BMC Clinical Pharmacology最新文献

Background: High dose oral thiamine may have a role in treating diabetes, heart failure, and hypermetabolic states. The purpose of this study was to determine the pharmacokinetic profile of oral thiamine hydrochloride at 100 mg, 500 mg and 1500 mg doses in healthy subjects.

Methods: This was a randomized, double-blind, single-dose, 4-way crossover study. Pharmacokinetic measures were calculated.

Results: The AUC₀₋₁₀ hr and C(max) values increased nonlinearly between 100 mg and 1500 mg. The slope of the AUC₀₋₁₀ hr vs dose, as well as the C(max) vs dose, plots are steepest at the lowest thiamine doses.

Conclusion: Our study demonstrates that high blood levels of thiamine can be achieved rapidly with oral thiamine hydrochloride. Thiamine is absorbed by both an active and nonsaturable passive process.

Trial registration: ClinicalTrials.gov: NCT00981877.

Background: Contrast-induced nephropathy is a common complication of contrast administration in patients with chronic kidney disease and diabetes. Its pathophysiology is not well understood; similarly the role of intravenous or oral acetylcysteine is unclear. Randomized controlled trials to date have been conducted without detailed knowledge of the effect of acetylcysteine on renal function. We are conducting a detailed mechanistic study of acetylcysteine on normal and impaired kidneys, both with and without contrast. This information would guide the choice of dose, route, and appropriate outcome measure for future clinical trials in patients with chronic kidney disease.

Methods/design: We designed a 4-part study. We have set up randomised controlled cross-over studies to assess the effect of intravenous (50 mg/kg/hr for 2 hrs before contrast exposure, then 20 mg/kg/hr for 5 hrs) or oral acetylcysteine (1200 mg twice daily for 2 days, starting the day before contrast exposure) on renal function in normal and diseased kidneys, and normal kidneys exposed to contrast. We have also set up a parallel-group randomized controlled trial to assess the effect of intravenous or oral acetylcysteine on patients with chronic kidney disease stage III undergoing elective coronary angiography. The primary outcome is change in renal blood flow; secondary outcomes include change in glomerular filtration rate, tubular function, urinary proteins, and oxidative balance.

Discussion: Contrast-induced nephropathy represents a significant source of hospital morbidity and mortality. Over the last ten years, acetylcysteine has been administered prior to contrast to reduce the risk of contrast-induced nephropathy. Randomized controlled trials, however, have not reliably demonstrated renoprotection; a recent large randomized controlled trial assessing a dose of oral acetylcysteine selected without mechanistic insight did not reduce the incidence of contrast-induced nephropathy. Our study should reveal the mechanism of effect of acetylcysteine on renal function and identify an appropriate route for future dose response studies and in time randomized controlled trials.

Trial registration: Clinical Trials.gov: NCT00558142; EudraCT: 2006-003509-18.

Background: Therapeutic drug monitoring of immunosuppressive drugs in organ-transplanted patients is crucial to prevent intoxication or transplant rejection due to inadequate dosage. The commonly used immunoassays have been gradually undergoing replacement by mass spectrometry, since this physical method offers both a higher sensitivity and specificity. However, a switch should be carefully considered because it is a challenging procedure and needs to be thoroughly validated. From an economic perspective it is reasonable to include mycophenolic acid into the assay, because this saves the necessity for an additional measurement. However, to date very few validation protocols for the measurement of immunosuppressants, including mycophenolic acid, are available. In order to adequately compensate for matrix effects, the use of stable isotope labeled internal standards is advisable. Here, the authors describe a single method suitable for the quantification of cyclosporine A, tacrolimus, sirolimus, everolimus and mycophenolic acid, based on deuterated internal standards.

Methods: Plasma proteins were precipitated with zinc-sulfate, followed by an online solid phase extraction in the flow-through direction. Chromatographic separation was performed by a c18-phenyl-hexyl column. For subsequent mass spectrometric analysis stable-isotope-labeled internal standards were used. Results were available after 3.5 minutes.

Results: Low quantification limits (accuracy: 104 - 118%) and linearity resulted in 2 -1250 ng/ml for cyclosporine A; 0.5 - 42.2 ng/ml for tacrolimus; 0.6 - 49.2 ng/ml for sirolimus; 0.5 - 40.8 ng/ml for everolimus and 0.01 - 7.5 μg/ml for mycophenolic acid. Intra-assay precision revealed a coefficient of variation (CV) of 0.9 - 14.7%, with an accuracy of 89 - 138%. The CV of inter-assay precision was 2.5 - 12.5%, with an accuracy of 90 - 113%. Recovery ranged from 76.6 to 84%. Matrix effects were well compensated by deuterated internal standards.

Conclusions: The authors present a fast, economical and robust method for routine therapeutic drug monitoring comprising five immunosuppressants including mycophenolic acid.

Background: We aimed to explore relations between symptomatic remission and functionality evaluation in schizophrenia patients treated with paliperidone extended-release (ER), as seen in a normal day-to-day practice, using flexible dosing regimens of paliperidone ER. We explored symptomatic remission rate in patients treated with flexibly dosed paliperidone ER by 8 items of Positive and Negative Syndrome Scale (PANSS) and change of Personal and Social Performance (PSP) scale.

Method: This was a 12-week multicenter, open-label, prospective clinical study conducted in in-patient and out-patient populations. Flexible dosing in the range 3-12 mg/day was used throughout the study. All subjects attended clinic visits on weeks 0, 4, 8, and 12 as usual clinical practice for the 12-week observation period. Data were summarized with respect to demographic and baseline characteristics, efficacy measurement with PANSS scale, PSP, and social functioning score, and safety observations. Descriptive statistics were performed to identify the retention rate at each visit as well as the symptomatic remission rate. Summary statistics of average doses the subjects received were based on all subjects participating in the study.

Results: A total of 480 patients were enrolled. Among them, 426 patients (88.8%) had evaluation at week 4 and 350 (72.9%) completed the 12-week evaluation. Patients with at least moderate severity of schizophrenia were evaluated as "mild" or better on PANSS scale by all 8 items after 12 weeks of treatment with paliperidone ER. There was significant improvement in patients' functionality as measured by PSP improvement and score changes. Concerning the other efficacy parameters, PANSS total scale, PSP total scale, and social functioning total scale at the end of study all indicated statistically significant improvement by comparison with baseline. The safety profile also demonstrated that paliperidone ER was well-tolerated without clinically significant changes after treatment administration.

Conclusions: Although the short-term nature of this study may limit the potential for assessing improvements in function, it is noteworthy that in the present short-term study significant improvements in patient personal and social functioning with paliperidone ER treatment were observed, as assessed by PSP scale.

Trial registration: Clinical Trials. PAL-TWN-MA3.

Background: Drospirenone/ethinyl-estradiol is an oral contraceptive (OC) that possesses unique antimineralocorticoid activity. It is conjectured that drospirenone, taken alone or concomitantly with spironolactone, may be associated with an increased risk of hyperkalemia.

Methods: A retrospective cohort study was conducted evaluating women between 18-46 years of age in the Lifelink™ Health Plan Claims Database. The study was restricted to new users of OCs between 1997-2009. Cox proportional hazards models were used to estimate the time to first occurrence of hyperkalemia diagnosis. The main analysis compared OCs containing drospirenone with OCs containing levonorgestrel, a second generation OC not known to impact potassium homeostasis. Logistic regression evaluated concomitant prescribing of drospirenone and spironolactone

Results: The cohort included 1,148,183 women, averaging 28.8 years of age and 280 days of OC therapy. 2325 cases of hyperkalemia were identified. The adjusted hazard ratio (HR) for hyperkalemia with drospirenone compared to levonorgestrel was 1.10 (95%CI 0.95-1.26). There was an increased risk of hyperkalemia with norethindrone HR 1.15 (95%CI: 1.00-1.33) and norgestimate HR 1.27 (95%CI: 1.11-1.46). Other OCs were unassociated with hyperkalemia. The odds of receiving spironolactone while taking drospirenone were 2.66 (95%CI 2.53-2.80) times higher than the odds of receiving spironolactone and levonorgestrel. Only 6.5% of patients taking drospirenone and spironolactone had a serum potassium assay within 180 days of starting concomitant therapy.

Conclusions: A clinically significant signal for hyperkalemia with drospirenone was not demonstrated in the current study. Despite the bolded warning for hyperkalemia with joint drospirenone and spironolactone administration, physicians are actually using them together preferentially, and are not following the recommended potassium monitoring requirements in the package insert.

Background: Clinical effects and outcomes of a single dose etomidate prior to intubation in the intensive care setting is controversial. The aim of this study is to evaluate the association of a single dose effect of etomidate prior to intubation on the mortality of septic cirrhotic patients and the impact of the subsequent use of low dose hydrocortisone.

Methods: This is a nested-cohort study within a randomized double blind placebo controlled study evaluating the use of low dose hydrocortisone in cirrhotic septic patients. Cirrhotic septic patients ≥ 18 years were included in the study. Patients who received etomidate prior to intubation were compared to those who did not receive etomidate for all cause 28-day mortality as a primary outcome.

Results: Sixty two intubated patients out of the 75 patients randomized in the initial trial were eligible for this study. Twenty three of the 62 intubated patients received etomidate dose prior to intubation. Etomidate use was not associated with all cause 28-day mortality or hospital mortality but was associated with significantly higher ICU mortality (91% vs. 64% for etomidate and controls groups, respectively; p = 0.02). Etomidate patients who received subsequent doses of hydrocortisone required lower doses of vasopressors and had more vasopressor-free days but no improvement in mortality.

Conclusions: In this group of septic cirrhotic patients with very high mortality, etomidate increased ICU mortality. Subsequent use of hydrocortisone appears to have no benefit beyond decreasing vasopressor requirements. The lowest mortality was observed in patients who did not receive etomidate but received hydrocortisone.

Background: This study aimed at describing the type and dosage of psychopharmaceuticals dispensed to patients with psychiatric disorders and to assess the percentage of patients treated with antipsychotics and antidepressants, the associated therapies, treatment adherence, and dosages used in individuals registered at the Psychiatric Disease Center (PDC), Regional Health Service of Ferrara.

Methods: The analysis focused on therapeutic programmes presented to the Department of Pharmacy of the University Hospital of Ferrara of 892 patients treated by the PDC (catchment area of 134605 inhabitants). All diagnoses were made according to International Classification of Diseases (ICD-9). The analysis focused on prescriptions from September 2007 to June 2009. Data on adherence to prescribed therapy have were processed by analysis of variance.

Results: Among the patients 63% were treated with antipsychotics and 40% with antidepressants. Among patients receiving antipsychotics 92% used second-generation antipsychotics (SGAs) whereas the remaining 8% used first generation antipsychotics (FGAs). Antipsychotic doses were lower than Daily Defined Dose (DDDs), and SGAs were often given with anticholinergics to decrease side effects. Mean adherence to antipsychotic therapy was 64%. Among antidepressants, selective serotonin reuptake inhibitors (SSRIs) were the most often prescribed, 55%. Dosages of these were within the limits indicated by the technical datasheet but higher than DDDs. Only 26% of patients underwent monotherapy. In antidepressants polytherapy, medication was associated with another antidepressant, 6% or with an antipsychotic, 51%. Mean adherence to the antidepressant therapy was 64%.

Conclusions: Patients treated with antipsychotics tend to use doses lower than DDDs. The opposite tendency was noted in patients treated with antidepressants. Only a small percentage of patients (14%) modified their neuroleptic therapy by increasing the dosage. On the contrary, patients treated with antidepressants mainly tended to reduce the doses of their drugs. This study highlights the tendency to follow combination therapies, prescribing SGAs together with anticholinergics in order to minimize extrapyramidal side effects or by combining two antidepressants. The study showed low adherence for both pharmaceutical therapies, which is typical in the setting of the analyzed diseases.

Background: Mandatory generic substitution (GS) was introduced in Finland at the beginning of April 2003. However, individual patients or physicians may forbid the substitution. GS was a significant change for Finnish medicine users. It was thought it would confuse people when the names, colors, packages, etc., changed. The purpose of this study was to explore what medicine-related factors influence people's choice of prescription drugs five years after generic substitution was introduced in Finland.

Methods: A population survey was carried out during the autumn of 2008. A random sample was drawn from five mainland counties. A questionnaire was mailed to 3000 people at least 18 years old and living in Finland. The questionnaire consisted of both structured and open-ended questions. Factors that influenced the subjects' choice of medicines were asked with a structured question containing 11 propositions. Descriptive statistical analyses were performed.

Results: In total, 1844 questionnaires were returned (response rate, 62%). The percentage of female respondents was 55%. Price, availability, and familiarity were the three most important factors that influenced the choice of medicines. For the people who had refused GS, the familiarity of the medicine was the most important factor. For the subjects who had allowed GS and for those who had both refused and allowed GS, price was the most important factor.

Conclusions: The present study shows that price, familiarity, and availability were important factors in the choice of prescription medicines. The external characteristics of the medicines, for instance the color and shape of the tablet/capsule or the appearance of the package, were not significant characteristics for people.

Background: The choices for self-medication in Hong Kong are much diversified, including western and Chinese medicines and food supplements. This study was to examine Hong Kong public knowledge, attitudes and behaviours regarding self-medication, self-care and the role of pharmacists in self-care.

Methods: A cross-sectional phone survey was conducted, inviting people aged 18 or older to complete a 37-item questionnaire that was developed based on the Thematic Household surveys in Hong Kong, findings of the health prorfessional focus group discussions on pharmacist-led patient self management and literature. Telephone numbers were randomly selected from residential phone directories. Trained interviewers invited eligible persons to participate using the "last birthday method". Associations of demographic characteristics with knowledge, attitudes and beliefs on self-medication, self-care and role of pharmacists, and spending on over-the-counter (OTC) products were analysed statistically.

Results: A total of 1, 560 phone calls were successfully made and 1, 104 respondents completed the survey which indicated a response rate of 70.8%. 63.1% had adequate knowledge on using OTC products. Those who had no formal education/had attended primary education (OR = 3.19, 95%CI 1.78-5.72; p < 0.001), had attended secondary education (OR = 1.50, 95%CI 1.03-2.19; p = 0.035), and aged ≥ 60 years (OR = 1.82, 95% CI 1.02-3.26; p = 0.042) were more likely to have inadequate knowledge on self-medication. People with chronic disease also tended to spend more than HKD100 on western (OR = 3.58, 95%CI 1.58-8.09; p = 0.002) and Chinese OTC products (OR = 2.94, 95%CI 1.08-7.95; p = 0.034). 94.6% believed that patients with chronic illnesses should self-manage their diseases. 68% agreed that they would consult a pharmacist before using OTC product but only 45% agreed that pharmacists could play a leading role in self-care. Most common reasons against pharmacist consultation on self-medication and self-care were uncertainty over the role of pharmacists and low acceptance level of pharmacists.

Conclusions: The majority of respondents supported patients with chronic illness to self-manage their diseases but less than half agreed to use a pharmacist-led approach in self-care. The government should consider developing doctors-pharmacists partnership programs in the community, enhancing the role of pharmacists in primary care and providing education to patients to improve their awareness on the role of pharmacists in self-medication and self-care.

Background: Misuse of antimicrobials (AMs) and antimicrobial resistance (AMR) are global concerns. The present study evaluated knowledge, attitudes and practices about AMR and AM prescribing among medical doctors in two large public hospitals in Lima, Peru, a middle-income country.

Methods: Cross-sectional study using a self-administered questionnaire

Results: A total of 256 participants completed the questionnaire (response rate 82%). Theoretical knowledge was good (mean score of 6 ± 1.3 on 7 questions) in contrast to poor awareness (< 33%) of local AMR rates of key-pathogens. Participants strongly agreed that AMR is a problem worldwide (70%) and in Peru (65%), but less in their own practice (22%). AM overuse was perceived both for the community (96%) and the hospital settings (90%). Patients' pressure to prescribing AMs was considered as contributing to AM overuse in the community (72%) more than in the hospital setting (50%). Confidence among AM prescribing was higher among attending physicians (82%) compared to residents (30%, p < 0.001%). Sources of information considered as very useful/useful included pocket-based AM prescribing guidelines (69%) and internet sources (62%). Fifty seven percent of participants regarded AMs in their hospitals to be of poor quality. Participants requested more AM prescribing educational programs (96%) and local AM guidelines (92%).

Conclusions: This survey revealed topics to address during future AM prescribing interventions such as dissemination of information about local AMR rates, promoting confidence in the quality of locally available AMs, redaction and dissemination of local AM guidelines and addressing the general public, and exploring the possibilities of internet-based training.