BMC Clinical Pharmacology - Latest Articles

Quality and safety of medication use in primary care: Consensus validation of a new set of explicit medication assessment criteria and prioritisation of topics for improvement

Tobias Dreischulte — 2012-02-08T00:00:00Z

Background: Addressing the problem of preventable drug related morbidity (PDRM) in primary care is a challenge for health care systems internationally. The increasing implementation of clinical information systems in the UK and internationally provide new opportunities to systematically identify patients at risk of PDRM for targeted medication review. The objectives of this study were (1) to develop a set of explicit medication assessment criteria to identify patients with sub-optimally effective or high-risk medication use from electronic medical records and (2) to identify medication use topics that are perceived by UK primary care clinicians to be priorities for quality and safety improvement initiatives. Methods: For objective (1), a 2-round consensus process based on the RAND/UCLA Appropriateness Method (RAM) was conducted, in which candidate criteria were identified from the literature and scored by a panel of 10 experts for 'appropriateness' and 'necessity'. A set of final criteria was generated from candidates accepted at each level. For objective (2), thematically related final criteria were clustered into 'topics', from which a panel of 26 UK primary care clinicians identified priorities for quality improvement in a 2-round Delphi exercise. Results: (1) The RAM process yielded a final set of 176 medication assessment criteria organised under the domains 'quality' and 'safety', each classified as targeting 'appropriate/necessary to do' (quality) or 'inappropriate/necessary to avoid' (safety) medication use. Fifty-two final 'quality' assessment criteria target patients with unmet indications, sub-optimal selection or intensity of beneficial drug treatments. A total of 124 'safety' assessment criteria target patients with unmet needs for risk-mitigating agents, high-risk drug selection, excessive dose or duration, inconsistent monitoring or dosing instructions. (2) The UK Delphi panel identified 11 (23%) of 47 scored topics as 'high priority' for quality improvement initiatives in primary care. Conclusions: The developed criteria set complements existing medication assessment instruments in that it is not limited to the elderly, can be implemented in electronic data sets and focuses on drug groups and conditions implicated in common and/or severe PDRM in primary care. Identified priorities for quality and safety improvement can guide the selection of targets for initiatives to address the PDRM problem in primary care.

Pharmacokinetics of high-dose oral thiamine hydrochloride in healthy subjects

Howard Smithline — 2012-02-04T00:00:00Z

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 AUC0-10hr and Cmax values increased nonlinearly between100 mg and 1500 mg. The slope of the AUC0-10hr vs dose, as well as the Cmax 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.

Mechanisms for an effect of acetylcysteine on renal function after exposure to radio-graphic contrast material: study protocol

Euan Sandilands — 2012-02-03T00:00:00Z

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: 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 20mg/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.DiscussionContrast-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.

Validation of an LC-MS/MS method to determine five immunosuppressants with deuterated internal standards including MPA

Armin Buchwald — 2012-01-11T00:00:00Z

Background: Therapeutic drug monitoring of immunosuppressive drugs in organ-transplanted patients is crucial to prevent intoxication or transplant rejection due to inadequate dosage. Recently, the commonly used immunoassays are about to be replaced by mass spectrometry, since this physical method offers a higher sensitivity and specificity. However, a switch should be carefully considered - it is challenging and needs a thorough validation procedure.From an economic perspective, it is reasonable to include mycophenolic acid, as an additional determination can be omitted. To date, few validation protocols for the measurement of immunosuppressants, including mycophenolic acid, are available. In order to compensate for matrix effects adequately, 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 flow-through direction. Chromatographic separation was performed by a c18-phenyl-hexyl column. For subsequent mass spectrometric analysis stable-isotope-labelled internal standards were used. Results were available after 3.5 minutes. Results: Low quantification limits (accuracy: 104 - 118 %), respectively 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 ug/ml for mycophenolic acid. Intra-assay precision revealed a coefficient of variation (CV) of 0.9 - 14.7 % and an accuracy of 89 - 138 %. 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 compensated well 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.

Effects of paliperidone extended release on the symptoms and functioning of schizophrenia

Min-Wei Huang — 2012-01-06T00:00:00Z

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.MethodThis 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

The association between drospirenone and hyperkalemia: a comparative-safety study

Steven Bird — 2011-12-30T00:00:00Z

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.

Etomidate and Mortality in Cirrhotic Patients with Septic Shock

Antoine Cherfan — 2011-12-30T00:00:00Z

ObjectiveClinical 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: 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 [greater than or equal to]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 significantly associated with 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.

Use of antipsychotic and antidepressant within the Psychiatric Disease Centre, Regional Health Service of Ferrara

Stefano Bianchi — 2011-12-20T00:00:00Z

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 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 Univerity 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 doses 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.

Price, familiarity, and availability determine the choice of drug - a population-based survey five years after generic substitution was introduced in Finland.

Reeta Heikkila — 2011-12-15T00:00:00Z

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.

Public perception on the role of community pharmacists in self-medication and self-care in Hong Kong

Joyce You — 2011-11-25T00:00:00Z

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.