Antimicrobial activity produced by six dentifrices

OBJECTIVE: To examine the effect of grapefruit juice on the bioavailability of carbamazepine in patients with epilepsy. METHODS: This was a randomized crossover study consisting of 2 phases. Ten patients with epilepsy who had received therapy with 200 mg carbamazepine 3 times a day for the previous 3 to 4 weeks participated. They were given either grapefruit juice or 300 mL water at 8 am along with 200 mg carbamazepine. Each treatment was separated by 2 days; subjects continued to receive carbamazepine therapy during the 2-day period. On both occasions, blood samples were collected at different time intervals between 0 to 8 hours. Carbamazepine levels were estimated by reversed-phase HPLC technique. RESULTS: Compared with water, grapefruit significantly increased the steady peak concentration (6.55 versus 9.20 microgram/mL), trough concentration (4.51 versus 6.28 microgram/mL), and area under the plasma concentration-time curve (43.99 versus 61.95 micrograms.h/mL) of carbamazepine. No significant effect was found in the time to reach peak plasma concentration. CONCLUSION: Grapefruit juice increases the bioavailability of carbamazepine by inhibiting CYP3A4 enzymes in gut wall and in the liver.     

Low-dose oral vitamin K reliably reverses over-anticoagulation due to warfarin

BACKGROUND: Patients receiving long-term warfarin frequently develop asymptomatic excessive prolongation of their international normalized ratio (INR) results. The most appropriate management strategy in these patients is unknown. This prospective cohort study was designed to address whether 1 mg of oral vitamin K effectively reduces the INR value of such patients. METHODS: A prospective cohort study was performed in two tertiary care teaching hospitals, in which 62 patients receiving warfarin who had INR values between 4.5 and 10.0 received 1 mg of oral vitamin K. All patients had daily INR values and clinical assessments performed. RESULTS: The mean INR value at presentation was 5.79 (95% confidence interval (CI) 5.48 to 6.09, range 4.5 to 9.5). Sixteen hours after receiving the 1 mg of oral vitamin K, the mean INR was 2.86 (95% CI 2.50 to 3.23). On the second and third days after vitamin K, the mean INR values were 2.20 (1.93 to 2.47) and 2.14 (1.85 to 2.44), respectively. No adverse events or bleeding complications were observed. In three patients (6%) the INR value rose between the time of vitamin K administration and the next INR determination; two patients received a further 2 mg dose of subcutaneous vitamin K. CONCLUSIONS: In patients receiving warfarin who have asymptomatic excessive prolongations in their INR results, 1 mg of oral vitamin K reliably reduces the INR to the therapeutic range within 24 h. This therapy is more convenient, less expensive, and might be safer than parenteral vitamin K. Thus, it should be considered in all non-bleeding patients receiving warfarin, who present with INR results of 4.5 to 9.5.     

Retrospective and prospective analyses of the treatment of overanticoagulated patients

STUDY OBJECTIVE: To compare withholding warfarin therapy with low-dose (2.5 mg) oral vitamin K therapy in excessively anticoagulated patients without bleeding complications. DESIGN: Prospective and retrospective studies. SETTING: Anticoagulation clinic at a Veterans Affairs institution. PATIENTS: Twenty-eight men were matched according to initial international normalized ratio (INR) and INR goal ranges. INTERVENTIONS: The retrospective arm of the study consisted of chart reviews of overanticoagulated patients whose warfarin doses were held until therapeutic INR values were reached. The prospective arm included overanticoagulated patients who were administered a single 2.5-mg dose of oral vitamin K. MEASUREMENTS AND MAIN RESULTS: Mean days to therapeutic INR values were 2.3+/-0.6 and 1.4+/-0.6 (p=0.001), and mean reduction in INR 1 day after treatment intervention was 1.32+/-0.79 and 3.46+/-1.31 (p<001) U for the withholding and vitamin K groups, respectively. CONCLUSION: Compared with withholding the warfarin dose, administration of 2.5 mg of oral vitamin K to excessively anticoagulated patients receiving warfarin significantly reduced the time required to reach a therapeutic INR as well as final INR.     

Relationship between prothrombin activation fragment F1.2 and international normalized ratio in patients with atrial fibrillation. Stroke Prevention in Atrial Fibrillation Investigators

BACKGROUND AND PURPOSE: The prothrombin time (expressed as the international normalized ratio [INR]) is the standard method of monitoring warfarin therapy in patients with atrial fibrillation. Prothrombin activation fragment F1.2 provides an index of in vivo thrombin generation and might provide a better index of the effective intensity of anticoagulation. We examined the relationship between F1.2 and INR in patients with atrial fibrillation. METHODS: We measured INR and F1.2 levels in 846 patients with atrial fibrillation participating in the Stroke Prevention in Atrial Fibrillation III study. Two hundred nineteen (26%) were taking aspirin alone, 326 (39%) were taking adjusted-dose warfarin, and 301 (36%) were taking a low fixed dose of warfarin (1 to 3 mg) plus aspirin (combination therapy). F1.2 levels were measured with an enzyme-linked immunosorbent assay. RESULTS: Patients receiving adjusted-dose warfarin or combination therapy had significantly higher INR and significantly lower F1.2 values than those on aspirin alone (P < or = .0001 for each of the four comparisons). F1.2 values (nanomolar) were inversely correlated with INR (F1.2 = -0.1 + 2.3[1/INR]; R2 = .37; P < .0001; simple linear regression). However, significant variability remained. Among patients receiving warfarin, older patients had higher F1.2 values than younger patients after adjustment for INR intensity (P < .001) in the model. There was no difference in the relationship between F1.2 and INR between men and women. CONCLUSIONS: Increasing intensity of anticoagulation, as measured by the INR, is associated with decreasing thrombin generation as measured by the F1.2 level, but significant variability exists in this relationship. Older anticoagulated patients have higher F1.2 values than younger patients at equivalent INR values. The clinical significance of these differences is not clear. F1.2 measurement might provide information regarding anticoagulation intensity in addition to that reflected by the INR.     

Variations in prothrombin time and international normalized ratio over 24 hours in warfarin-treated patients

STUDY OBJECTIVE: To determine the variation of prothrombin times and international normalized ratio (INR) over 24 hours in humans. DESIGN: Prospective, parallel study. SETTING: University-affiliated general clinical research center. PATIENTS: Six patients receiving long-term warfarin therapy and six sex-matched controls. INTERVENTIONS: Warfarin was administered to the patients at 6:00 P.M. MEASUREMENTS AND MAIN RESULTS: Prothrombin times and INR were determined every 2 hours over 24 hours. Time of study entry, meals, and sleep cycles were controlled. A significant cosinor rhythm for prothrombin times and INR (p < or = 0.03) occurred in warfarin-treated patients, suggesting that diurnal variation occurs. The mean difference between the peak and trough prothrombin times was 1.8 +/- 0.9 seconds (range 0.8-3 sec) with a mean change of 9.3% +/- 3.7%. The peak prothrombin time and INR values occurred between 4:00 A.M. and 8:00 A.M. in five patients, and trough values between 6:00 P.M. and midnight in five. No significant cosinor rhythm was noted for controls (p > 0.5). CONCLUSION: Significant variations in prothrombin time and INR occurred in patients receiving warfarin therapy, with the highest values occurring in the morning and the lowest in the evening. These results may have clinical implications for patients receiving either high- or low-intensity warfarin therapy.     

13C-Octanoic acid breath test for gastric emptying rate of solids

We performed a retrospective chart review of 60 patients after mechanical heart valve replacement to assess warfarin sensitivity. The overall international normalized ratio (INR) on day 3 of therapy was 4.1+/-3.9 (range 1.1-17.1). In a control group of 100 patients who received anticoagulation for atrial fibrillation, pulmonary embolism, and deep vein thrombosis, the overall mean INR at day 3 was 1.9+/-0.7 (range 1.0-4.9). The difference between groups was statistically significant (p<0.05). We conclude that patients receiving warfarin after mechanical heart valve replacement are more sensitive to the drug than those receiving it for other indications, and reduced dosages may be necessary during the first 3 days after valve replacement.     

Prothrombin time: one tube or two

This study compares the prothrombin times (PTs) and calculated international normalized ratios (INRs) from first and second evacuation blood tubes to determine the clinical importance of using a second tube specimen for protime coagulation studies. The National Committee for Clinical Laboratory Standards (NCCLS) currently recommends that all coagulation studies be done on a second or later drawn blood tube. For patients on long-term anticoagulation therapy, this often requires that first blood tubes be drawn and discarded at each prothrombin evaluation. In this prospective study, a first and second evacuation blood tube was drawn from 343 outpatients who had a physician-ordered prothrombin time test performed. There was no statistically significant difference in the paired PT or calculated INR from any of the first and second tubes. The average difference in the INR from tube 1 to tube 2 was 2% (standard deviation [SD] 1.1%). In this sample of outpatients, the use of a second tube for PT testing was not clinically justified.     

Protective immunity induced in rat schistosomiasis by a single dose of the Sm28GST recombinant antigen: effector mechanisms involving IgE and IgA antibodies

BACKGROUND: Oral anticoagulation is most frequently monitored using the prothrombin time, but an alternative approach is measurement of native, fully carboxylated, prothrombin antigen (NPA). We have correlated results of the prothrombin time and NPA with development of venous thrombosis or bleeding complications in a clinical trial of warfarin prophylaxis following total hip arthroplasty to determine the potential value of NPA measurement for monitoring oral anticoagulation. METHODS AND RESULTS: Patients in one arm of a prospective, randomized trial received warfarin prophylactically beginning 10 to 14 days before total hip arthroplasty in a dose adjusted to prolong the international normalized ratio (INR) to 1.5 on the day of surgery and 2.5 after surgery. NPA was measured by ELISA, and the prothrombin time was measured using rabbit brain thromboplastin. Samples were tested from 97 patients, and data from 81 patients who had adequate venography were analyzed to correlate test results with occurrence of thrombosis. The prothrombin time and INR were less sensitive than NPA to the lowest intensities of anticoagulation, with the prothrombin time index increasing from 1.0 to 1.3 and the INR increasing from 1.0 to 2.0, whereas the NPA concentration decreased fourfold, from 200 to 50 micrograms/mL. There was little correlation between either the prothrombin time index or the INR and the development of thrombosis, whereas NPA concentrations were significantly higher on the day of surgery and on postoperative days 1, 3, 5, and 7 in patients who developed venous thrombosis. Higher concentrations of NPA were associated with an increased risk of venous thrombosis, but there was no relation between thrombosis and the prothrombin time index or INR. There was no significant correlation between surgical blood loss and prothrombin time index, INR, or NPA concentration. However, patients who received the largest number of transfusions on the day of surgery had significantly lower NPA concentrations than patients who required no transfusion. CONCLUSIONS: These results indicate that the NPA concentration more accurately reflects the antithrombotic effect of warfarin than does prothrombin time and may be superior in monitoring prophylactic oral anticoagulation.     

Incidence and characteristics of fall-related emergency department visits

BACKGROUND: Patients with acute ischemic syndromes (AIS) suffer high rates of recurrent ischemic events despite aspirin treatment. Long-term therapy with oral anticoagulants in addition to aspirin may reduce this risk. We studied the effects of long-term warfarin at 2 intensities in patients with AIS without ST elevation in 2 consecutive randomized controlled studies. METHODS AND RESULTS: In phase 1, after the cessation of 3 days of intravenous antithrombotic therapy, 309 patients were randomized to receive fixed low-dose (3 mg/d) warfarin for 6 months that produced a mean international normalized ratio (INR) of 1.5+/-0.6 or to standard therapy. Eighty-seven percent of patients received aspirin in both groups. The rates of cardiovascular (CV) death, new myocardial infarction (MI), and refractory angina at 6 months were 6.5% in the warfarin group and 3.9% in the standard therapy group (relative risk [RR], 1. 66; 95% CI, 0.62 to 4.44; P=0.31). The rates of death, new MI, and stroke were 6.5% in the warfarin group and 2.6% in the standard therapy group (RR, 2.48; 95% CI, 0.80 to 7.75; P=0.10). The overall rate of rehospitalization for unstable angina was 21% and did not differ significantly between the groups. Four patients in the warfarin group (2.6%) and none in the control group experienced a major bleed (RR, 2.48; 95% CI, 0.80 to 7.75), and there was a significant excess of minor bleeds in the warfarin group (14.2% versus 2.6%; RR, 5.46; 95% CI, 1.93 to 15.5; P=0.001). In phase 2, the protocol was modified, and 197 patients were randomized <48 hours from the onset of symptoms to receive warfarin at an adjusted dose that produced a mean INR of 2.3+/-0.6 or standard therapy for 3 months. Eighty-five percent received aspirin in both groups. The rates of CV death, new MI, and refractory angina at 3 months were 5. 1% in the warfarin group and 12.1% in the standard group (RR, 0.42; 95% CI, 0.15 to 1.15; P=0.08). The rates of all death, new MI, and stroke were 5.1% in the warfarin group and 13.1% in the standard therapy group (RR, 0.39; 95% CI, 0.14 to 1.05; P=0.05). Significantly fewer patients were rehospitalized for unstable angina in the warfarin group than in the control group (7.1% and 17.2%, respectively; RR, 0.42; 95% CI, 0.18 to 0.96; P=0.03). Two patients in the warfarin group and 1 in the control group experienced a major bleed, and there was a significant excess of minor bleeds in the warfarin group (28.6% versus 12.1%; RR, 2.36; 95% CI, 1.37 to 4.36; P=0.004). CONCLUSIONS: Long-term treatment with moderate-intensity warfarin (INR, 2.0 to 2.5) plus aspirin but not low-intensity warfarin (INR, 1.5) plus aspirin appears to reduce the rate of recurrent ischemic events in patients with AIS without ST elevation.     

Interstitial pregnancy and management with a single systemic administration of methotrexate

OBJECTIVE: To examine the effect of grapefruit juice on the disposition of oral administered itraconazole in healthy subjects. METHODS: Twenty-two healthy male subjects received a single 100 mg dose of itraconazole with either 350 ml grapefruit juice, orange juice or mineral water. Plasma concentrations of itraconazole were measured by HPLC, and pharmacokinetic parameters; Cmax, Tmax, T1/2, AUC, and AUC corrected by human body surface area: AUC/S, were calculated. RESULTS: Grapefruit juice had no effect on any pharmacokinetic parameter of itraconazole. However, T1/2, AUC, or AUC/S were significantly decreased in orange juice treatment group compared to those in mineral water group (average decrease 56%, p < 0.01, 41%, p < 0.05, and 43%, p < 0.05, respectively). CONCLUSION: Coadministration of grapefruit juice did not affect any pharmacokinetic parameter of itraconazole while that of orange juice decreased the parameters of T1/2, AUC, and AUC/S of the drug.     

Changes in plasma warfarin levels and variations in steady-state prothrombin times

OBJECTIVE: To determine the relative contribution of changes in the plasma warfarin level to variation in the serial steady-state prothrombin times. METHODS: This was a prospective observational cohort study performed at two outpatient anticoagulation clinics. Serial prothrombin times and paired plasma total warfarin levels were determined in a convenience sample of otherwise healthy patients who required long-term oral anticoagulation therapy with warfarin. RESULTS: Serial measurements were obtained from 129 patients, 60 of whom provided three or more serial samples. Analysis of covariance showed a highly significant (p = 0.0001) relationship between the anticoagulant effect and the logarithm of the warfarin concentration (R2 = 0.75), with 15.3% of the total variance attributable to the effect of warfarin and 31.1% attributable to individual variation in sensitivity to warfarin. In an analysis of the subjects who had three or more serial measurements, the mean weighted correlation coefficient for the relationship between the logarithm of the warfarin concentration and the anticoagulant response varied widely, from strongly negative to strongly positive, and as the range of observed prothrombin times increased, stronger positive correlation was observed. CONCLUSIONS: In this cohort, the plasma warfarin level was a strong predictor of observed changes in serial prothrombin time measurements. However, the correlation between clotting times and warfarin levels varied widely among subjects, particularly when the range of observed prothrombin times was moderate. This suggests that in these subjects, other factors, such as measurement error or pharmacodynamic changes, played a major role.     

Grapefruit juice increases felodipine oral availability in humans by decreasing intestinal CYP3A protein expression

The increase in oral availability of felodipine and other commonly used medications when taken with grapefruit juice has been assumed to be due to inhibition of CYP3A4, a cytochrome P450 that is present in liver and intestine. To evaluate the effect of repeated grapefruit juice ingestion on CYP3A4 expression, 10 healthy men were given 8 oz of grapefruit juice three times a day for 6 d. Before and after receiving grapefruit juice, small bowel and colon mucosal biopsies were obtained endoscopically, oral felodipine kinetics were determined, and liver CYP3A4 activity was measured with the [14C N-methyl] erythromycin breath test in each subject. Grapefruit juice did not alter liver CYP3A4 activity, colon levels of CYP3A5, or small bowel concentrations of P-glycoprotein, villin, CYP1A1, and CYP2D6. In contrast, the concentration of CYP3A4 in small bowel epithelia (enterocytes) fell 62% (P = 0.0006) with no corresponding change in CYP3A4 mRNA levels. In addition, enterocyte concentrations of CYP3A4 measured before grapefruit juice consumption correlated with the increase in Cmax when felodipine was taken with either the 1st or the 16th glass of grapefruit juice relative to water (r = 0. 67, P = 0.043, and r = 0.71, P = 0.022, respectively). We conclude that a mechanism for the effect of grapefruit juice on oral felodipine kinetics is its selective downregulation of CYP3A4 in the small intestine.     

Eradication of Helicobacter pylori in patients with end-stage renal disease undergoing dialysis treatment

The aim of the present study was to examine the efficacy and safety of combination therapy with amoxicillin (AMPC), lansoprazole, and plaunotol for the eradication of H. pylori in dialysis patients. The subjects consisted of 15 dialysis patients (10 men and 5 women, mean age of 56 +/- 2.4 years) in whom H. pylori was found in the stomach. H. pylori status was evaluated by histology, culture and rapid urease test with biopsy specimens of the gastric mucosa. The patients were treated with AMPC 500 mg once a day for 3 weeks, lansoprazole 30 mg once a day for 8 weeks and plaunotol 80 mg three times a day for 24 weeks. In addition, the concentrations of serum gastrin and gastric juice ammonia were measured. Fourteen patients completed the treatment schedule, while one discontinued treatment because of nausea and diarrhea. Among the 14 patients, H. pylori was eradicated in 11 without any side effects (eradication rate 78.6%). Concentrations of gastric juice ammonia and serum gastrin were reduced significantly in patients who became H. pylori-negative. The present study indicates that combination therapy with AMPC, lansoprazole and plaunotol is safe and efficient for the eradication of H. pylori in dialysis patients. The results also suggested that elevated concentrations of gastric juice ammonia and serum gastrin in dialysis patients can be attributed, at least in part, to H. pylori infection.     

The effect of N-alkyloxycarbonyl group on the anticonvulsant activities of N-alkyloxycarbonyl-alpha-aminoglutarimides

The aim of this study was to determine the effect of heparin therapy on the international normalized ratio (INR). In vitro heparin sensitivity curves were created using normal and warfarinized plasma samples from patients. The INR results were measured with each of two reagents. In addition, a comparison of INR values with these two reagents was performed on plasma from patients receiving therapeutic heparin and warfarin. The INR values were measured before and after heparin removal with a heparin adsorbent system. While one of the reagents was found to be sensitive to even low levels of therapeutic heparin, the other thromboplastin was resistant up to at least 0.9 U/mL. The INR values determined for patients with one of the reagents were found to be erroneously elevated by an average of 16%. The error ranged from 2% to 55% depending on the in vivo heparin concentration. With the other reagent, the INR values were not substantially affected by heparin. Previous studies have described the effect or lack thereof of heparin on the prothrombin time. The present study demonstrates that the degree to which INR results are prolonged by heparin therapy depends on the reagent formulation. As the therapeutic index for monitoring warfarin is relatively narrow (2.0-3.0), an INR value that is falsely elevated due to reagent sensitivity may precipitate premature cessation of heparin therapy and place certain patients at risk for recurrent thrombosis in the short term.     

Comparison of advanced glycation endproducts on haemoglobin (Hb-AGE) and haemoglobin A1c for the assessment of diabetic control

In a pilot study (1997) using POTENS+, our coagulation instrument, we determined that: (a) an Anticoagulant Therapy Factor (ATF) was comparable to the International Normalized Ratio (INR) for monitoring warfarin anticoagulant therapy, (b) one could use any of the four thromboplastins with which the ATF was derived with comparable results, and (c) the ATF could be proposed to monitor warfarin therapy. The ATF-INR comparisons correlated well statistically; but when individual ATF-INR comparisons were later studied, there were frequent discrepancies. The pilot study (1997) was based on hospitalized patients, so almost all patients were undergoing induction of warfarin anticoagulation. Since none of them had taken warfarin for at least six weeks, none of them could be considered "stable" on warfarin. In the present study, all patients were on warfarin therapy for at least six weeks, and the ATF equation was modified by multiplying it by the prothrombin ratio (PR) to give a corrected ATF (CATF). This CATF was then further modified to achieve agreement with the INR by adjusting the linear regression line by means of analytic geometry, so that the CATF-INR regression line now had a slope of one and passed through the origin. With these changes, the modified ATFs (MATF) and INRs correlated well and were nearly equal numerically when using two of the four thromboplastins. Reason for the discrepancies with the other two thromboplastins will be discussed.     

Genotoxicity of hydrazino-phtalazine antihypertensive drugs assessed by an in vitro micronucleus assay

Oral anticoagulant therapy is effective antithrombotic treatment for several indications. The results of prothrombin time monitoring should be reported as the International Normalized Ratio (INR). An INR of 2 to 3 is the recommended therapeutic range for all indications except for the prevention of systemic embolism in patients with mechanical heart valves and for the long-term treatment of patients with myocardial infarction, for whom an INR range of 2.5 to 3.5 is recommended. Oral anticoagulant therapy with warfarin sodium is the preferred approach for preventing stroke in most patients with atrial fibrillation. The available data suggest that warfarin is more effective than aspirin. Aspirin, 325 mg/d, is indicated for patients in whom warfarin is contraindicated or in patients less than 75 years of age who are at low risk for stroke because risk factors are absent. In patients 75 years of age or more, close monitoring of warfarin treatment is prudent to avoid major bleeding due to poor anticoagulant control. In selected patients, patient-self-monitoring and adjustment of warfarin treatment using a portable prothrombin time monitor may be effective and safe.     

Fixed minidose warfarin and aspirin alone and in combination vs adjusted-dose warfarin for stroke prevention in atrial fibrillation: Second Copenhagen Atrial Fibrillation, Aspirin, and Anticoagulation Study

BACKGROUND: Despite the efficacy of warfarin sodium therapy for stroke prevention in atrial fibrillation, many physicians hesitate to prescribe it to elderly patients because of the risk for bleeding complications and because of inconvenience for the patients. METHODS: The Second Copenhagen Atrial Fibrillation, Aspirin, and Anticoagulation Study was a randomized, controlled trial examining the following therapies: warfarin sodium, 1.25 mg/d; warfarin sodium, 1.25 mg/d, plus aspirin, 300 mg/d; and aspirin, 300 mg/d. These were compared with adjusted-dose warfarin therapy (international normalized ratio of prothrombin time [INR], 2.0-3.0). Stroke or a systemic thromboembolic event was the primary outcome event. Transient ischemic attack, acute myocardial infarction, and death were secondary events. Data were handled as survival data, and risk factors were identified using the Cox proportional hazards model. The trial was scheduled for 6 years from May 1, 1993, but due to scientific evidence of inefficiency of low-intensity warfarin plus aspirin therapy from another study, our trial was prematurely terminated on October 2, 1996. RESULTS: We included 677 patients (median age, 74 years). The cumulative primary event rate after 1 year was 5.8% in patients receiving minidose warfarin; 7.2%, warfarin plus aspirin; 3.6%, aspirin; and 2.8%, adjusted-dose warfarin (P = .67). After 3 years, no difference among the groups was seen. Major bleeding events were rare. CONCLUSIONS: Although the difference was insignificant, adjusted-dose warfarin seemed superior to minidose warfarin and to warfarin plus aspirin after 1 year of treatment. The results do not justify a change in the current recommendation of adjusted-dose warfarin (INR, 2.0-3.0) for stroke prevention in atrial fibrillation.     

Patient outcomes after reoperation on the lumbar spine

A prospective, randomized trial was conducted to compare the effectiveness and safety of warfarin given in two regimens in prevention of venous thrombosis after total knee replacement. Adult patients scheduled for primary or revision total knee replacement were randomly assigned to receive either a "two-step" warfarin regimen beginning 10-14 days pre-operatively or, alternatively, to begin warfarin the night before surgery. Post-operatively, the dose was adjusted in both groups to achieve a target International Normalized Ratio (INR) of 2.2 and prophylaxis was continued until venography on post-operative days five through nine. Bleeding was assessed by surgical blood loss, transfusion requirements, changes in hematocrit, and clinically identified bleeding complications. The occurrence of deep vein thrombosis was nearly the same in the two treatment groups, 39% in patients randomized to the two-step regimen as compared to 38% in those beginning the night before surgery. The occurrence of proximal vein thrombosis was also similar, 5% versus 7% (p = NS). Patients in the two-step group received 1.33 +/- 1.26 transfusions compared to 0.95 +/- 1.22 in the night before group (p < 0.05) and also had a lower nadir post-operative hematocrit of 26.7 +/- 3.1 as compared to 28.5 +/- 3.2 (p < 0.0001). Major bleeding complications were associated with excessively prolonged INRs and occurred in five patients in the two-step group and two in the night before group. Patients in both groups who developed thrombosis had a significantly lower INR on post-operative days two and three compared to those without thrombosis. We conclude that a prophylactic warfarin regimen for prevention of deep vein thrombosis after total knee replacement beginning the night before surgery is more convenient and may be associated with less bleeding than a regimen beginning warfarin 10-14 days pre-operatively. Careful control of anticoagulant intensity is needed to achieve maximum effectiveness and avoidance of bleeding complications.     

Subglottic tracheal stenosis in Wegener''s granulomatosis. Report of 3 cases]

OBJECTIVE: This study was performed to assess whether coadministration with grapefruit juice significantly affects the pharmacokinetics of amlodipine, a dihydropyridine class calcium antagonist with slow absorption, distribution and low plasma clearance. The primary objective was to evaluate whether short exposure to grapefruit juice could affect the metabolism of amlodipine to an extent similar to that previously demonstrated for other dihydropyridines (e.g. felodipine, nisoldipine, nitrendipine). METHODS: Twelve healthy male volunteers followed a randomised, open crossover study design, comparing the effect of a single oral dose of amlodipine (5 mg) taken together with a glass of grapefruit juice (250 ml) vs water. Blood samples to determine plasma concentration were taken and blood pressure (BP) and heart rate (HR) were measured throughout the study. RESULTS: When amlodipine was coadministered with grapefruit juice, Cmax was 115% and AUC(0-72 h) was 116% compared with water, but tmax was not significantly changed. There were no significant differences in BP and HR between the two treatments. A small decrease in diastolic BP, however, was observed in both treatments 4-8 h after drug administration, coinciding with Cmax, but this was normalised after 12 h. The BP reduction seen was compensated by a slight increase in HR, which remained throughout the study. CONCLUSION: An interaction between grapefruit juice and amlodipine was demonstrated. The haemodynamic data showed that a dose of 5 mg was sufficient to achieve a BP reduction in healthy subjects, but the increase in amlodipine plasma concentration seen after intake of grapefruit juice was too small to significantly affect BP or HR. The clinical significance of this food/drug interaction, however, cannot be ignored since there is considerable variation between individuals and a more extensive intake of grapefruit juice might give more pronounced effects.