Review article: the diagnosis and investigation of obscure gastrointestinal bleeding

Aliment Pharmacol Ther 2011; 34: 416–423

Summary

Background Obscure gastrointestinal bleeding (OGIB) is a commonly encountered clinical problem in gastroenterology and is associated with significant morbidity and mortality. The investigation and management of OGIB has changed dramatically over the past decade with the advent of newer gastroenterological and radiological technologies. Aim To review the current evidence on the diagnosis and investigation of OGIB. Methods We searched the PubMed database (1985–2010) for full original articles in English‐language journals relevant to the investigation of OGIB. The search terms we used were ‘gastrointestinal bleeding’ or ‘gastrointestinal hemorrhage’ or ‘small bowel bleeding’ each in combination with ‘obscure’, or ‘capsule endoscopy’, or ‘enteroscopy’ or ‘enterography’ or ‘enteroclysis’. Results Capsule endoscopy (CE) or double balloon enteroscopy (DBE) should be first line investigations. They are complimentary procedures with comparable high diagnostic yields. DBE is also able to provide therapeutic intervention. Newer technologies such as single balloon and spiral enteroscopy are currently being evaluated. Radiological and nuclear medicine investigations, such as CT enterography and CT enteroclysis, are alternative diagnostic tools when CE or DBE are contraindicated. Repeating the gastroscopy and/or colonoscopy may be considered in selective situations. An algorithm for investigation of obscure bleeding is proposed. Conclusions The development of capsule endoscopy and double balloon enteroscopy has transformed the approach to the evaluation and management of obscure gastrointestinal bleeding over the past decade. Older diagnostic modalities still play a complementary, but increasingly selective role.     

Can CAM treatments be evidence‐based?

In this article, we first take a critical look at the definitions of evidence‐based medicine (EBM) and complementary and alternative medicine (CAM). We then explore the question of whether there can be evidence‐based forms of CAM. With the help of three examples, we show that EBM and CAM are not opposites, but rather concepts pointing at different dimensions. Each of the three examples is an evidence‐based treatment according to three to five randomised, double‐blind placebo controlled trials with consistent findings and narrow pooled confidence intervals. The most reasonable interpretation for the existence of evidence‐based CAM treatments seems to be that the opposite of CAM is ‘mainstream medicine’, and the demarcation line between CAM and mainstream medicine is not simply defined by the question of whether a treatment works or not. Some effective treatments may belong to the CAM domain for historical reasons and because of preconceptions within mainstream medicine. Therefore, some treatments that currently lie outside mainstream medicine can be evidence‐based.     

Adverse reactions to complementary medicines: the Australian pharmacy experience

Objectives The primary aim was to determine the prevalence of adverse reactions to over‐the‐counter complementary medicines and their severity, as described by consumers. Secondary aims were to identify consumers' reporting behaviours and understanding of the AUST L designation on product labels. Methods An anonymous, self‐administered survey was completed by randomly selected pharmacy customers at 60 community pharmacy locations between August 2008 and February 2009. Key findings Of the 1121 survey participants (response rate 62%), 72% had used a complementary medicine product in the previous 12 months, and 7% of this group (n = 55) reported having experienced an adverse reaction at some time. Of these, 71% described the reaction as mild and not requiring treatment, 22% as moderate and/or requiring advice from a healthcare professional and 7% (n = 4) described it as severe and requiring hospitalisation. If they were to report the reaction, it was most commonly to a medical practitioner. Most (88%) of complementary medicine consumers had never noticed the term ‘AUST L’. Conclusions Complementary medicines are widely used by pharmacy customers. Adverse reactions to these products are under‐reported to healthcare authorities. Most adverse reactions are mild and serious reactions are rare. Customers have little awareness of the designation AUST L.     

Personalized medicine: impact of subject matter and utility requirements on patentability in the United States

Personalized medicine is a relatively new field that recognizes and takes advantage of a patient's individual genetic and physiologic make-up, as well as specific environmental influences. Obtaining and defending patents this field, however, can raise legal issues, such as those relating to ‘subject matter’ patentability and ‘utility,’ two requirements under US law. This perspective article provides an analysis of certain US patent cases relevant to these requirements, including Lab. Corp. v. Metabolite pertaining to subject matter patentability of certain types of diagnostic methods, and In re Fisher addressing the utility of certain DNA-related research tools. Understanding such cases can provide guidance as to how to avoid certain pitfalls when preparing, prosecuting and defending patents in the field of personalized medicine.     

Pharmacologic treatment of obsessive-compulsive disorder comorbidity

Introduction: Obsessive-compulsive disorder (OCD) is clearly a heterogeneous syndrome in which comorbidity is the rule rather than the exception and is often ‘phase-specific’. Comorbid conditions have a negative impact on OCD outcome and may clearly impact the disease trajectory. Nevertheless, in the current literature there is an impressive neglect of comorbidities in clinical trials and treatment approaches for these conditions are still not evidence-based.

Areas covered: In this paper we summarized the available data on the treatment of the main OCD comorbidities (mood and anxiety disorders, ‘bipolar neurosis’, tics and OCD-related disorders, addictions and impulsive disorders, eating disorders, attention deficit hyperactivity disorder, psychoses, and post-infective syndromes).

Expert opinion: To achieve the goals of ‘precision medicine’ there is a critical need for deconstructing current diagnostic groups with biomarkers to predict and improve response to treatment. Despite the continuous efforts of several researchers in subtyping homogeneous samples of OCD patients (for example the comorbidity-based subclassification), current available treatments are still syndrome-based rather than network dysfunctions-based. Identifying the homogenous subgroup, subtyping patients according to comorbidity patterns, symptom dimensions, clinical course, neurocognitive and neurophysiological dysfunctions, could represent an essential first step in the direction of a ‘precision medicine’ approach.     

New formulations of bupivacaine for the treatment of postoperative pain: liposomal bupivacaine and SABER-Bupivacaine

Introduction: Although generally considered both safe and effective, local anesthetics are often used in conjunction with opioids postoperatively in part because of the limited duration of drug action of local anesthetics. Much interest exists in extending the duration of local anesthetics’ effects, which may reduce the requirement for opioid pain medications that are frequently associated with side effects, including nausea and vomiting, pruritus and respiratory depression.

Areas covered: This article introduces liposomal bupivacaine and SABER®-Bupivacaine, two new formulations of bupivacaine that increase the duration of analgesia postoperatively through two novel slow-release technologies. The pharmacodynamics, pharmacokinetics, efficacy and safety of both preparations of bupivacaine are reviewed. An electronic database search conducted using the Cochrane Central Register of Controlled Trials and MEDLINE/PubMed with the following search terms: ‘bupivacaine,’ ‘liposomal bupivacaine’, ‘liposome bupivacaine’, ‘Exparel’, ‘SABER-Bupivacaine’, ‘SABER Bupivacaine’, and ‘SABER’ yielded 90 articles (no language or date of publication restrictions were imposed).

Expert opinion: Clinical trials involving liposomal bupivacaine and SABER-Bupivacaine indicate that both safely prolong analgesia, while decreasing opioid requirements when compared with placebo. However, additional clinical studies are necessary to better determine the efficacy and cost-effectiveness of these long-acting local anesthetic formulations.     

Advances in the treatment options for vitiligo: activated low-dose cytokines-based therapy

Introduction: Vitiligo is a skin disorder characterized by a progressive depigmentation, which is caused by the loss of melanocytes at the cutaneous level. A shift of the immune system with a prevalence of T helper (Th)1/Th17 response instead of a Tregs/Th2 one and may be part of etiology of 10 vitiligo.

Areas covered: This review describes the major points of vitiligo onset and shows the cutting-edge results in the field of low-dose medicine in the treatment of dermatologic diseases and, in particular. in vitiligo. In this review on advances in vitiligo pharmacotherapy, the most pertinent recent publications are reported. Electronic databases such as PubMed were searched for terms ‘low-dose medicine’ or ‘low dose and vitiligo’ or ‘low dose and psoriasis.’

Expert opinion: The availability of a systemic treatment for vitiligo, based on the oral administration of low-dose activated signaling molecules represents an opportunity for the dermatologists to overcome some specific pitfalls of currently available therapeutic protocols.     

Knowledge and Use of Complementary and Alternative Medicine among British Undergraduate Pharmacy Students

Aim: Attitudes and practice concerning complementary and alternative medicine (CAM) are currently an area of considerable importance. However, little is known about the overall importance of CAM in groups of health care professionals. Therefore, the primary objective was to analyse the knowledge about and use of CAM in an ethnically diverse student population at the London School of Pharmacy. Methods: A questionnaire was administered to students (264 completed questionnaires, response rate: 59.1%) and in-depth interviews were carried out with a sample of seven students. Results: Forty-three percent reported using at least one type of CAM during the last 12 months. The types of CAM used that were most frequently mentioned include aromatherapy, Traditional Chinese Medicine (TCM) and medicinal herbalism. TCM was reported by students of Chinese origin and by students from other ethnic backgrounds. However, Ayurvedic (Indian) medicine and medicine from Africa were only used in cultures from which the users originated. The study shows that a large number of herbal medical products were commonly reported by students of pharmacy. Conclusion The knowledge about and use of CAM is widespread among this group of future health care professionals and the students also expressed a strong interest in the topic. In-depth studies on the knowledge and use of CAM among other health care professionals and among ethnic minorities are urgently needed and may help to better manage the treatment of minor disorders as well as chronic diseases.     

Opioid risk assessment in palliative medicine

Introduction: Pain management with opioids is a fundamental element of palliative medicine. Since the risks of chronic opioid therapy have emerged, a reassessment of these risks in the setting of palliative care is warranted.

Areas covered: This article presents information about opioid-related risks including i) sedation, cognitive impairment and falls; ii) constipation; iii) addiction to opioids and associated aberrant behavior; and iv) death due to respiratory depression. For this article, the medical literature was searched using PubMed and Web of Science for appropriate terms including ‘palliative care’ and ‘opioid risk.’ Medical subject headings were used to identify suitable articles including ‘Analgesics, Opioid’, ‘Pain/drug therapy,’ ‘Palliative Care’ and ‘Hospice Care.’ Further sources were identified by following cross-references within the literature and with the help of the University of Washington library staff.

Expert opinion: Palliation of severe pain at the end of life is probably the most widely accepted indication for chronic opioid therapy. At increased doses, adverse effects of opioids may limit or interfere with the benefits of treatment. Careful screening and follow-up will allow risk factors to be recognized and addressed when possible. The use of adjunctive treatments for pain may reduce opioid requirements and yield better outcomes.     

Complementary and alternative medicine in the treatment of substance use disorders--a review of the evidence

Issues. Substance use disorders are chronic relapsing disorders, leading to significant impairment in psychosocial functioning. Conventional therapies have not been able to alter the outcome of these disorders significantly and frequent relapses continue to occur, despite the development of newer medications, like baclofen, ondansetron, etc. Hence, there is a need to look at complementary and alternate systems of medicine. Approach. This article is a review of the evidence for complementary and alternate systems of medicine in substance use disorders. Articles were searched using the Medical Subject Headings (MeSH) database of the PubMed search engine and further non‐indexed information was obtained from the Google search engine. The article is organised in parts, each reviewing a different system of medicine in the following order—alternate medical systems, biologically based therapies, energy‐based interventions and mind–body interventions; as classified by the National Center for Complementary and Alternative Medicine, National Institutes of Health, USA. Key Findings. The currently available evidence is limited and not very encouraging. At present only acupuncture, herbal therapies and mind–body interventions have shown some positive results in human trials and hold promise for the future. Implications. This review emphasises the paucity of research into this important field especially the lack of rigorous human trials. Conclusion. More systematic studies are required before these systems of medicine can be widely recommended in the treatment of substance use disorders.[Behere RV, Muralidharan K, Benegal V. Complementary and alternative medicine in the treatment of substance use disorders—a review of the evidence. Drug Alcohol Rev 2009]     

Pharmacotherapy for lower respiratory tract infections

Introduction: Bacterial infections play an important role as etiological agents in acute exacerbations of chronic obstructive pulmonary disease (AECOPD), and exacerbations of non-cystic fibrosis (CF) bronchiectasis. In acute bronchitis and asthma exacerbations their role is less well defined than with patients with COPD. The clinical features, causative pathogens and therapies of common acute respiratory tract infections are detailed in this review.

Areas covered: This article covers medical literature published in any language from 2000 to 2014, on ‘lower respiratory tract infections’, identified using PubMed, MEDLINE and ClinicalTrial.gov. The search terms used were ‘COPD exacerbations’, ‘bronchiectasis’, ‘macrolides’ and ‘inhaled antibiotics’.

Expert opinion: Given that almost half of AECOPD are caused by bacteria, administration of antibacterial agents is recommended for patients with severe exacerbations or severe underlying COPD. Chronic prophylactic use of macrolides seems to be of benefit, particularly in patients with bronchiectasis and chronic mucous hypersecretion. In an effort to manage chronic airway infection non-CF bronchiectasis due to drug-resistant pathogens, aerosolized antibiotics may be of value, and the data from recent studies are examined to demonstrate the potential value of this therapy, which is often used as an adjunctive measure to systemic antimicrobial therapy.     

Drug discovery paradigms: past,present, future – a centennial symposium of the American Society for Pharmacology and Experimental Therapeutics

Background: The American Society for Pharmacology and Experimental Therapeutics (ASPET) celebrated its centennial during the April 2008 Experimental Biology meeting held in San Diego, CA, USA. Objectives: This report summarizes a centennial symposium on past, present and future paradigms in drug discovery. The John Langley (1905) concept of ‘receptive substances’ initiated a cascade of cardinal discoveries for pharmacology. During the following 100 years, receptors achieved the status of well-defined multifunctional cellular proteins mediating all drug effects. The G-protein-coupled receptors (GPCRs) were discussed in relation to multiple targets they represent for clinically used or new medicines. The development of inbred and transgenic animal strains is a fundamental twentieth century achievement for biological research activities. Progress in treating CNS disorders still awaits breakthrough treatments. Drug development remains a risky and expensive venture; improvements are expected from emerging biomarker and translational medicine technologies. Future clinical research has to document the benefits that new medications provide to concerned stakeholders. Conclusions: We wish ASPET a new century of great achievements and acknowledge the dedication of several generations of colleagues, many of whom are our ‘unsung heroes’. They have left us a precious heritage to be pursued with passion in the quest for better medicines.     

Perspectives in therapy for hepatitis C

Background: Chronic hepatitis C virus (HCV) infection is a worldwide health problem. Response rates to current standard of treatment (pegylated IFNs and ribavirin) are low in patients with the prevailing genotype 1. Objective: To review papers published or presented at recent international meetings showing the results of trials of new anti-HCV drugs. Methods: Literature search using the terms ‘antivirals’, ‘interferon’, ‘pegylated interferon’, ‘ribavirin’, ‘polymerase inhibitors’, ‘protease inhibitors’, ‘cyclophilin inhibitors’ and ‘hepatitis C virus’. Search of abstracts containing the same terms in the title and presented at the American Association for the Study of Liver Diseases 2007 and at the European Association for the Study of the Liver 2008 meetings. Results/conclusion: Preliminary results of Phase II studies of new compounds look promising, although side effects are higher than with current standard of treatment.     

Botanicals used in complementary and alternative medicine treatment of cancer: clinical science and future perspectives

Background: Botanicals and herbal combinations are among the most common complementary and alternative medicine (CAM) approaches used by cancer patients both for cancer treatment and management of cancer symptoms. Despite their widespread use, however, the safety and efficacy of many botanicals has not been established in controlled clinical trials. Objectives: This article reviews the published evidence for the safety and clinical benefit of botanicals used in the treatment of cancer and cancer symptom management and describes the continuing clinical trials of botanicals with applications in oncology. Methods: Literature searches were conducted in PubMed, EMBASE, Cochrane Clinical Trials databases, Pharmaprojects and CRISP (Computer Retrieval of Information on Scientific Projects) clinical trials databases. Conclusion: A number of botanicals have shown promise for cancer symptom management but need further study. A limited number of multi-agent nutritional supplement approaches are being explored in clinical trials. Botanical immunomodulators and botanical products shown to affect pathways of angiogenesis, apoptosis and cell signaling in vitro have stimulated research interest and may broaden the range of available cancer treatments.     

Intermediate and long-acting insulins: a review of NPH insulin,insulin glargine and insulin detemir

ABSTRACT

Objective: To review intermediate- and long-acting insulins with specific emphasis on the newer insulin analogs.

Methods: A MEDLINE search, in English, was conducted with a cut-off of June 30, 2006, using the terms ‘NPH insulin’, ‘insulin analogs’, ‘insulin glargine’, ‘insulin detemir’ and ‘long-acting insulins’. All clinical trials from within the search period were included.

Results: The insulin analogs, insulin glargine and insulin detemir, were introduced in an attempt to improve glycemic control among patients with diabetes, without increasing the risk of hypoglycemia. This review indicates that both insulin analogs demonstrate better glycemic control than NPH insulin, based on measurements of HbA_1c, fasting glucose and intra-subject variability in blood glucose. This was accomplished with similar or reduced risk of hypoglycemia. Also, insulin detemir appears to be associated with less body weight increase than NPH insulin or insulin glargine.

Conclusion: The newer long-acting insulin analogs, insulin detemir and glargine, appear to provide better glycemic control than NPH insulin without increasing the risk of hypoglycemia.     

Abatacept in biologic-naive patients and TNF inadequate responders: clinical data in focus

ABSTRACT

Background: Advances in the understanding of rheumatoid arthritis (RA) immunopathogenesis support the hypothesis for a ‘window of opportunity’ for therapeutic intervention in RA and the need for rapid and effective treatment strategies, with the ultimate goal of alleviating symptoms and halting progressive joint damage. Biologic therapies targeting pro-inflammatory cytokines have significantly improved the outlook for patients with RA; however, some patients still experience inadequate treatment responses. Recently, therapeutic agents targeting alternative pathways have been developed. One such therapy – abatacept – targets T-cell activation and is approved in the United States for treatment of moderate-to-severe RA and juvenile idiopathic arthritis.

Objective: To overview the efficacy and safety of abatacept in the treatment of adult patients with active RA and an inadequate response to methotrexate (MTX) or tumor necrosis factor (TNF) antagonists.

Search methodology: A comprehensive literature search was performed using the National Library of Medicine (MEDLINE), EMBASE and BIOSIS databases (restricted to articles in the English language posted between January 2000 and February 2007). The search terms ‘CTLA-4Ig’, ‘abatacept’ and ‘ORENCIA’^* were used, and data from randomized clinical trials were summarized.

Results: Abatacept provided clinically meaningful improvements in the signs and symptoms of RA in both MTX and TNF antagonist inadequate responders in Phase II and III studies. Health-related quality of life was also improved with abatacept, which demonstrated an acceptable safety and tolerability profile in both patient populations. Additionally, when assessed in patients with an inadequate response to MTX, abatacept inhibited structural damage progression.

Conclusion: Although longer-term data are required and differing study designs preclude direct comparisons with other RA therapies, results of clinical trials to date suggest that abatacept has an acceptable safety profile and is an effective treatment option for patients with RA, whether treating biologic-naïve patients or those who have already had an inadequate response to TNF antagonists.     

Practitioners of complementary and alternative medicine should value their strengths

The patient‐experienced effect of complementary and alternative medicine (CAM) can primarily be attributed to a personal relationship between the provider and patient, and health recommendations within a context with potential symbolic value. The current important challenge for CAM practitioners is to acknowledge that their specific ‘treatments’ should also be mostly reclassified as important symbols, not treatments with direct pathophysiological effects. If this were done, they would hopefully achieve a constructive dialogue with representatives of conventional medicine.