The optimal means of initiating warfarin therapy for acute venous thromboembolism in the outpatient setting remains controversial. We have previously demonstrated the efficacy of a 10 mg initiation nomogram in a randomized controlled trial; however, some clinicians remain reluctant to use this nomogram due to a fear of potential increased bleeding. To review the safety and efficacy of a 10 mg warfarin nomogram we conducted a retrospective cohort study of patients prospectively treated for venous thromboembolism according to a 10 mg nomogram in an outpatient thrombosis clinic. All patients received standard treatment with low molecular weight heparin for 5 to 7 days and warfarin for at least 3 months. Four-hundred and fourteen patients were included in the analysis, of whom 295 (71%) fully adhered to the nomogram. In the whole cohort, 8 patients (1.9%) experienced recurrent thrombosis, 4 (0.97%) suffered a major bleeding event, and 3 (0.72%) suffered a minor bleeding event. There were no deaths related to thrombosis or bleeding. Four patients (0.97%) died from unrelated causes. Twenty-two (5.3%) patients experienced an INR > or =5.0 in the first 8 days of therapy, and none of these patients experienced a bleeding event. Eighty-four percent of patients achieved a therapeutic INR by day 5. In outpatients, a 10 mg nomogram results in timely achievement of a therapeutic INR with an acceptable incidence of bleeding and recurrent thromboembolism.
Seven hundred fifty-six women had abortions induced with methotrexate and misoprostol. Various protocols were compared. In Group 1, phase 1, after receiving 50 mg/m2 methotrexate IM, 289 women were randomized to receive either 750 or 500 micrograms of vaginal misoprostol. In Group 1, phase 2, 84 women who had failed to abort after one dose of misoprostol were randomized to receive either vaginal or oral routes for the second dose of misoprostol given on Day 8. In Group 2, a cohort of 226 women who received 60 mg/m2 methotrexate were compared to the 289 women who received 50 mg/m2 in Group 1. There were no differences in rates of effectiveness in the various trial groups. Side effects were greater with 60 mg/m2 of methotrexate. In Group 3, a cohort of 241 women received the misoprostol in three vaginal doses 8 hr apart starting on Day 5, and were compared to the 289 women in Group 1 receiving one vaginal dose. In women whose medical abortion failed, fetuses were found to have limb abnormalities In the total group of 756 women, 88.8% aborted successfully without surgical aspiration, with only minor side effects, and the acceptance rate was high. This study indicates that medical abortions induced with methotrexate and misoprostol are safe and effective, but more research is needed to find a more effective protocol.
The thiazolidinediones were introduced as oral hypoglycemic drugs in Sweden during the fall of 2000. A case is reported in which a woman with insulin-dependent type-2 diabetes and both macro- and microangiopathy and pronounced insulin resistance was treated with rosiglitazone (Avandia). Within three months insulin doses could be reduced by 36% (from 176 to 112 units insulin daily) and concomitantly Ery-HbA1c was reduced from 8.4 to 5.3%. In spite of this dramatic effect on glucose homeostasis administration of the drug had to be discontinued due to critical congestive heart failure.
Acetyldinaline: a new oral cytostatic drug with impressive differential activity against leukemic cells and normal stem cells--preclinical studies in a relevant rat model for human acute myelocytic leukemia.
Acetyldinaline [CI-994; GOE 5549; PD 123 654; 4-acetylamino-N-(2'-aminophenyl)-benzamide] is the acetylated derivative form of the original compound Dinaline (GOE 1734; PD 104 208). The efficacy and toxicity of Acetyldinaline for remission-induction treatment of leukemia were evaluated and compared with those observed in previous studies of Dinaline in the Brown Norway acute myelocytic leukemia, as a preclinical model for human acute myelocytic leukemia. There were three treatment groups. Leukemic animals received either 1 or 2 courses of 5 daily p.o. administrations of Acetyldinaline with a "full dose" of 23.7 mg/kg once daily (first group), a twice daily "half dose" of 11.85 mg/kg with an interval of 8 h (second group), or a "half dose" of 11.85 mg/kg once daily (third group). The drug-free interval between the 2 courses was 2 or 9 days. With repeated daily p.o. administrations of 23.7 mg/kg either in a single daily dose or a split daily dose of 2 x 11.85 mg/kg for 1 course, at least an 8-log leukemic cell kill was achieved. In contrast, with these treatment schedules, less than a 1-log cell kill of normal pluripotent hemopoietic stem cells (CFU-S) in the femoral bone marrow was found. Split daily dose treatment was more effective resulting in 37.5% cures, while no cures were observed with the single daily treatment for one course. Treatment with single daily dose of 23.7 mg/kg or a split daily dose of 2 x 11.85 mg/kg for 2 courses, with either a 2- or 9-day interval in between, resulted in lethal toxicity in most of rats. This result was comparable with that previously observed after equimolar doses of Dinaline (20 mg/kg). The half-dose once daily treatment with Acetyldinaline (11.85 mg/kg) for 1 or 2 cycles resulted in about a 4.5 or > 8-log leukemic cell kill, respectively. Toxic side effects, i.e., damage to the gastro-intestinal tract and hemorrhages in the lungs, were more pronounced with full dose either in the single or the split daily dose regimen. No significant toxicity was observed at the half-dose treatment once daily. In conclusion, the impressive differential activity against leukemic cells and normal stem cells observed in this relevant rat model for human acute myelocytic leukemia warrants the introduction of this compound in clinical phase I/II studies.
Pulse therapy with methylprednisolone (Solu-Medrol, Upjohn), 1000 mg daily over three successive days, was administered to patients in two randomized groups of 14 patients in each (23 patients with systemic lupus erythematosus, 5 with rheumatoid arthritis). In one of the groups the drug was taken per os, the other received it intravenously. There was no significant difference between the two groups in terms of clinical effectiveness and incidence of side effects However, the time-related course of such indices as erythrocyte sedimentation rate, the level of leukocytes, of total protein, urea, the blood antioxidant potential, permeability of erythrocytic membranes and capillary and tissue barrier proteinuria as well as the content of immune complexes in the arterial and venous blood was more striking with per os intake. Of the 14 patients, 11 demonstrated short-continued asymptomatic 35% rise in the activity of alaninaminotransferase.
Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, 58758 Linköping, Sweden. Electronic address: davide.guerrieri@rmv.se.
The European Nordic Countries are the most exposed to opioid-related deaths. Between April and October 2016, a series of forty lethal intoxications occurred in Sweden, in which the presence of the synthetic opioid acrylfentanyl was determined to be the main - or a contributing - cause of death. In the reported cases, the blood concentration of acrylfentanyl - mostly detected in combination with other drugs - ranged from 0.01ng/g to 5ng/g; victims were predominantly males (34 males and 6 females), and their age varied between 18 and 53 years. We further describe five cases, representative of the different drug administration route (nasal spray, tablets) and intentions (accidental or voluntary intoxication). Moreover, we address nine cases of non-lethal intoxication, in single (8 cases) or polydrug scenario (1 case). We discuss the present characteristics of the Swedish drug market for fentanyl-analogs in general and acrylfentanyl in particular, reporting a structural difficulty to effectively counteracting the appearance of unscheduled substances due to the constant turnover of new molecules on the recreational drug market.
The short- and long-term hemodynamic effects of encainide, a new class IC antiarrhythmic agent, were studied in 25 patients (mean age 61 +/- 11) with complex symptomatic ventricular arrhythmia and left ventricular dysfunction. Ninety-two percent had previous myocardial infarction and 8% had dilated cardiomyopathy. Seventy-five percent had congestive heart failure, class III or IV, according to the New York Heart Association. All patients underwent a nuclear ventriculogram performed at least 3 days after discontinuing previous antiarrhythmic drugs. Nuclear ventriculograms were repeated 1 to 6 weeks later while the patients were receiving therapeutic doses of encainide ranging from 75 to 300 [corrected] mg/day. Nuclear ventriculograms were also repeated after 6 months or 1 year of encainide therapy in 16 of these patients. Encainide did not have significant effects on heart rate, blood pressure, left ventricular ejection fraction, systolic or end-diastolic volumes. None of the patients showed a worsening of congestive heart failure during encainide therapy. These results compare favorably with those of other class I antiarrhythmic agents. A review of published reports on the hemodynamic effects of intravenous encainide shows it to have a mild but statistically significant dose-related depressant effect on cardiac function. This effect, however, appears to be no different from that of other newer class I agents.
Added predictive ability of the CHA2DS2VASc risk score for stroke and death in patients with atrial fibrillation: the prospective Danish Diet, Cancer, and Health cohort study.
The objective of this study was to evaluate the added predictive ability of the CHA(2)DS(2)VASc prediction rule for stroke and death in a nonanticoagulated population of patients with atrial fibrillation.
We included 1603 nonanticoagulated patients with incident atrial fibrillation from a Danish prospective cohort study of 57 053 middle-aged men and women. The Net Reclassification Improvement was calculated as a measure to estimate any overall improvement in reclassification with the CHA(2)DS(2)VASc sore as an alternative to the CHADS(2) score. After 1-year follow-up, crude incidence rates were 3.4 per 100 person-years for stroke and 13.6 for death. After a mean follow-up of 5.4 years (± 3.7 years), the crude incidence rates for stroke and death were 1.9 and 5.6, respectively. During the entire observation period, the c-statistics and negative predictive values were similar for both risk scores. The Net Reclassification Improvement analysis showed that 1 of 10 reclassified atrial fibrillation patients would have been upgraded correctly using the CHA(2)DS(2)VASc score.
Both the CHADS(2) as well as the CHA(2)DS(2)VASc risk score can exclude a large proportion of patients from having high risk of stroke or death. However, using the CHA(2)DS(2)VASc risk score, fewer patients will fulfill the criterion for low risk (and are truly low risk for thromboembolism). For every 10 extra patients transferred to the treatment group at 5 years, using the CHA(2)DS(2)VASc risk score, 1 patient would have had a stroke that might have been avoided with effective treatment.
Results of continuous sunitinib, in combination with cetuximab and irinotecan every other week (SIC) for compassionate use in heavily pre-treated patients with mCRC are presented.
Patients with mCRC resistant to oxaliplatin, irinotecan, 5-FU and cetuximab received SIC at two Danish oncologic departments. The regimen consisted of sunitinib given as a continuous-dosing in combination with cetuximab and irinotecan every other week (CetIri). The first six patients started with a daily oral dose of sunitinib of 12.5 mg. Subsequent patients started at a daily dose of 25 mg with the possibility to escalate to 37.5 mg.
Twenty-nine patients received SIC. No patient had an objective response, but 13 patients had subjective relief and 42% had stable disease. The median time to progression was 3.2 months and median overall survival was 7.4 months. Fatigue and leukopenia were the most frequently reported severe adverse event (18% grade 3 and 18% grade 3/4, respectively).
Sunitinib continuous-dosing with 25 mg/day can safely be combined with CetIri administered every other week.
