Although the long-term infusion of ANP has proved effective to treat heart failure, no published randomized controlled study has been reported to confirm the efficacy of the short-term ANP infusion in congestive heart failure (CHF) patients. This study was designed to assess the efficacy and safety of short-term infusion of recombinant human atrial natriuretic peptide (rhANP) in CHF patients.

A total of 48 patients with CHF were enrolled and randomized into four groups, treated with standard therapy or rhANP (0·05, 0·1 or 0·2 μg/kg/min) for 1-hour infusion in addition to standard therapy. The hemodynamics were assessed for 12 h by Swan–Ganz catheter.

The effect of the 0·05 μg/kg/min rhANP dose group on CO was modest and transient. The 0·2 μg/kg/min rhANP dose group tended to be associated with better effect on SV, CO and dyspnoea improvement, but modest effect on PCWP and more adverse events probably attributed to the study drug. However, the 0·1 μg/kg/min rhANP infusion was well tolerated and effective both on PCWP decrease (maximum:−9·46 ± 5·81 mmHg compared with baseline (P = 0·0002) and −6·75 mmHg compared with standard therapy, the 95% confidential interval [−13·43, −0·06 mmHg] at 1 h) and CO increase (maximum: 1·02 ± 1·43 L/min [P = 0·0308] at 1 h).

In this small-sample study, 1-hour infusion of rhANP produced beneficial hemodynamic effects in CHF patients compared with standard therapy, and it was well tolerated. 0·1 μg/kg/min may be the optimum dose for short-term rhANP infusion to treat CHF for the further large sample trial before clinical application.

Safety of the anti-inflammatory drug flurbiprofen is comparable with that of other non-steroidal anti-inflammatory drugs of the propionic acid class, which are commonly associated with gastrointestinal and renal side effects. Here we report a case of a fatal hypersensitivity reaction to an oral spray of flurbiprofen taken for sore throat.

A 29-year-old man came to the emergency care unit reporting sore throat with an intense burning sensation associated with fever. Pharyngotonsillitis was diagnosed, and local treatment with oral flurbiprofen spray was prescribed. Immediately after using the spray, the patient experienced a severe reaction characterized by serious dyspnoea, followed by death. The cause of death was heart failure with acute asphyxia from oedema of the glottis. The cause of death was concluded to be hypersensitivity to flurbiprofen spray.

Oral propionic acid derivatives have been associated with a relatively high frequency of allergic reactions. However, allergy to flurbiprofen has rarely been documented. Scientific literature reports two relevant cases of hypersensitivity reaction to flurbiprofen: in one case, a patient presented with a maculopapular rash 48 h after having taken oral flurbiprofen followed by angio-oedema and hypotension. In another case, a single oral dose of flurbiprofen caused itching and swelling around the eyes, redness and increased lacrimation. We describe, for the first time, a fatal case of hypersensitivity reaction to flurbiprofen oral spray. Hypersensitivity reactions to flurbiprofen are infrequent; however, health professionals should be aware of potential adverse reactions, even during topical administration as oral spray.

Cancer chemotherapy-associated cognitive impairments (termed ‘chemo-fog’ or ‘chemo-brain’), particularly in memory, have been self-reported or identified in cancer survivors previously treated with chemotherapy. Although a variety of deficits have been detected, a consistent theme is a detriment in visuospatial working memory. The parietal cortex, a major site of storage of such memory, is implicated in chemotherapy-induced damage. However, if the findings of two recent publications are combined, the (pre)frontal cortex might be an equally viable target. Two recent studies, one postulating a mechanism for ‘top-down control’ of working memory capacity and another visualizing chemotherapy-induced alterations in brain activation during working memory processing, are reviewed and integrated.

A computational model and the proposal that the prefrontal cortex plays a role in working memory via top-down control of parietal working memory capacity is consistent with a recent demonstration of decreased frontal hyperactivation following chemotherapy.

Chemotherapy-associated impairment of visuospatial working memory might include the (pre)frontal cortex in addition to the parietal cortex. This provides new opportunity for basic science and clinical investigation.

Health economic evaluation (HEE) is increasingly used in healthcare decision-making on the allocation of limited resources in national healthcare systems. Although the methods used for HEE vary in different countries, all economic evaluations address two questions: Are limited resources used optimally? Is value for money achieved in their use? Our objective is to explain some fundamental concepts in HEE and how these concepts are adapted in different countries, notably in Germany.

We performed a bibliographic search to identify existing methods of health economic evaluation of new drugs used by the official agencies of 11 countries (Austria, Australia, Canada, Finland, France, the Netherlands, Norway, New Zealand, Sweden, the United States and England and Wales) and compared them with that used by the German national agency IQWiG.

All countries considered follow internationally established standards of HEE. The majority of countries, including Germany, utilize primary outcome parameters such as disease-related morbidity and mortality for assessing relative efficacy and effectiveness. The most frequently recommended form of health economic evaluation is the cost–utility analysis (CUA). The German IQWIG is the only HTA body to use the cost–benefit concept of ‘efficiency frontier’ in its assessment.

While the core principles of HEE are the same worldwide, there is a lack of harmonization in the details. This requires resource-consuming adaptations in the analyses to meet different national requirements. We describe the core principles of HEE as a common basis for further discussions by all stakeholders.

Limited and conflicting evidence exists on the effect of a multicomponent pharmaceutical care intervention (i.e. medication review, involving collaboration between general practitioners (GPs), pharmacists and patients) on medication-related hospitalizations, survival, adverse drug events (ADEs) and quality of life. We aimed to investigate the effect of a multicomponent pharmaceutical care intervention on these outcomes.

An open controlled multicentre study was conducted within primary care settings. Patients with a high risk on medication-related hospitalizations based on old age, use of five or more medicines, non-adherence and type of medication used were included. The intervention consisted of a patient interview, a review of the pharmacotherapy and the execution and follow-up evaluation of a pharmaceutical care plan. The patient's own pharmacist and GP carried out the intervention. The control group received usual care and was cared for by a GP other than the intervention GP. The primary outcome of the study was the frequency of hospital admissions related to medication within the study period of 12 months for each patient. Secondary outcomes were survival, quality of life and ADEs.

364 intervention and 310 control patients were included. Less medication-related hospital admissions were found in the intervention group (n = 6; 1·6%) than in the control group (n = 10; 3·2%) but the overall effect was not statistically significant (hazard ratio (HR) 0·50, 95% confidence interval (CI) 0·12–1·59). The secondary outcomes were not statistically significantly different either. The study was underpowered, which may explain the negative results. A post hoc analysis showed that the effect of the intervention was statistically significant for patients with five diseases or more: five diseases, HR 0·28 (95% bootstrap CI: 0·056–0·73) and eight diseases, HR 0·11 (95% CI: 0·013–0·34).

A multicomponent pharmaceutical care intervention does not prevent medication-related hospital admissions. Whether this is true for such interventions in general is unknown, because the PHARM study was underpowered. The intervention may significantly reduce medication-related hospitalizations in patients with five or more comorbidities, but this is only based on a post hoc analysis and thus needs confirmation in large controlled trials.

Italian children receive a high number of antibiotic prescriptions, and the use of second-choice antibiotics is common. A few studies in other countries have demonstrated that the implementation of international guidelines for the most common paediatric diseases may reduce the associated costs. A cost analysis of the expenditure for antibiotic prescriptions in outpatient children in the Lombardy region (Italy) and for each of the region's local health units (LHUs) was performed using a pharmacoepidemiological approach. The safety and cost impact associated with a quali-quantitative improvement in antibiotic prescribing was estimated.

The data source was the Lombardy region's prescription database (year 2008) for outpatient children <14 years old. The average total expenditure for each package, and per capita, was calculated for each active substance considered and for each LHU. An estimate of the possible cost reduction was elaborated using, as a reference, the prescription profile of a group of paediatricians that has been involved in initiatives concerning care for years. The hospital admission rates for acute respiratory infections (ARI) and their major complications were evaluated at the regional level and in the group of children followed by the reference paediatricians.

The cost reduction estimate reveals a possible decrease in antibiotic expenditure of about 3·6 million euros (−19·5%) in the Lombardy region. Large variability was observed between different LHUs (−33·3 to +9·2% of difference). The hospital admission rate was not different when comparing the group of children followed by the reference paediatricians to the rest of the study population, but the hospital admission rate for ARI was lower in the reference group (χ² = 16·4, P < 0·001).

This is the first Italian study to evaluate the costs related to a specific prescription profile, which already exists in the real setting, hypothesizing its application in a large outpatient child population of the same geographical area. The results show that by improving prescribing appropriateness, it is possible to reduce the expenditure associated with antibiotic prescriptions to outpatient children in the Lombardy region by about one-fifth. The lower rate of hospital admissions for ARI suggests that the adopted profile is also beneficial to children's health.

Administering oral medications to patients with nasogastric tube (NGT) is a challenging patient-care issue. Inappropriate prescribing behaviour and incorrect procedure for extemporaneous preparation of oral suspensions given via NGT may result in significant harm to patients. There are many drugs which have not been tested regarding oral absorption profile and bioavailability derived from NGT dosing. Although several studies and case-reports have been reported, there is no up-to-date review of drug administration via NGT. The aim of this review is to increase awareness of rational drug administration via NGT and to encourage relevant research in this area.

Full prescribing information from each currently available oral medication was reviewed for any data indicating that the medication could not be crushed or opened. Literature was identified by searching PubMed (1988 to Aug 2012).

There is evidence to show that NGT dosing of some medications may bring both benefits (e.g. cost saving) and disadvantages (e.g. decrease in efficacy and/or safety). For medications with package inserts that warn that they should not be crushed or opened, alternatives are usually recommended. However, in some cases, there is evidence to support NGT dosing. Sometimes special procedures are required to avoid problems such as instability, interaction with enteral nutrition, adsorption, tube obstruction and low recovery when preparing extemporaneous oral suspensions.

Physicians, pharmacists and nurses should know the procedures for drug administration by NGT, as well as the latest evidence on such administrations. There may not be bioequivalence between oral and nasogastric administrations. Care must be taken to avoid compromising the physicochemical, biopharmaceutical and pharmacological properties of drugs given by NGT to ensure their safety and efficacy.

Positive inotropic agents are frequently used in acute decompensated heart failure (ADHF) due to left ventricular systolic dysfunction. These agents are known to improve cardiac performance and peripheral perfusion in the short-term treatment. However, several preclinical and clinical studies emphasized detrimental effects of these drugs on myocardial oxygen demand and on sympathetic tone entailing arrhythmogenesis. Levosimendan is an inotropic agent with an original mechanism of action. This review focuses on major data available for levosimendan.

A literature search was conducted in the PubMed database by including studies published in English using combinations of the following key words, levosimendan, inotropic drugs and acute heart failure. Furthermore, bibliographies of selected references were also evaluated for relevant articles. The collection for this review was limited to the most recently available human and animal data.

Levosimendan's vasodilatory and cardioprotective effects are mediated by calcium sensitization of contractile proteins and opening of adenosine triphosphate (ATP)-dependent K+ channels in vascular smooth muscle cells and on mitochondrial ATP-sensitive potassium [mito.K(ATP)] channels. This inotropic agent has mild PDE inhibitory action. Unlike other inotropic agents, levosimendan improves cardiac performance without activating the sympathetic nervous system. Moreover, there are evidences that levosimendan has additional anti-inflammatory and anti-apoptotic properties that prevent cardiac toxicity and contributes to positive hemodynamic response of the drug. Four randomized trials evaluated the effects of levosimendan on mortality in patients with acute decompensated chronic heart failure; nevertheless, a clear benefit has not been demonstrated so far. Although levosimendan is indicated for the treatment of ADHF (class of recommendation IIa, level of evidence B), it is has not been approved in all countries.

This review summarizes the characteristics and the current knowledge of the literature on levosimendan and its active metabolite OR-1896.

Psoriatic arthritis is an autoimmune disease characterized by chronic inflammation of the skin and joints. Anti-TNF drugs reduce the severity of the disease in the long term. This study compares the efficacy and safety of adalimumab, etanercept, infliximab and golimumab in patients with psoriatic arthritis.

Direct comparison was based on a literature search of drug comparison studies, whereas indirect treatment comparison was based on phase III clinical trials with biological agents, involving similar populations and durations, and with the same outcome. ACR50 was taken as primary outcome for comparison, whereas ACR20 and ACR70 were used as secondary outcomes. Indirect comparisons were made using infliximab as the reference drug and the Bucher method. In calculating δ (the maximum acceptable difference as a clinical criterion of equivalence), use was made of half of the absolute risk reduction obtained in the meta-analysis of the clinical trials included in the indirect comparison (ARR 32%; δ: 16%). The four anti-TNF drugs were also compared in relation to the secondary outcomes and adverse effects.

Reported direct and indirect comparisons of the four drugs did not include golimumab, and did not yield conclusive results. Four clinical trials – one for each drug studied – were identified. The estimated differences for the primary outcome, ACR50, between infliximab and the other drugs were adalimumab (ARR 4%, 95% CI −9·5 to 17·5), etanercept (ARR 4%, 95% CI −10·5 to 18·5) and golimumab (ARR 9%, 95% CI −5·4 to 23·4). Likewise, there were no relevant differences between the drugs in relation to the secondary efficacy outcomes, except for etanercept, which was less effective in ACR70 response. For adverse reactions, there were also no significant differences except for injection site, reactions which were more frequent with etanercept, with a mean difference of 26% relative to infliximab.

No significant differences were found in ACR50 responses to the four drugs after 24 weeks. Injection-site reactions were more common with etanercept, but this was insufficient to invalidate the inference that clinically the four drugs can be regarded as clinically equivalent for the treatment of psoriatic arthritis.

The US Food and Drug Administration approved ceftaroline in 2010 for the treatment of community-acquired pneumonia and skin and soft-tissue infections. The most common adverse reactions are diarrhoea, nausea and rash. To present the first case of neutropenia directly related to ceftaroline.

A 90-year-old female was given ceftaroline for treatment of a pneumonia complicated by methicillin-resistant Staphylococcus aureus bacteraemia and possible vertebral osteomyelitis. After 25 days of ceftaroline, she developed neutropenia. Ceftaroline was discontinued and her white blood cell count returned to normal within one week.

Although neutropenia is a potential cephalosporin class effect, we present the first case of neutropenia directly related to ceftaroline. Agranulocytosis and neutropenia are rare, yet potentially life-threatening adverse effects of cephalosporins. Healthcare providers should be aware of the potential for ceftaroline to cause neutropenia, particularly in patients treated for greater than two weeks.

Adefovir dipivoxil (ADV) is one of the commonly used antiviral agents in the treatment of chronic hepatitis B (CHB) infection. Safety of a daily dose of 10 mg ADV is advocated by the registration trials. We report a case of severe hypophosphatemic osteomalacia and renal Fanconi syndrome induced by low-dose ADV in a CHB-related cirrhosis patient, and discuss the case through a thorough review of other cases reported in the literature.

A 48-yr-old Chinese man with CHB-related cirrhosis developed severe progressive generalized bone pain and muscle weakness after receiving ADV 10 mg daily for 54 months. The laboratory results showed severe hypophosphatemia and features of proximal renal tubule dysfunction. Imaging studies were consistent with osteomalacia. After discontinuation of ADV, his symptoms resolved, laboratory abnormalities normalized and imaging studies showed improvement. In addition to our case, 12 other patients have been reported to have developed hypophosphatemic osteomalacia induced by low-dose ADV. Most of the reported cases were of subjects of East-Asian ethnicity. After discontinuation or reduction of ADV, serum phosphate level increased and clinical symptoms significantly improved in all cases.

Hypophosphatemic osteomalacia and renal Fanconi syndrome can be associated with low-dose ADV. Clinicians treating CHB patients with ADV 10 mg daily over long periods of time should be aware of this infrequent but serious complication

Sunitinib can improve progression-free survival and overall survival in patients with advanced pancreatic neuroendocrine tumor (PNET). From clinical trial, most commonly reported adverse events of sunitinib were neutropenia (12%), diarrhea (10%), asthenia (7%), erythrodysesthesia (7%), hypertension (7%) and thrombocytopenia (6%).

We report a patient with PNET with liver metastases who developed hyperammonemia with a low dosage of sunitinib probably contributed by the presence of liver metastases.

We would like to draw attention to the potential risk of sunitinib induced hyperammonemic encephalopathy even with a low dosage of sunitinib. The absence of sunitinib-induced hyperammonemia during its initial course does not rule out this possibility if there is increased in liver metastases. We suggest checking the ammonia level if patient on sunitinib presented with altered sensorium even if the liver function is normal.

Tacrolimus has a narrow therapeutic index and shows large interindividual variations in pharmacokinetics, which may be partly explained by genetic variability in metabolic enzymes of the cytochrome P450 (mainly CYP3A4 and CYP3A5) and transport P-glycoprotein (encoded by the ABCB1 gene). Genetic variability in the expression of biotransformation enzymes and drug transporters may also predispose individuals to tacrolimus-induced nephrotoxicity.

We report a case of severe biopsy-proven Tacrolimus (TAC) nephrotoxicity that occurred 1 month after renal transplantation despite persistently low TAC levels. The donor genotype was CYP3A5*3/*3 (loss-of-function genotype), whereas that of the recipient was CYP3A5*1/*3. The donor and recipient genotypes did not differ with respect to either CYP3A4 rs35599367C>T (both were CC homozygotes) or ABCB1 gene polymorphisms (both TT homozygotes for the 1236C>T polymorphism and CT heterozygotes for the 3435C>T polymorphism).

This case study suggests that donor/recipient genetic mismatch in metabolic enzymes may have an important role in modulating tacrolimus nephrotoxicity. It provides a possible explanation for the intriguing observation that for a subset of patients, cumulative TAC doses appear to correlate better with nephrotoxicity than trough levels.

Many drugs fail during development. However, detailed reasons for failure during drug development are almost never disclosed. We focused on the drugs whose clinical development and registration were initially hampered, but which were finally approved to identify reasons that delayed their marketing approval in Japan.

We analysed 727 new drug applications (NDAs) approved in Japan between 2001 and 2011.

Fifty-three NDAs had serious and identifiable problems during drug development. Of these, 43 NDAs had ‘problem related to clinical data’. We found that the problems for withdrawal of these NDAs could be ascribed largely to inappropriate clinical data package and study design for supporting the intended indications and usage and to unclear clinical results for defining dosage regimen or efficacy of the drugs.

Our results indicate the importance of careful determination of the optimal dosage regimen and the choice of objective endpoints in clinical trials. Further, it is important to establish a clear strategy for generating the clinical data package, to include careful design of clinical trials on the basis of the nature of the target disease and target population. For drugs marketed in Japan, there is a need to include sufficient numbers of Japanese patients in the trials.

Single-dose rasburicase for the treatment and prevention of hyperuricaemia in adult and paediatric patients with cancer at high risk of tumour lysis syndrome (TLS) has been widely adopted in pharmacy practice as unlabelled use with limited clinical evidence. This meta-analysis study evaluated the efficacy and cost savings of a single-dose rasburicase (SDR) regimen compared with the Food and Drug Administration-approved daily dosing of rasburicase (DDR) for 5 days or the traditional treatment with allopurinol in adult cancer patients with hyperuricaemia or at high risk for TLS.

Prospective and retrospective studies were retrieved from a systemic search of major electronic data sources. Studies included in the meta-analysis were those with SDR for the prophylaxis of high-risk TLS or treatment of hyperuricaemia in adult patients with cancer. The results of response rate and controlling of time-dependent plasma uric acid (UA) reduction were pooled and compared with the results from patients treated with DDR for 5 days or patients treated with allopurinol. A cost analysis was performed to analyse the treatment costs for adults with hyperuricaemia or at high risk for TLS.

Ten studies (eight retrospective and two prospective) evaluated the SDR response rate and plasma UA level reduction over time. The pooled total number of patients treated with SDR (from 0·05 mg/kg to 0·20 mg/kg) was 269. The pooled response rate of the SDR arm was not significantly different than that of DDR (0·2 mg/kg) arm (88·15% vs. 90·18%, P = 0·542), but significantly stronger than that of allopurinol (300 mg/day orally days 1 to 5) arm (response rate: 88·15% vs. 66%, P < 0·0005). Pooled SDR group efficiently controlled the plasma uric acid (UA) level below 4·5 mg/dL over 24 h, 48 h and 72 h, whereas DDR reduced plasma UA levels to hypouricaemia level (<2 mg/dl). In addition, cost analysis demonstrated that standard-dose SDR (≥6 mg) has non-inferior clinical benefit and significant cost savings compared with the DDR regimen.

Single-dose rasburicase (SDR) for adult cancer patients with hyperuricaemia or at high risk for TLS demonstrated better response rate and stronger control of uric acid level compared with allopurinol. SDR response rate was not inferior to that of DDR, and the standard-dose SDR generates more cost savings compared with the DDR. It suggests that the single-dose rasburicase is clinically effective and cost efficient for the prophylaxis of high-risk TLS and the treatment of hyperuricaemia in adult patients with cancer. Additional randomized control studies are needed to confirm the findings of this meta-analysis study.

Ulipristal acetate (UPA) is a novel selective progesterone receptor modulator for benign gynaecological conditions such as uterine myoma. The safety and pharmacokinetics of multiple-dose UPA and its N-mono-demethylated metabolite, PGL4002, were investigated in women.

The double-blind, placebo-controlled study randomized 32 healthy women of reproductive age to receive 10 consecutive daily doses of placebo, 10, 20 or 50 mg UPA. Safety assessments included vital signs, physical examination, ECG, clinical laboratory tests and reporting of adverse events. Blood samples for pharmacokinetic analysis were collected on Days 1 and 10 at intervals until 168 h after multiple dosing.

UPA was well tolerated at all doses. Mild or moderate adverse events occurred with similar frequency in UPA and placebo groups. UPA median t_max was 0·75 and 0·89 h, and mean plasma half-life was between 38 and 49 h. C_max values (Day 1) were 42·2, 130·9 and 354·8 ng/mL for the UPA 10, 20 and 50 mg treatment groups, respectively. Corresponding C_max values for Day 10 were 63·7, 169·8 and 454·9 ng/mL. AUC_SS values on Day 10 were 216·6, 602·8 and 1655·7 ng h/mL after 10, 20 and 50 mg UPA, respectively. For the principal metabolite PGL4002, t_max and plasma elimination half-life values were similar to those of UPA. PGL4002 AUC_SS Day 10 values were 84·7, 203·6 and 452·1 ng h/mL for 10, 20 and 50 mg groups, respectively.

Daily administration of UPA at therapeutic and supratherapeutic doses was well tolerated by women of reproductive age. UPA exposure increases with dose. Exposure to PGL4002 is approximately one-third that of UPA.

Potentially inappropriate prescribing (PIP) has significant clinical, humanistic and economic impacts. Identifying PIP in older adults may reduce their burden of adverse drug events. Tools with explicit criteria are being developed to screen for PIP in this population. These tools vary in their ability to identify PIP in specific care settings and jurisdictions due to such factors as local prescribing practices and formularies. One promising set of screening tools are the STOPP (Screening Tool of Older Person's potentially inappropriate Prescriptions) and START (Screening Tool of Alert doctors to the Right Treatment) criteria. We conducted a systematic review of research studies that describe the application of the STOPP/START criteria and examined the evidence of the impact of STOPP/START on clinical, humanistic and economic outcomes in older adults.

We performed a systematic review of studies from relevant biomedical databases and grey literature sources published from January 2007 to January 2012. We searched citation and reference lists and contacted content experts to identify additional studies. Two authors independently selected studies using a predefined protocol. We did not restrict selection to particular study designs; however, non-English studies were excluded during the selection process. Independent extraction of articles by two authors used predefined data fields. For randomized controlled trials and observational studies comparing STOPP/START to other explicit criteria, we assessed risk of bias using an adapted tool.

We included 13 studies: a single randomized controlled trial and 12 observational studies. We performed a descriptive analysis as heterogeneity of study populations, interventions and study design precluded meta-analysis. All observational studies reported the prevalence of PIP; however, the application of the criteria was not consistent across all studies. Seven of the observational studies compared STOPP/START with other explicit criteria. The STOPP/START criteria were reported to be more sensitive than the more-frequently-cited Beers criteria in six studies, but less sensitive than a set of criteria developed in Australia. The STOPP criteria identified more medications associated with adverse drug events than the 2002 version of the Beers criteria. Patients with PIP, as identified by STOPP, had an 85% increased risk of adverse drug events in one study (OR = 1·85, 95% CI: 1·51–2·26; P < 0·001). There was limited evidence that the application of STOPP/START criteria optimized prescribing. Research involving the application of STOPP/START on the impact on the quality of life was not found. The direct costs of PIP were documented in three studies from Ireland, but more extensive analyses on the economic impact or studies from other jurisdictions were not found.

The STOPP/START criteria have been used to review the medication profiles of community-dwelling, acute care and long-term care older patients in Europe, Asia and North America. Observational studies have reported the prevalence and predictors of PIP. The STOPP/START criteria appear to be more sensitive than the 2002 version of the Beers criteria. Limited evidence was found related to the clinical and economic impact of the STOPP/START criteria.

Paroxetine is both a substrate and an inhibitor of CYP2D6. The objective of the presented study was to determine the persistence of CYP2D6 inhibition after short term (6 weeks) and long term (18·7 ± 10·6 weeks) paroxetine treatment.

Two the studies consisted of 30 depressive/anxiety patients each. In the first study, patients were subdivided into three groups treated with paroxetine (A1), alprazolam (A2) and paroxetine + alprazolam (A3). After 6 weeks, all the patients (A1+A2+A3) were switched to alprazolam treatment; metabolic activity was evaluated at the beginning, after 6 weeks of paroxetine/alprazolam/alprazolam + paroxetine treatment (A1/A2/A3) and 4 weeks after the switch to alprazolam treatment (Week 0, 6, 10). In the second study patients on previous long term paroxetine treatment were subdivided into two groups treated with mirtazapine (B1) or paroxetine (B2); metabolic activity of CYP2D6 was evaluated at the beginning and after 6 weeks of therapy.

Metabolic ratio of dextromethorphan to dextrorphan has normalized in all subjects after 4 weeks of paroxetine wash out in the first study. In the second study, 6 weeks after paroxetine discontinuation, restoration of metabolic activity of CYP2D6 was observed in only five of eight originally poor metabolizers.

We conclude that a wash-out period of 4 weeks seems to be sufficient for CYP2D6 disinhibition after short-term paroxetine treatment (6 weeks). On the other hand, treatment with a CYP2D6 substrate less than 6 weeks after long-term paroxetine treatment (18·7 weeks on average) could result in elevated drug plasma levels and occasionally also in drug toxicity.

The 2012 position statement from the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) recommends a haemoglobin A1c level of <7% for most patients with type 2 diabetes (T2D). Initial therapy consists of lifestyle changes plus metformin, with an emphasis on a patient-centred approach to management. Addition of incretin-based therapy is recommended as an add-on after metformin failure, and later on in combination with basal insulin. Basal insulin is recommended from the onset in patients with A1c ≥10%. The possibility of incorporating incretin-based therapy in the patient-centred approach will be investigated both in the literature and clinical experience.

Incretin-based therapy targets multiple dysfunctional organ systems in T2D and provides sustained glycaemic control, with extraglycaemic benefits and low risk of hypoglycaemia. To initiate an incretin-based therapy that best fits an individual patient's needs, the patient's A1c level, preference and comorbid conditions should be considered along with any drug safety and adherence-related issues.

There is good evidence to support the patient-centred approach to T2D management. This approach allows patient treatment goals and personal preferences to be matched with the clinical profile(s) of one or more agents to formulate a treatment plan that can best achieve the goals. Incretin-based therapies are an important class of agents to consider after metformin monotherapy failure and later in combination with basal insulin. By matching patient needs with the clinical profiles of the various treatment options, pharmacists can actively engage in the practice of patient-centred care and management.

Individuals who abuse drugs usually use more than one substance. Toxic consequences of single and multi-drug use are well documented in the Treatment Episodes Data Set that lists drug combinations that result in hospital admissions. Using this list as a guide, we focused our attention on combinations that result in the most hospital admissions and searched the PubMed database with the objective of determining the number of such publications and, in particular, those that used the term synergism in their titles or abstracts.

Using the search criteria produced an extensive list of published articles. However, a further intersection of the search terms with the term isobole revealed a surprisingly small number of literature reports.

Because the method of isoboles is the most common quantitative method for distinguishing between drug synergism and simple additivity, the small number of investigations that actually employed this quantification suggests that the term synergism is not properly documented in describing the toxicity among abused substances. The possible reasons for this lack of quantification may be related to a misunderstanding of the modelling equations. To help rectify this possible hurdle to understanding and clinical utility, the theory and modelling are discussed here.

Prescribing sulfonamide-containing medications for patients with sulfonamide allergy continues to complicate medical decisions. We examined the cautionary recommendations in the approved drug monographs and primary literature, and formulated an evidence-based grading of cautionary recommendations for sulfonamide allergy and cross-reactivity among sulfonamide-containing medications.

Drug monographs were collected from six countries and three drug compendia. Two reviewers independently extracted the data from the contraindication, warning and/or precaution sections of drug monographs. Evidence for cross-reactivity was examined in the primary literature and compared with drug monograph recommendations. Consequently, medications were categorized based on the strength of recommendation and level of evidence by consensus.

We identified wide variability in cautionary recommendations ranging from no warning or precaution to contraindication among the sources reviewed. The recommendations were located mainly in the contraindication section of monographs for France (65·2%), United Kingdom (51·9%), Italy (50·0%), South Korea (43·5%), United States (38·2%) and Canada (37·0%), whereas in drug compendia, the recommendations were found in the precaution section for Martindale (51·4%) and Micromedex-Drugdex (33·3%), and contraindication and precaution section for the American Hospital Formulary Service Drug Information 2010 (30·8%). Evidence from the primary literature varied with recommendation included in drug monographs. Evidence-based categorization was carried out for 16 medications. Two sulfonamide-moiety-containing drugs were considered safe, six non-sulfonylarylamines required precaution, and eight medications from all three sulfonamide chemical classes were considered mostly unsafe.

There are significant discrepancies in cautionary recommendations included in drug-labels and drug compendia. Statements concerning cross-reactive hypersensitivity with other sulfonamides generally suggest theoretical possibilities. The consensus evidence-based grading instrument developed may be useful for deriving cautionary recommendations for sulfonamide-allergic patients.

Combining methotrexate (MTX) with trimethoprim-sulfamethoxazole (TS) is associated with a potential drug interaction that increases MTX toxicity. The aim of this article is to review the current literature about the potential drug interaction resulting from combining MTX with TS, and to establish therapeutic recommendations regarding their use together.

Literature for relevant evidence was searched by Medline (through PubMed), Cochrane library and a manual search through major journals for articles referenced in those located through PubMed.

One systematic review, three studies and 17 case reports were found to be relevant to the topic. Results from the current available literature clearly indicate a major drug interaction between MTX and TS, which increases the risk of MTX toxicity, like severe pancytopenia, which was fatal in some cases. Recommendations to prevent this serious interaction should be developed and implemented in the currently available therapeutic guidelines related to MTX therapy.

MTX and TS is an extremely serious and life-threatening combination that should be avoided. Practical recommendations regarding MTX use can be established to prevent harm from drug interactions. Increasing awareness of physicians, pharmacist and patients is essential to assure safe and effective MTX therapy.

The medication reconciliation process begins by identifying which medicines a patient used before presentation to hospital. This is time-consuming, labour intensive and may involve interruption of clinicians. We sought to identify the availability and accuracy of data held in a national dispensing database, relative to other sources of medication history information.

For patients admitted to two acute hospitals in Ireland, a Gold Standard Pre-Admission Medication List (GSPAML) was identified and corroborated with the patient or carer. The GSPAML was compared for accuracy and availability to PAMLs from other sources, including the Health Service Executive Primary Care Reimbursement Scheme (HSE-PCRS) dispensing database.

Some 1111 medication were assessed for 97 patients, who were median age 74 years (range 18–92 years), median four co-morbidities (range 1–9), used median 10 medications (range 3–25) and half (52%) were male. The HSE-PCRS PAML was the most accurate source compared to lists provided by the general practitioner, community pharmacist or cited in previous hospital documentation: the list agreed for 74% of the medications the patients actually used, representing complete agreement for all medications in 17% of patients. It was equally contemporaneous to other sources, but was less reliable for male than female patients, those using increasing numbers of medications and those using one or more item that was not reimbursable by the HSE.

The HSE-PCRS database is a relatively accurate, available and contemporaneous source of medication history information and could support acute hospital medication reconciliation.

Diuretics can cause changes in calcium levels due to renal effects. Moreover, calcium levels can also vary as a result of changes in intestinal absorption and in the activity of osteoclastic cells. A marker of osteoclastic bone-resorption activity is the level of urinary free deoxypyridinoline (FDP). Deoxypyridinoline (DP) acts as a cross-link between adjacent collagen chains to provide structural rigidity. Our aim was to investigate the association between use of thiazides and loop diuretics and urinary levels FDP.

In this follow-up study, data were obtained from the Rotterdam Study, a large population-based prospective cohort study. For a subset of 658 participants, urinary levels of FDP were measured at baseline. Linear regression analysis was performed to assess the association between the use of thiazides and loop diuretics and the urinary levels of FDP.

In women, current use of loop diuretics for less than 42 days was associated with an increased level of urinary FDP (+3·43 nmol deoxypyridinoline per mmol urinary creatinine; 95% CI 1·85; 5·02) compared with no use. However, use for a period of more than 42 days was not associated with an increased level of FDP, nor was past use of loop diuretics. For thiazide diuretics, no statistically significant associations were found.

In women, short-term use of loop diuretics is associated with an increased level of FDP, reflecting increased bone resorption by osteoclasts. As the difference disappears with longer term use, the clinical significance is unclear and the value of FDP as a biomarker in this setting is not established. The molecular mechanism for the observed differences in bone fracture rates with use of diuretics remains unclear.

Demonstration of the utility of electronic medical records (EMRs) for pharmacovigilance (PV) has been highly anticipated. Analysis using appropriately selected EMRs should enable accurate estimation of adverse drug event (ADE) frequencies and thus promote appropriate regulatory actions. Statin-induced myopathy (SIM) is a clinically important ADE, but pharmacoepidemiological methodology for detecting this ADE with high predictability has not yet been established. This study aimed to develop a detection algorithm, highly selective for SIM using EMRs.

We collected EMRs on prescriptions, laboratory tests, diagnoses and medical practices from the hospital information system of Kobe University Hospital, Japan, for a total of 5109 patients who received a statin prescription from April 2006 to March 2009. The current algorithm for extracting SIM-suspected patients consisted of three steps: (i) event detection: increase in creatine kinase (CK) and subsequent statin discontinuation, (ii) filtration by exclusion factors (disease diagnosis/medical practices) and (iii) refinement by the time course of CK values (baseline, event and recovery). A causal relationship between the event and statin prescription (probable/possible/unlikely) was judged by review of patient medical charts by experienced pharmacists. The utility of the current algorithm was assessed by calculating the positive predictive value (PPV). In a comparative analysis, subjects screened in step 1 were extracted by the diagnostic term/code for ‘myopathy/rhabdomyolysis’, and the PPV of this diagnostic data approach was also estimated.

Five subjects with suspected SIM were identified using our proposed algorithm, giving a frequency of 0·1% for the adverse event. Review of the medical charts revealed that the causal association of SIM with statin use was judged as ‘Likely (probable/possible)’ for all five suspected patients; thus, the PPV was estimated as 100% (95% confidence interval: 56·6–100%). The higher utility of the current algorithm compared with the diagnostic data approach was also shown by assessing the PPV (100 vs. 33·3%).

We report on a detection algorithm with high predictability for SIM using EMRs. Combined use of exclusion criteria for disease, medical practice data and time course of CK values contributes to better prediction of SIM. The utility of the proposed algorithm should be further confirmed in a larger study.

Neuraminidase inhibitors are important options for the treatment of infection by the influenza virus. For the treatment of severe influenza, parenteral administration of a neuraminidase inhibitor may be desirable. This study was conducted to evaluate the pharmacokinetic and safety profiles of intravenous zanamivir, an influenza viral neuraminidase inhibitor, in Japanese subjects to further characterize these profiles particularly following relatively high-doses when compared with inhalation doses and to provide reassurance that there are no marked differences with profiles reported for other ethnically different populations.

Single doses of 100, 300, 600 mg zanamivir were administered to healthy Japanese men in a randomized, double-blind, ascending dose, placebo-controlled, incomplete three-period cross-over study. In period 3, subjects were given 600 mg of zanamivir on day 1, followed by a 60 h washout period and then a 5-day course of 600 mg zanamivir twice daily. Each subjects received two of three active dosages of zanamivir from 100, 300 and 600 mg, and placebo.

Adverse events reported in the study were all mild in intensity and resolved without any treatment. The mean AUC_0–∞ values after single intravenous administration of 100, 300 and 600 mg were 16768, 53462 and 100400 ng·h/mL, respectively, demonstrating dose proportionality. No accumulation or time variance was observed after 5 days of twice-daily administration of 600 mg zanamivir. Urinary concentrations of zanamivir after single doses ranging from 100 to 600 mg indicated that over 94% of the zanamivir administered was excreted in urine within 24 h.

Single and 5-day BID repeat dosing of 600 mg were safely administered in Japanese healthy subjects. The pharmacokinetic profile of zanamivir after intravenous administration was consistent with previously reported findings in non-Japanese subjects.

Anidulafugin is an echinocandin used for the treatment of candida infections in non-neutropenic adults. Echinocandins show few drug–drug interactions and are usually well tolerated. We report a case of acute hypotension, bradycardia and haemodynamic instability with consecutive cardiopulmonary resuscitation during anidulafungin administration.

A 41-year-old man ICU patient received anidulafungin for a suspected Candida glabrata infection. During the first administration of the drug, he developed acute haemodynamic instability with hypotension and bradycardia. The infusion was discontinued immediately and cardiopulmonary resuscitation was performed successfully. The patient regained haemodynamic stability.

To the authors' knowledge, this is the first report of a life-threatening adverse event due to haemodynamic instability during anidulafungin administration. Cardiac toxicity associated with echinocandins has been described. Further studies seem to be mandatory to investigate this potential risk.

Colchicine is an anti-inflammatory agent used primarily in treatment of gout and familial Mediterranean fever. Toxicity is uncommon, and depends on dose, hepatic or renal impairment, co-administration with P-glycoprotein or CYP3A4 inhibitors and route of administration. In patients taking p-glycoprotein inhibitors, maximum recommended dose is 0·3 mg per day. In renal or hepatic impairment, recommendation is to avoid concomitant administration of p-glycoprotein inhibitors and colchicine.

We present an 82 year old patient, with a history of gout, chronic kidney disease and recurrent renal cell carcinoma who was admitted with features of colchicine toxicity after taking a cumulative dose of 41·4 mg over ten days, and taking sunitinib 50 mg daily from day seven of his high dose colchicine regimen. Symptoms started after commencing his cycle of sunitinib, which he had taken in 14 day cycles for many years. He developed severe diarrhea, normal anion gap metabolic acidosis, fever, pneumonia, white cell abnormalities including 30% bands and toxic granulation with Dohle bodies. Red cell abnormalities included anemia, burr cells and acanthocytosis. He also developed acute cardiovascular collapse with hypotension and acute systolic heart failure. Cardiac catheterization showed previously known coronary artery disease, with no significant progression to explain degree of cardiovascular collapse.

P-glycoprotein inhibition by sunitinib has been demonstrated. Interaction with colchicine metabolism precipitated colchicine toxicity in this case. Knowledge of p-glycoprotein and its role in drug interactions and potential drug toxicity may not be widespread among clinicians. We report the first case of colchicine toxicity precipitated by interaction with a tyrosine kinase inhibitor.

Rituximab, an anti-CD20 monoclonal antibody, is widely used with good response for the treatment of B-cell lymphoma and various refractory autoimmune diseases. Although rituximab is effective, rare but serious pulmonary adverse reactions have been reported. We report on a case of rituximab-induced life-threatening interstitial lung disease in a patient with diffuse large B-cell lymphoma (DLBCL), and describe the patient's serum cytokine profile during anti-TNF-α treatment.

Case summary: A 71-year-old woman diagnosed with DLBCL was treated with three cycles of rituximab-containing chemotherapy. She developed a fatal respiratory failure, which was eventually diagnosed as rituximab-induced interstitial lung disease (R-ILD). The R-ILD in this patient did not respond to intensive steroid treatment, or to enternacept, an anti-TNF therapy. During therapy, we observed that the serum level of IL-6 was much higher at the beginning of treatment than was usual for other DLBCL patients. Levels of IL-6 and TNF-α also increased during the course of the clinical exacerbation. We undertook a literature search and reviewed similar cases of R-ILD.

Although rituximab is generally effective and safe, caution is required for high-risk patients, as in our case, and as reported in several other cases in the literature. Cytokine analysis may help in identifying patients at high risk of R-ILD. Better intensive therapeutic approaches other than steroids are required even during the early stages of the complication.

Complementary medicines are commonly used by many patients. Caesium, a complementary therapy said to be of benefit for cancer treatment, has been associated with cardiac arrhythmias in the literature. We report a case of caesium-induced torsades de pointes and provide an evidence review.

A 46-year-old woman with syncope experienced torsades de pointes and cardiac arrest. Upon admission her QTc was 620 ms. The patient had taken caesium carbonate 10 g daily for 1 month prior to admission. The patient was successfully resuscitated and discharged home after 35 days in hospital.

Ten cases of caesium-induced cardiac arrhythmias have previously been reported in the literature. Treatment strategies differed significantly among the cases. However, all patients recovered from the event. Complementary and alternative medicines should not be overlooked as a potential cause of serious adverse events.

Febuxostat is a new non-purine selective inhibitor of xanthine oxidase for the treatment of hyperuricaemia in patients with gout. Febuxostat is recommended as the first-line pharmacologic urate-lowering therapy for gout in the American College of Rheumatology guidelines. Febuxostat has not been reported to cause severe complications, especially haematological abnormalities. Our objective is to report two cases of neutropenia associated with initiation of febuxostat therapy for hyperuricaemia in patients with chronic kidney disease (CKD).

A 74-year-old woman with liver cirrhosis and CKD was treated with febuxostat for hyperuricaemia during hospitalization. Eleven days after febuxostat administration, she developed neutropenia. A 68-year-old man with type 2 diabetes mellitus on intermittent haemodialysis was treated with febuxostat for hyperuricaemia during hospitalization. Three days after febuxostat administration, he developed neutropenia. In the two cases, febuxostat treatment was discontinued and granulocyte colony-stimulating factor was administered, with concomitant recovery of the neutrophil count.

We believe this to be the first published case of neutropenia associated with initiation of febuxostat therapy for hyperuricaemia. According to the Naranjo probability scale, febuxostat was the probable cause of neutropenia. In view of the wide clinical usage of this drug, physicians and pharmacists should be alerted to this possible complication.

Congenital leukaemia is the most common leukaemia in newborns with Down syndrome, but it must be differentiated from transient myeloproliferative disorder. The majority of transient myeloproliferative disorders regresses spontaneously during the first few months of life. Data on the treatment outcomes of transient myeloproliferative disorder in premature infants are very rare. We present a case of a very-low-birthweight (1350 g) premature newborn with Down syndrome, diagnosed as having transient myeloproliferative disorder and treated with chemotherapy due to recurrent hyperleucocytosis (WBC: 148 000/mm³) after repeated exchange transfusions.

The patient's WBC count regressed to 24 000/mm³ without treatment. During the follow-up period, the WBC increased on consecutive days and reached 95 000/mm³ on the 16th day of the hospitalization. Therefore, chemotherapy was started. Single-agent cytarabine infusion was administered over five days. After the therapy, the WBC count stayed stable and remained steady in the range 4600–13600/mm³ in the second month.

A very-low-birthweight infant with Down syndrome and recurrent transient myeloproliferative disorder was successfully treated with cytarabine.