To evaluate the impact on lipid and carbohydrate variables of a combined one-third ethinyl estradiol (EE)/levonorgestrel (LNG) dose reduction in oral contraceptives.
In an open-label, randomized study, a dose-reduced oral contraceptive containing 20 microg EE and 100 microg LNG (20 EE/100 LNG) was compared with a reference preparation containing 30 microg EE and 150 microg LNG (30 EE/150 LNG). One-year data from 48 volunteers were obtained.
We found a decrease of HDL2 cholesterol and increases of low-density lipoprotein cholesterol, very low-density lipoprotein cholesterol and total triglycerides in both treatment groups from baseline to the 13th treatment cycle. Although for four of six variables, the changes in the 20 EE group were lower compared with the 30 EE group, none of the differences between the two treatments were statistically significant. The median values for the fasting levels of insulin, C-peptide and free fatty acids slightly increased or remained unchanged while the fasting glucose levels slightly decreased after 13 treatment cycles. While the glucose area under the curve (AUC) (0-3 h) was similar in both groups during the OGTT, the insulin AUC(0-3 h) was less increased in the 20 EE/100 LNG group compared with the 30 EE/150 LNG group. None of the differences between the treatment groups for any of the carbohydrate metabolism variables were statistically significant at any time point. Both study treatments were safe and well tolerated by the volunteers.
Similar effects on the lipid and carbohydrate profiles were found for both preparations. The balanced one-third EE dose reduction in this new oral contraceptive caused slightly lower, but insignificant, changes in the lipid and carbohydrate variables compared with the reference treatment.
An open-label randomized study was undertaken to compare a 2-dose regimen (Months 0 and 6) of hepatitis B surface antigen (HBsAg) vaccine formulated with a novel adjuvant (HBsAg/AS04) with a standard 3-dose regimen (Months 0, 1 and 6) of licensed recombinant HBsAg vaccine in terms of immunogenicity and reactogenicity when administered to healthy subjects aged between 15 and 40 y. At 1 and 6 months after the full vaccination course there was a 100% seroprotection rate (anti-HBs > or = 10 mIU/ml) with the HBsAg/AS04 vaccine, compared with a 99% response rate with the licensed vaccine. The corresponding geometric mean titres were significantly higher for the novel vaccine compared to the standard vaccine: 15,468 and 2,745 mIU/ml at Months 7 and 12 vs. 6,274 and 1,883 mIU/ml, respectively. There was a higher prevalence of local symptoms with the adjuvant vaccine (90% of doses) than with the standard vaccine (48% of doses). However, these symptoms (pain, swelling and redness) were predominantly of mild-to-moderate intensity and resolved rapidly without treatment. A 2-dose regimen of the new HBsAg/AS04 adjuvant vaccine therefore compared favourably to the standard regimen in healthy young adults. It is anticipated that the simplified vaccination schedule may improve compliance and reduce costs.
AIM: To investigate the effect of photodynamic therapy (PDT) with 5-aminolevulinic acid (ALA) as a photosensitizer on the character of infiltration of experimental tumors by different cells of immune system. METHODS: The effect of ALA-PDT on subcutaneously implanted Lewis lung carcinoma in c57Bl/6 mice was studied. ALA at a dose of 500 mg/kg was given per os, and 4 h later tumors were subjected to laser irradiation (632 nm, 150 mW/cm(2), 20 min). The evaluation of the tumor infiltration by myelomonocytic and lymphoid cells and oxygen-dependent metabolism of peritoneal macrophages (NBT-test) were carried out. RESULTS: It is shown that ALA-PDT resulted in fast and massive infiltration of irradiated tumors by myelomonocytic cells, stimulation of the peritoneal macrophages metabolic activity and augmentation of the content of tumor infiltrating lymphocytes. CONCLUSION: The immunomodulation after ALA-PDT occurs via generation of inflammation and direct laser light activation of immune system cells.
PURPOSE: Despite more than four decades of fluoro-pyrimidine treatment in different cancers, the optimal schedule is still not known. The plasma half-life of 5-fluorouracil (5-FU) is extremely short and continuous infusion has gained popularity. In this study we explored whether repeated bolus 5-FU injections could improve the results. PATIENTS AND METHODS: Forty-three patients with advanced gastrointestinal carcinoma, where no standard treatment was available, were included in the phase I study. The initial dose of 5-FU was 250 mg/m2 with 30 mg/m2 leucovorin, repeated three hours later. Treatments were repeated every week. Twenty-six patients were recruited in the following phase II after maximal-tolerated dose (MTD) was reached. Plasma was collected for 5-FU pharmacokinetics. RESULTS: Diarrhoea was the dose-limiting toxicity (DLT), and was reached at 450 mg/m2. One complete and three partial responses (24%) were seen in the phase II study at 400 mg/m2. In addition, several patients had lasting subjective improvements. The treatments were well-tolerated but accumulated toxicity was seen after several months. Dose intensity was 89% after four months of treatment. A great interpatient variability was seen in 5-FU pharmacokinetics. The plasma AUC correlated with the 5-FU dose and toxicity, but not with the tumour response. CONCLUSION: A split of the 5-FU push bolus injection is possible with maintained treatment activity and surprisingly high doses can be tolerated; a weekly dose intensity of 800 mg/m2 could be reached compared with 500 mg/m2 in the standard Nordic FLv schedule.
The effect of a selective 5-HT(1A) antagonist, 4-(2'-methoxy-)phenyl-1-[2'-(N-2"-pyridinyl)-p-iodobenzamino-]ethyl-piperazine (p-MPPI), on acute ethanol-induced hypothermia, sleep and suppression of acoustic startle reflex in C3H/He mice and Wistar rats was studied. Administration of p-MPPI at the doses of 0.4, 0.7 and 1.0 mg/kg reduced in a dose-dependent manner the ethanol-induced hypothermia and the sleep time and attenuated the ethanol-induced decrease of acoustic startle reflex magnitude in mice. Similar p-MPPI (0.4 mg/kg) effects on ethanol-induced sleep and hypothermia were obtained in rats. It was concluded that 5-HT(1A) receptors were involved in the mechanisms of the ethanol-induced hypothermia and sleep, and that 5-HT(1A) antagonist increased acute ethanol tolerance.
Drug dependency may develop during long-term benzodiazepine use, indicated, for example, by dose escalation. The first benzodiazepine chosen may affect the risk of dose escalation.
To detect possible differences in benzodiazepine use between new users of diazepam and oxazepam over time.
This 5-year prescription database study included 19 747 new benzodiazepine users, inhabitants of Norway, aged 30-60 years, with first redemption for diazepam or oxazepam.
Individuals starting on diazepam versus oxazepam were analysed by logistic regression with sex, age, other drug redemptions, prescriber's specialty, household income, education level, type of work, and vocational rehabilitation support as background variables. Time to reach a daily average intake of =1 defined daily doses (DDD) over a 3-month period was analysed using a Cox proportional hazard regression model.
New users of oxazepam had a higher risk for dose escalation compared with new users of diazepam. This was true even when accounting for differences in sociodemographic status and previous drug use (hazard ratio [HR] 1.33, 95% confidence interval = 1.17 to 1.51).
Most doctors prescribed, according to recommendations, oxazepam to individuals they may have regarded as prone to and at risk of dependency. However, these individuals were at higher risk for dose escalation even when accounting for differences in sociodemographic status and previous drug use. Differences between the two user groups could be explained by different preferences for starting drug, DDD for oxazepam being possibly too low, and some unaccounted differences in illness.
To determine the risk of injury associated with the new use of individual benzodiazepines and dosage regimens in the elderly.
Prospective database cohort study with 5 years of follow-up.
Two hundred fifty-three thousand two hundred forty-four persons aged 65 and older who were nonusers of benzodiazepines in the year before follow-up.
Population-based hospitalization and prescription and medical services claims databases were used to compare the risk of injury during periods of benzodiazepine use with those of nonuse. Periods of use were measured for 10 insured benzodiazepines by drug and dose as time-dependent covariates. Injury was defined as the first occurrence of a nonvertebral fracture, soft-tissue injury, or accident-related hospital admission. Patient age, sex, previous injury history, concomitant medication use, and comorbidity were measured as fixed and time-dependent confounders. Cox proportional hazards models were used to estimate the risk of injury with benzodiazepine use and to determine the extent to which patient characteristics, differences in dosage, or in the effect of increasing dosage for individual drugs explained differences between drugs.
More than one-quarter (27.6%) of 253,244 elderly were dispensed at least one prescription for a benzodiazepine, and 17.7% of elderly were treated for at least one injury during follow-up, of which fractures were the most common. Patient characteristics, systematic differences in the risk of injury in elderly prescribed different benzodiazepines, and differences in dosage prescribed for individual drugs confounded the risk of injury with benzodiazepine use. The risk of injury with increasing dosage varied by drug from a hazard ratio of 0.92 (95% confidence interval (CI)=0.60, 1.42) for alprazolam to 2.20 (95% CI=1.39, 3.47) for flurazepam per 1 standardized adult dose increase.
The risk of injury varied by benzodiazepine, independent of half-life, as did the risk associated with increasing dosage for individual products. Higher doses of oxazepam, flurazepam, and chlordiazepoxide are associated with the greatest risk of injury in the elderly.
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.
OBJECTIVE: To assess the safety and health-related quality of life (HRQOL) of continuous combined hormone replacement therapy (ccHRT) with estradiol valerate/medroxyprogesterone acetate (E(2)V/MPA) over nine years and at follow-up one year after discontinuation. Study design: A total of 419 women were randomized to one of four treatments: once-daily 1 mg E2V/2.5 mg MPA (1 + 2.5 group); 1 mg E2V/5 mg MPA daily (1 + 5 group); 2 mg E2V/2.5 mg MPA daily (2 + 2.5 group); 2 mg E2V/5 mg MPA daily (2 + 5 group) (Indivina, Orion Pharma). For the last six months, all received the 1 + 2.5 dosage. The 2 + 2.5 dosage was discontinued at the end of year 7. A total of 198 women continued after year 7. RESULTS: Annualized percentage rates for cardiovascular events [corrected] and endometrial cancers [corrected] were below national rates for Finland and those reported for the Women's Health Initiative. There were no serious events with the 1 + 2.5 dosage or after ccHRT discontinuation. Climacteric symptoms remained significantly below baseline values after dosage reduction; some symptoms recurred after discontinuation of ccHRT. HRQOL ratings improved with ccHRT, irrespective of dosage, including depressed mood, anxiety, health perception and sexual interest. Scores on a scale assessing daily functioning and enjoyment (Q-LES-Q) improved from year 7 to year 9. They deteriorated during follow-up in women not continuing ccHRT. CONCLUSIONS: Lower dosages of HRT were as effective as higher doses in improving climacteric symptoms and HRQOL ratings and had fewer safety concerns. Following discontinuation of ccHRT, patient satisfaction was variable, with 15% electing to continue or restart HRT and 7% resuming at follow-up. This supports the need for an individualized approach to therapy recommendations.