Which drugs cause preventable admissions to hospital? A systematic review

AIMS: Previous systematic reviews have found that drug-related morbidity accounts for 4.3% of preventable hospital admissions. None, however, has identified the drugs most commonly responsible for preventable hospital admissions. The aims of this study were to estimate the percentage of preventable drug-related hospital admissions, the most common drug causes of preventable hospital admissions and the most common underlying causes of preventable drug-related admissions. METHODS: Bibliographic databases and reference lists from eligible articles and study authors were the sources for data. Seventeen prospective observational studies reporting the proportion of preventable drug-related hospital admissions, causative drugs and/or the underlying causes of hospital admissions were selected. Included studies used multiple reviewers and/or explicit criteria to assess causality and preventability of hospital admissions. Two investigators abstracted data from all included studies using a purpose-made data extraction form. RESULTS: From 13 papers the median percentage of preventable drug-related admissions to hospital was 3.7% (range 1.4-15.4). From nine papers the majority (51%) of preventable drug-related admissions involved either antiplatelets (16%), diuretics (16%), nonsteroidal anti-inflammatory drugs (11%) or anticoagulants (8%). From five studies the median proportion of preventable drug-related admissions associated with prescribing problems was 30.6% (range 11.1-41.8), with adherence problems 33.3% (range 20.9-41.7) and with monitoring problems 22.2% (range 0-31.3). CONCLUSIONS: Four groups of drugs account for more than 50% of the drug groups associated with preventable drug-related hospital admissions. Concentrating interventions on these drug groups could reduce appreciably the number of preventable drug-related admissions to hospital from primary care.     

A comprehensive review on Brigatinib – A wonder drug for targeted cancer therapy in non-small cell lung cancer

The mortality rate in patients suffering from non-small cell lung cancer (NSCLC) is quite high. This type of cancer mainly occurs due to rearrangements in the anaplastic lymphoma kinase (ALK) gene which leads to form an oncogene of fused gene NPM-ALK. Brigatinib is recently approved by FDA in April 2017 as a potent tyrosine kinase inhibitor (TKI) for the NSCLC therapy. In the present scenario, it is no less than a wonder drug because it is indicated for the treatment of advanced stages of metastatic ALK positive NSCLC, a fatal disease to overcome the resistance of various other ALK inhibitors such as crizotinib, ceritinib and alectinib. In addition to ALK, it is also active against multiple types of kinases such as ROS1, Insulin like growth factor-1Receptor and EGFR. It can be synthesized by using N-[2-methoxy-4-[4-(dimethylamino) piperidin-1-yl] aniline] guanidine and 2,4,5-trichloropyrimidine respectively in two different ways. Its structure consists of mainly dimethylphosphine oxide group which is responsible for its pharmacological activity. It is active against various cell lines such as HCC78, H2228, H23, H358, H838, U937, HepG2 and Karpas- 299. Results of ALTA (ALK in Lung Cancer Trial of AP26113) phase ½ trial shows that 90?mg of brigatinib for 7?days and then 180?mg for next days is effective in the treatment of NSCLC. Brigatinib has been shown to have favorable risk benefit profile and is a safer drug than the available cytotoxic chemotherapeutic agents. In comparison to other FDA approved drugs for the same condition, it causes fewer minor adverse reactions which can be easily managed either by changing the dose or by providing good supportive care. This article is intended to provide readers with an overview of chemistry, pharmacokinetic, pharmacodynamic and safety profile of brigatinib, which addresses an unmet medical need.     

Does pharmacist-led medication review help to reduce hospital admissions and deaths in older people? A systematic review and meta-analysis

We set out to determine the effects of pharmacist-led medication review in older people by means of a systematic review and meta-analysis covering 11 electronic databases. Randomized controlled trials in any setting, concerning older people (mean age > 60 years), were considered, aimed at optimizing drug regimens and improving patient outcomes. Our primary outcome was emergency hospital admission (all cause). Secondary outcomes were mortality and numbers of drugs prescribed. We also recorded data on drug knowledge, adherence and adverse drug reactions. We retrieved 32 studies which fitted the inclusion criteria. Meta-analysis of 17 trials revealed no significant effect on all-cause admission, relative risk (RR) of 0.99 [95% confidence interval (CI) 0.87, 1.14, P  = 0.92], with moderate heterogeneity (I² = 49.5, P  = 0.01). Meta-analysis of mortality data from 22 trials found no significant benefit, with a RR of mortality of 0.96 (95% CI 0.82, 1.13, P  = 0.62), with no heterogeneity (I² = 0%). Pharmacist-led medication review may slightly decrease numbers of drugs prescribed (weighted mean difference = −0.48, 95% CI −0.89, −0.07), but significant heterogeneity was found (I² = 85.9%, P  < 0.001). Results for additional outcomes could not be pooled, but suggested that interventions could improve knowledge and adherence. Pharmacist-led medication review interventions do not have any effect on reducing mortality or hospital admission in older people, and can not be assumed to provide substantial clinical benefit. Such interventions may improve drug knowledge and adherence, but there are insufficient data to know whether quality of life is improved.     

Comparative epidemiology of hospital-acquired adverse drug reactions in adults and children and their impact on cost and hospital stay – a systematic review

Purpose

To study and analyze the comparative impact of hospital-acquired adverse drug reactions (ADRs) in adult and pediatric patients in terms of the economic implications, (length of) hospital stay, and salient features in relation to the incidence rate, severity, morbidity, mortality, and preventability of the ADRs.

Methods

A systematic search to identify and retrieve relevant articles/studies in the PubMed, Medline, Scopus, MEDPAR, and Cochrane databases and by the Google search engine was performed for the study period 2000 to April 2013. In total, 51 studies were identified on patients hospitalized for ADRs, and these were included in the study. The incidence rate of ADRs, their severity, mortality, morbidity, preventability, cost, and association with extended hospital stay due to ADRs were extracted and scrutinized.

Results

Hospital-acquired ADRs are more widely studied in adults than in children, and the incidence rate is higher in the former. However, a wide variation in the incidence rate worldwide is observed in both groups. Irrespective of the ages of patients, ADRs are among the most frequent causes of morbidity and mortality. Interestingly, preventable ADRs are more frequently observed in patients at the younger and older ends of the age spectrum. Hospital-acquired ADRs place an immense economic burden on healthcare systems, with the overall cost for a hospitalized patient with an ADR reported to be $2,401 per patient, which is equivalent to a 19.86 % additional increase in the total cost of care and an increase in average length of hospital stay of 8.25 %.

Conclusion

Based on the findings of this review, we suggest that excellent assertive measures of pharmacovigilance with the aim to diminish the incidence rate of hospital-acquired ADRs and support the development of interventions are needed to promote vital facets of drug safety with an overall objective to avert potential ADRs.     

Fragment based drug discovery: practical implementation based on ¹⁹F NMR spectroscopy

Fragment based drug discovery (FBDD) is a widely used tool for discovering novel therapeutics. NMR is a powerful means for implementing FBDD, and several approaches have been proposed utilizing (1)H-(15)N heteronuclear single quantum coherence (HSQC) as well as one-dimensional (1)H and (19)F NMR to screen compound mixtures against a target of interest. While proton-based NMR methods of fragment screening (FBS) have been well documented and are widely used, the use of (19)F detection in FBS has been only recently introduced (Vulpetti et al. J. Am. Chem. Soc.2009, 131 (36), 12949-12959) with the aim of targeting "fluorophilic" sites in proteins. Here, we demonstrate a more general use of (19)F NMR-based fragment screening in several areas: as a key tool for rapid and sensitive detection of fragment hits, as a method for the rapid development of structure-activity relationship (SAR) on the hit-to-lead path using in-house libraries and/or commercially available compounds, and as a quick and efficient means of assessing target druggability.     

Clinically based evidence of drug–herb interactions: a systematic review

Importance of the field: Healthcare practitioners are deeply concerned about drug–herb interactions and how concurrent administration may affect both the safety and effectiveness of prescribed drugs. Interactions between botanical medicines and synthetic drugs can be clinically relevant and it is important to understand what kinds of interactions are possible. Better knowledge in this area will help avoid negative interactions and may also help enable synergistic interactions.

Areas covered in this review: Includes articles related to the investigation of Western botanicals or whole herbal extracts in human subjects, investigating either the impact on Cytochrome P450 isoenzymes or an assessment of specific drug–herb interactions within a clinical trial. Searches were conducted in both Pubmed and EMBASE from inception to March 2009.

What the reader will gain: Knowledge regarding specific interactions to consider in clinical practice. The reader will also gain an appreciation of the complexities associated with the area of drug–herb interactions. Summary tables of relevant drug–herb interactions are presented both for the individual herbs included and at the level of the CYP450 enzymes.

Take home message: Knowledge of drug–herb interactions is limited and much more research needs to be done to further document clinically relevant interactions. Even though preclinical data are often poorly generalizable to the human situation, caution must be taken in the absence of clinical evidence especially where drugs with narrow therapeutic windows are concerned.     

Driving among drug users: Are we doing enough? A chart review of assessment of driving and related issues in drug misusers

Aim: Driving among drug users is a major health concern. Professionals working in substance misuse service have a duty of care to manage the risks involved. We analysed the practice of multidisciplinary team in drug treatment service discussing driving with the patient and providing them with relevant information regarding the regulations. We compared this practice with the existing policies and guidelines.

Method: A chart review of healthcare professionals in the drug treatment services discussing driving and related issues with the patient was carried out. One hundred case records were analysed for evidence of documentation of the above information.

Results: A clear record of discussion of all driving-related issues was documented in only 28% of records reviewed. In more that half of the cases there was no record as to whether the patient was driving or not.

Conclusions: The results raised some ethical questions that would influence the policy makers and practitioners. These finding suggest that major changes are needed in our practice both for our legal protection and for the best interests of patients and public.     

An update on adverse drug reactions related to β-lactam antibiotics

Introduction: β-lactams have been consistently associated with the majority of drug-related adverse events. Generally, these are mild under proper dosing and judicious selection.

Areas covered: Immediate hypersensitivity reactions are the most feared adverse events encountered after β-lactam administration. Emerging evidence shows that immediate reactions are not as common as previously thought. Specialist consultation and testing seems prudent before a patient is officially declared allergic to β-lactams. The risk of cross-reactions between not only members of the β-lactam super-family but also between specific classes is also lower than previously thought. Newer studies have shown that cross-reactions are not universal and pertain to specific agents with similar side chains or metabolites of the β-lactam core. The frequency of severe kidney or liver toxicity, neurotoxicity, cytopenias and Clostiridium difficile infection following β-lactam administration seem to be agent-specific.

Expert opinion: The currently available data denote that in addition to age, gender, co-morbidity, renal or liver function, and co-administered agents, the antibiotic levels rather than the dose itself seem to be associated with the emergence of adverse events. Most of them subside with time after withdrawal of the offending agent, but the number of cases resulting in chronic disabilities or even deaths in not negligible.     

Antiplasmodial drug targets: a patent review (2000 – 2013)

Introduction: New antimalarials with novel modes of action are crucial in countering the challenge of emerging drug-resistant Plasmodium falciparum. Equally significant is the identification and characterization of the targets these compounds inhibit. Biochemical evidence from seminal studies, whole genome clues and high-throughput chemical screening data provide starting points worth exploring in target identification efforts. Several proteins and biochemical processes/pathways critical to parasite survival have since been profiled and patented.

Areas covered: In this review, an analysis of patents describing the characterization of different enzymatic and/or biosynthetic targets in P. falciparum over the last fourteen years is presented. The review also details structures, biological evaluation, potential modes of action and therapeutic utilities of small molecule antiplasmodial compounds from ongoing research, designed to inhibit these targets.

Expert opinion: Though various strategies to address antimalarial drug resistance exist, direct inhibition of unrelated targets and non-genome coded processes potentially present the most effective options. Additionally, interest in peptides as antimalarials merits further exploration especially in view of their unique low susceptibility to resistance, wider spectrum of action and faster activity. Finally, target-based optimization and chemical validation of novel targets can be facilitated by routine phenotypic whole-cell screening of antiplasmodial hits against any new target(s).     

Novel oral dosage regimen based on self-nanoemulsifying drug delivery systems for codelivery of phytochemicals – Curcumin and thymoquinone

BackgroundCurcumin and Thymoquinone are very well-known phytochemicals for their potent anti-inflammatory and anticancer properties. The major challenges for curcumin is its poor aqueous solubility and erratic oral bioavailability.ObjectiveTo develop a novel liquid self-nanoemulsifying drug delivery system (SNEDDS) containing curcumin and thymoquinone and further converted into a solid dosage form using adsorbents Syloid® and Neusilin® as the solid carrier.MethodsThe characterization of the liquid and solid SNEDDS was performed by particle size & zeta potential analysis, scanning electron microscopy, differential scanning calorimetry, fourier transform infrared spectroscopy and X-ray powder diffraction. The drug loading, and in vitro release studies were carried out to investigate the efficiency of curcumin release from SNEDDS.ResultsThe liquid SNEDDS containing black seed oil showed excellent self-emulsification performance with transparent appearance. The results of characterization studies showed that solidification using 50% (w/w) Syloid® and Neusilin® in the liquid formulation yield free flowing powder with no agglomeration but Neusilin® produced smooth granules than Syloid® and kept the drugs stable in amorphous state. In vitro dissolution studies indicated that liquid SNEDDS formulations of F4 and its solid SNEDDS using Neusilin® provided high dissolution efficiency and reproducibility for curcumin and thymoquinone. However, Neusilin® showed higher rate of dissolution (more than 65%, p < 0.05) compared to Syloid® for curcumin.ConclusionsCurcumin loaded-SNEDDS formulation containing thymoquinone in liquid & solid dosage forms were successfully developed with an increased drug loading and dissolution rate, which could be the potential combined delivery system for various anti-inflammatory and anti-cancer treatments.     

An update on PTEN modulators – a patent review

ABSTRACT

Introduction: A multitude of cellular and physiological functions have been attributed to the biological activity of PTEN (Phosphatase and tensin homolog) such as inhibiting angiogenesis, promoting apoptosis, preventing cell proliferation, and maintaining cellular homeostasis. Based on whether cell growth is needed to be initiated or to be inhibited, enhancing PTEN expression or seeking to inhibit it was pursued.

Areas covered: Here the authors provide recent updates to their previous publication on ‘PTEN modulators: A patent review’, and discuss on new specificities that affirm the therapeutic potential of PTEN in promoting neuro-regeneration, stem cell regeneration, autophagy, bone and cartilage regeneration. Also, targeting PTEN appears to be effective in developing new treatment strategies for Parkinson’s disease, Alzheimer’s disease, macular degeneration, immune disorders, asthma, arthritis, lupus, Crohn’s disease, and several cancer types.

Expert opinion: PTEN mainly inhibits the PI3k/Akt pathway. However, the PI3k/Akt pathway can be activated by other signaling proteins. Thus, novel treatment strategies that can regulate PTEN alone, or combinational treatment approaches that can induce PTEN and simultaneously affect downstream mediators in the PI3K/Akt pathway, are needed, which were not investigated in detail. Commercial interests associated with molecules that regulate PTEN are discussed here, along with limitations and new possibilities to improve them.     

Why did drug spending increase during the 1990s? A decomposition based on Swedish data

OBJECTIVE: To decompose drug spending in Sweden between the years 1990 and 2000. This paper updates a previous study, which looked at the period 1990-1995, by providing an additional 5 years of data (1995-2000) and extending the previous analysis in a number of ways. METHODS: The paper builds on the earlier work that showed that changes in drug spending could be decomposed into three components: price, quantity and a residual. The size of the residual is a measure of the impact of changes in drug treatment patterns on drug spending. The data set used in this paper was collected from Apoteket AB (The National Corporation of Swedish Pharmacies) and was based on comprehensive information (inpatients as well as outpatients) on drug deliveries from wholesalers to pharmacies. Data were obtained for aggregate drug spending (from 1990-2000) and for spending according to anatomical therapeutic chemical (ATC) classification system group. RESULTS: Real drug spending increased by 119% during the study period. The residual rose by 67% indicating the switch from cheaper to more innovative and expensive drug therapies was a major cost driver. Real drug spending would have increased by about 31% if there had been no changes in treatment patterns. The second driver of drug spending was the quantity of drugs consumed, which increased by 41%. The main reason for the larger quantity sold appears to be increases in the intensity of medication in terms of defined daily doses per patient, rather than a larger number of patients starting drug treatment. Real prices decreased during the 10-year study period.We found large differences between ATC groups in terms of spending growth. The ATC groups that have contributed the most to the increase in spending are: drugs that affect the CNS (N), the alimentary tract and metabolism (A) and the cardiovascular system (C), which are also the three largest groups in terms of sales. For all three groups, it was the residual that mainly drove costs. CONCLUSION: This study indicates very clearly that the main driving force behind the increase in drug costs in Sweden between 1990 and 2000 was the change in drug therapy from old to new and more innovative and expensive drug therapies. This shows the importance of carrying out economic evaluations of new more costly drugs in order to make an assessment of the social benefits of a switch from a cheaper to a more expensive drug.     

Is the decision on the use of biosimilar growth hormone based on high quality scientific evidence? – a systematic review

Background

The authors carried out a systematic and critical review of the scientific literature regarding the possible development of neutralising antibodies developed in patients treated with growth hormone biosimilars (defined as a drug expected to be similar to the originator or original pharmaceutical -European Medicines Agency) as compared to the reference drug. As a consequence, we discovered two major issues, namely, the poor quality of the comparative clinical trials and the poor quality of the antibody assays used during the trials.

Methods

The literature review was performed according to the principle of the Cochrane Collaboration and SBU. The electronic literature search included the databases PubMed, EMBASE and The Cochrane Library up to December 2012. Two independent reviewers assessed abstracts and full-text articles.

Results

The search identified 1,553 abstracts related to the subject. Only six articles contained data on biosimilar growth hormone or antibody results obtained with appropriate methods. None of the studies fulfilled the criteria for high quality randomised controlled trials. Qualitative rather than quantitative assays were used for monitoring antibody formation.

Conclusions

It is our firm opinion , that since biosimilars are not identical, emphasis must be placed on the quality of the comparative clinical trials performed and the quality of the analytical studies in order to guarantee patient safety. Clinical trials should follow established quality rules for controlled comparative randomised clinical trials. A whole set of new guidelines is required.     

Selecting immuno-oncology–based drug combinations – what should we be considering?

ABSTRACT

Introduction: Checkpoint inhibitor immunotherapy has revolutionized the treatment of many advanced stage cancers. Preexisting immunity is necessary for a response to these agents, which are most effective in inflamed tumors since they principally act by reinforcing preexisting antitumor T-cell responses. An important goal of therapy is to convert the tumor environment from non-inflamed to inflamed in order to facilitate subsequent response to checkpoint inhibitors. Clinical trials are underway to identify checkpoint inhibitor-based combination approaches, which may help to achieve this goal.

Areas covered: Anti-PD-1 agents are being assessed in combination with different treatments (e.g. TLR9 agonists, oncolytic peptides, oncolytic vaccines, LAG-3, HDAC inhibitors, GITR, recombinant human interleukin-2) with promising results. PD-1 agents are also being assessed in combination with other locoregional or systemic treatment modalities, including ECT, radiotherapy, chemotherapy, and targeted therapy, with promising results being achieved.

Expert commentary: Emerging approaches based on combinations with anti-PD-1 agents seem to offer increased efficacy compared to anti-PD-1 monotherapy. Such combinations also appear to be well tolerated, with safety profiles often comparable to those seen with anti-PD-1 monotherapy. These combination approaches are likely to become an increasing focus of research. There is also the potential for triplet anti-PD-1 combinations.     

Advances in nanotechnology-based carrier systems for targeted delivery of bioactive drug molecules with special emphasis on immunotherapy in drug resistant tuberculosis – a critical review

Abstract

From the early sixteenth and seventeenth centuries to the present day of life, tuberculosis (TB) still is a global health threat with some new emergence of resistance. This type of emergence poses a vital challenge to control TB cases across the world. Mortality and morbidity rates are high due to this new face of TB. The newer nanotechnology-based drug-delivery approaches involving micro-metric and nano-metric carriers are much needed at this stage. These delivery systems would provide more advantages over conventional systems of treatment by producing enhanced therapeutic efficacy, uniform distribution of drug molecule to the target site, sustained and controlled release of drug molecules and lesser side effects. The main aim to develop these novel drug-delivery systems is to improve the patient compliance and reduce therapy time. This article reviews and elaborates the new concepts and drug-delivery approaches for the treatment of TB involving solid-lipid particulate drug-delivery systems (solid-lipid micro- and nanoparticles, nanostructured lipid carriers), vesicular drug-delivery systems (liposomes, niosomes and liposphere), emulsion-based drug-delivery systems (micro and nanoemulsion) and some other novel drug-delivery systems for the effective treatment of tuberculosis and role of immunomodulators as an adjuvant therapy for management of MDR-TB and XDR-TB.     

Quality in the pharmaceutical industry – A literature review

Objectives

The aim of this study is to:

• a.Highlight the most important guidelines and practices of quality in the pharmaceutical industry.
• b.Organize such guidelines and practices to create a guide to pave the way for other researchers who would like to dig deeper into these guidelines and practices.

Design

A review was conducted of 102 publications; 56 publications were concerned with the pharmaceutical quality directly while 46 publications were concerned with the general quality practices. The content of those sources was analyzed and the following themes were identified:

• a.Research theme 1: Guidelines of the pharmaceutical quality.
• b.Research theme 2: General practices recently applied in the pharmaceutical industry.

Main outcome measures

The following guidelines were identified and reviewed: WHO guidelines, FDA guidelines, EU guidelines and ICH guidelines in the research theme I.In research theme II; the following topics were identified and reviewed: quality risk management, quality by design, corrective actions and preventive actions, process capability analysis, Six Sigma, process analytical technology, lean manufacturing, total quality management, ISO series and HACCP.

Results

Upon reviewing the previously highlighted guidelines and the practices that are widely applied in the pharmaceutical industry, it was noticed that there is an abundant number of papers and articles that explain the general guidelines and practices but the literature lack those describing application; case studies of the pharmaceutical factories applying those guidelines and significance of those guidelines and practices.

Conclusions

It is recommended that the literature would invest more in the area of application and significance of guidelines and practices. New case studies should be done to prove the feasibility of such practices.     

Albumin corona on nanoparticles – a strategic approach in drug delivery

Nanomaterials have been used widely for delivery of therapeutic agents. Protein–nanoparticle (NP) complexes have gained importance as vehicles for targeted drug delivery due to increased ease of administration, stability and half-life of drug, and reduced toxic side effects. Designing of phospholipid–bovine serum albumin (BSA) complexes and stealth NPs with BSA has paved the way for drug delivery carriers with prolonged blood circulation times. Preformed albumin corona has shown to decrease non-specific association and thereby reduce the clearance rate. Albumin corona has enabled the localization of drug carriers in specific tissues such as liver and heart, thus regulating biodistribution. Tailored albumin–NP conjugates have also enabled controlled degradation of NP and drug release. However, the binding of albumin with NP is associated with conformational and functional modulations in protein as observed with silver, gold and superparamagnetic iron oxide NPs. In this review, we highlight the various potential albumin–NP hybrids as nano drug carriers.     

Focusing on shared subpockets – new developments in fragment-based drug discovery

Introduction: Protein–protein interactions (PPIs) are important targets for understanding fundamental biology and for the development of therapeutic agents. Based on different physicochemical properties, numerous pieces of software (e.g., POCKETQUERY, ANCHORQUERY and FTMap) have been reported to find pockets on protein surfaces and have applications in facilitating the design and discovery of small-molecular-weight compounds that bind to these pockets.

Areas covered: The authors discuss a pocket-centric method of analyzing PPI interfaces, which prioritize their pockets for small-molecule drug discovery and the importance of multicomponent reaction chemistry as starting points for undruggable targets. The authors also provide their perspectives on the field.

Expert opinion: Only the tight interplay of efficient computational methods capable of screening a large chemical space and fast synthetic chemistry will lead to progress in the rational design of PPI antagonists in the future. Early drug discovery platforms will also benefit from efficient rapid feedback loops from early clinical research back to molecular design and the medicinal chemistry bench.