to warfarin within individuals, as well as the contribution of dietary vitamin K to differences in warfarin dose requirements between individuals were investigated in 53 patients on warfarin therapy who had stably controlled anticoagulation. Each patient completed a dietary record of all foods consumed on a daily basis for 4 weeks. Each week a blood sample was taken for measurement of the international normalized ratio (INR), plasma vitamin K, triglycerides and warfarin enantiomer concentrations. The patients' genotype for CYP2C9 was also determined. Regression analysis of the data showed that, for each increase of 100 microg in the daily dietary intake of vitamin K averaged over 4 d, the INR was reduced by 0.2. There was no correlation between warfarin daily dose and average daily dietary vitamin K intake when calculated over 28 d. The regression model for warfarin dose showed that, while dietary vitamin K had no effect, CYP2C9 genotype (P = 2%) and age (P < 1%) significantly contributed to inter-patient variability in warfarin dose requirements. A consistent intake of vitamin K could reduce intrapatient variability in anticoagulation response and thus improve the safety of warfarin therapy.

Long-lasting analgesic effect of radiofrequency treatment of the lumbosacral dorsal root ganglion.

OBJECT: The authors conducted a study to establish the benefit of radiofrequency (RF) treatment of the lumbosacral dorsal root ganglion (DRG) as a therapy to reduce symptomatic pain in patients with chronic spinal pain radiating to the leg. METHODS: Two hundred seventy-nine patients were evaluated after undergoing their first RF treatment of the DRG. A four-point pain perception scale was used. Short-term effect was documented after 2 months. The influence of surgical history on outcome was examined by using chi-square analysis. The mean duration of analgesic effect was calculated by applying a probit survival analysis. Two months after undergoing RF treatment, 59% of patients reported satisfactory pain reduction. No serious adverse effects were noted. Surgical history was shown to have no significant effect on outcome. The long-term half-life time of pain reduction was 44.5 months. CONCLUSIONS: The use of RF in the treatment of DRG appears to be a useful and safe therapy in patients with chronic spinal pain that radiates to the leg. The initial success rate is approximately 60%. It seems to lead to a time-limited effect on the target structure, and the mean duration of pain reduction is approximately 3.7 years. The mechanism of action remains unclear.

Temporal variations in plasma vitamin K and lipid concentrations and clotting factor activity in humans.

There is no information available on temporal variability in plasma vitamin K concentrations and its relationship to coagulation processes. We investigated the possible existence of temporal changes in plasma vitamin K and lipid concentrations and activity of clotting factors II, VII, IX, and X and relationships between these variables. Plasma vitamin K and lipid concentrations and clotting factor activity were measured at four-hour intervals for 28 hours in a group of healthy volunteers. Temporal variations existed in plasma vitamin K concentrations, with a mean maximum at 22:00 hr and a mean minimum (32% of the maximum) at 10:00 hr. Plasma triglycerol concentrations mirrored the changes in vitamin K concentrations. Mean factor VII activity was positively correlated with mean total plasma cholesterol concentrations (r = 0.714; P < 0.0001) and with mean plasma low density lipoprotein (LDL) cholesterol concentrations (r = 0.461; P < 0.0001). No distinct correlations were found between plasma vitamin K concentrations and either high density lipoprotein (HDL) or LDL cholesterol concentrations, or between triglycerol, HDL, or LDL cholesterol concentrations and functional activity of factors II, IX, and X. Plasma vitamin K concentrations did not correlate with the functional activity of any of the clotting factors. The presence of a correlation between plasma cholesterol concentrations and factor VII activity for blood samples collected at four-hour intervals suggests that plasma cholesterol concentrations may have a more acute effect on factor VII activity. Temporal variations in plasma vitamin K concentrations indicate that a single time point measurement may be an inappropriate method of establishing vitamin K status in an individual.

The influence of (R)- and (S)-warfarin, vitamin K and vitamin K epoxide upon warfarin anticoagulation.

The contribution of (R)- and (S)-warfarin enantiomers, vitamin K and vitamin K epoxide and patient factors to inter-individual variability in daily warfarin requirements were examined in a group of 73 patients. Simple correlation analysis showed a significant positive relationship between INR values and plasma (S)-warfarin concentrations (r = 0.25; p = 0.038). Multivariate analysis for relationships with INR demonstrated a highly significant positive relationship between INR and (S)-warfarin (p = 0.004) and plasma vitamin K epoxide concentrations (p = 0.028), and a significant negative relationship between INR and plasma vitamin K concentrations (p = 0.034). Twenty five percent of variation in INR could be explained by these variables (adjusted R2 = 0.25). Correlation analysis of data showed that warfarin dosage was significantly and negatively correlated with patient age (r = -0.42; p <0.0001). Patient age accounted for 25% of variation in warfarin dosage requirements (R2 = 0.25). The combined effects of age and vitamin K appear to account for much of the inter-individual variability in warfarin dosage requirements.

Prescription and usage of long-term oxygen therapy in patients with chronic obstructive pulmonary disease in The Netherlands.

Long-term oxygen therapy (LTOT) has been shown to improve survival in hypoxaemic patients with chronic obstructive pulmonary disease (COPD). This has resulted in recommending the prescription of oxygen for at least 15 h day-1 in most European countries. In order to examine the prescription and usage of LTOT and to assess the adherence to international recommendations for its prescription, a survey was set up in a random sample of clients of the largest oxygen company in the Netherlands. After patients had been visited for an interview, additional postal surveys were sent to the physician who had prescribed LTOT and to the oxygen company. For 175 COPD patients the mean oxygen prescription and mean oxygen usage were 15.6 +/- 5.8 and 14.1 +/- 6.8 h day-1, respectively. In 62 patients (35%) oxygen was prescribed < 15 h day-1, more often by non-chest physicians than by chest physicians (P < 0.0001), and 91 patients (52%) used oxygen < 15 h day-1. Of 113 patients with a prescription > or = 15 h day-1, 39 (35%) used oxygen < 15 h day-1 and 74 for > or = 15 h day-1. The latter were prescribed oxygen for more h day-1, had been longer on LTOT, had a higher resting flow rate, were prescribed a concentrator, employed portable cylinders and used oxygen in public significantly more often than the former. We conclude that in a selected group of LTOT patients with COPD both oxygen prescription and usage were often inadequate, particularly if LTOT was prescribed by non-chest physicians.

D-cycloserine increases positive symptoms in chronic schizophrenic patients when administered in addition to antipsychotics: a double-blind, parallel, placebo-controlled study.

A hypofunction of the glutamatergic system and NMDA receptors in schizophrenia has been hypothesized. Therefore, stimulation of these receptors could be of benefit to patients with schizophrenia. D-cycloserine has been used for this purpose. This study reports the effects of 100 mg D-cycloserine, when added to typical antipsychotics in chronic schizophrenic patients exhibiting prominent negative symptoms, using a placebo-controlled, double-blind, parallel, design. D-cycloserine slightly worsened psychotic symptoms and general psychopathology as compared to placebo. D-cycloserine failed to change negative symptoms and had no effect on extrapyramidal symptoms. The exacerbation of schizophrenic symptoms may be explained by the antagonistic effects of this dose of D-cycloserine at the glycine recognition site of the NMDA receptor due to competition with the endogenous agonist glycine. Another explanation for the increase in psychopathology may be an interaction with the effects of antipsychotics on NMDA mediated neurotransmission. Thus, D-cycloserine in this study did not ameliorate schizophrenic symptoms. However, the fact that they actually worsened suggests that NMDA systems may be involved in the pathogenesis of schizophrenia. Further placebo-controlled studies with lower dosages of D-cycloserine, preferably in drug-free patients, are necessary to evaluate if D-cycloserine is of use for the treatment of patients with schizophrenia.