De-escalation of medical therapy in inflammatory bowel disease.

Treatment strategies for inflammatory bowel disease (IBD) now increasingly target deep remission, yet the resultant more aggressive use of medical therapy is associated with potentially serious adverse events and significant costs. It is, therefore, of vital importance to consider when, how and in whom medical therapy may be safely de-escalated. This issue is of great potential relevance in the current SARS-Cov-2 pandemic. In this review, we first discuss the rationale for drug withdrawal in IBD, before considering the available data on withdrawal of 5-aminosalicylates (5-ASA), immunomodulators (IM) and biological therapy in both ulcerative colitis (UC) and Crohn's Disease (CD). We consider how to identify patients most appropriate for drug withdrawal and outline a potential monitoring strategy for the early detection of relapse following drug withdrawal. We conclude with important future perspectives in this challenging field, and highlight ongoing trials that are likely to shape practice in the years to come.

Reducing the use of opioids by patients with chronic pain: an effectiveness study with long-term follow-up.

This study addresses the problem of long-term opioid use by chronic pain patients. The study involved a secondary analysis of unanalyzed data from a published study of 2 versions of cognitive-behavioural therapy-based interdisciplinary treatment for chronic pain. In this study, we examined whether the use of opioids by 140 chronic pain patients could be ceased sustainably over 12 months after participation in the comprehensive interdisciplinary pain management program aimed at enhancing pain self-management. On admission to the treatment, there were no significant differences between those patients taking or not taking opioids on usual pain, pain interference in daily activities, pain-related disability, depression severity, as well as in pain cognitions. After the treatment, the use of opioids was significantly reduced, both in numbers taking any and in mean doses, and these gains were maintained over the 12-month follow-up. Finally, cessation of opioids during treatment was associated with more substantial and consistent improvements in usual pain, depression severity, pain interference, pain-related disability, and pain cognitions, relative to those who reduced their opioids but did not cease them. These findings support the idea of using training in pain self-management strategies as a viable alternative to long-term opioid use by patients with chronic pain.

Voriconazole Autoinduction and Saturable Metabolism After Cessation of Rifampin in a Patient With Invasive Central Nervous System Aspergillus: Importance of Therapeutic Drug Monitoring.

PURPOSE: Optimization of antifungal therapy with voriconazole can be challenging due to inter- and intrapatient variability in voriconazole pharmacokinetics (PK). In this case, we introduce challenges in voriconazole therapy due to drug-drug interactions, autoinduction, and saturable metabolism. SUMMARY: A 32-year-old male on chronic prednisone developed central nervous system (CNS) aspergillosis. He was started on high-dose intravenous (IV) voriconazole 8.5 mg/kg every 12 hours due to concerns for lasting induction effects of recent rifampin therapy. The initial voriconazole trough was 2 µg/mL. Frequent dose adjustments were made to maintain the therapeutic trough goal. On day 24 of voriconazole therapy, his trough was undetectable on IV voriconazole 5.5 mg/kg every 12 hours. His dose was escalated to 8.5 mg/kg every 12 hours to avoid subtherapeutic levels and therapeutic failure. On day 48, his trough level was 1.1 µg/mL on the same dose. His regimen was changed to 6.5 mg/kg every 8 hours at this point. Sixteen days after this regimen on day 74 of voriconazole therapy, his trough was 27.2 µg/mL indicating saturable PK of voriconazole in the absence of interacting drugs. CONCLUSION: Our findings highlight the unpredictable PK of voriconazole and reinforce the importance of continuous therapeutic drug monitoring in critically ill patients.

Levamisole-Adulterated Cocaine-Induced Skin Lesions: A Case Report and Literature Review.

Levamisole is used as an agent to increase the total weight of street cocaine. We report the case of a 28-year-old female who presented with multiple painful, ulcerating lesions. She tested positive for cocaine and levamisole. Her skin lesions improved with abstinence from cocaine. Patients with levamisole-induced toxicity most often present with skin manifestations or joint pain. Leukopenia, neutropenia, and agranulocytosis are common lab abnormalities seen in these patients. Complete resolution of the skin lesions are observed approximatelythree weeks after abstinence. Patients known to use street drugs, who present with unexplained skin rash, neutropenia, and multiple immunological abnormalities, should be tested for both cocaine and levamisole. Urine toxicology screen is positive for cocaine approximately 72 hours after ingestion. Levamisole requires specialized testing that is not readily available commercially andis positive forless than 48 hours after exposure.

Implementation of the 2013 Psychoactive Substances Act and mental health harms from synthetic cannabinoids.

AIMS: Use of synthetic cannabinoids is associated with a range of mental health harms. The 2013 Psychoactive Substances Act (PSA) was intended to limit retail availability of synthetic cannabinoids which had acceptable safety profiles. We evaluated numbers and clinical characteristics of patients presenting with mental health harms associated with use of synthetic cannabinoids for three months before and after implementation of the PSA on 18July 2013. METHODS: Retrospective audit of case notes of patients presenting to an emergency psychiatric service (EPS) in Dunedin. RESULTS: In the three months post-PSA, there was a 42% reduction in EPS contacts and 52% reduction in patient presentations, compared with the three months pre-PSA. Patient demographics (predominantly young males with prior contact with mental health services), presenting symptoms (mood and psychotic symptoms and suicidality), and management and disposition were identical in both periods. CONCLUSIONS: The decrease in mental health harms, as measured by frequency of EPS contacts, appeared to be due to reduced retail availability of synthetic cannabinoids rather that reduced toxicity of available products.

Evidence-based guideline: treatment of tardive syndromes: report of the Guideline Development Subcommittee of the American Academy of Neurology.

OBJECTIVE: To make evidence-based recommendations regarding management of tardive syndromes (TDS), including tardive dyskinesias (TDD), by addressing 5 questions: 1) Is withdrawal of dopamine receptor blocking agents (DRBAs) an effective TDS treatment? 2) Does switching from typical to atypical DRBAs reduce TDS symptoms? 3) What is the efficacy of pharmacologic agents in treating TDS? 4) Do patients with TDS benefit from chemodenervation with botulinum toxin? 5) Do patients with TDS benefit from surgical therapy? METHODS: PsycINFO, Ovid MEDLINE, EMBASE, Web of Science, and Cochrane were searched (1966-2011). Articles were classified according to a 4-tiered evidence-rating scheme; recommendations were tied to the evidence. RESULTS AND RECOMMENDATIONS: Clonazepam probably improves TDD and ginkgo biloba probably improves TDS (both Level B); both should be considered as treatment. Risperidone may improve TDS but cannot be recommended as treatment because neuroleptics may cause TDS despite masking symptoms. Amantadine and tetrabenazine might be considered as TDS treatment (Level C). Diltiazem should not be considered as TDD treatment (Level B); galantamine and eicosapentaenoic acid may not be considered as treatment (Level C). Data are insufficient to support or refute use of acetazolamide, bromocriptine, thiamine, baclofen, vitamin E, vitamin B6, selegiline, clozapine, olanzapine, melatonin, nifedipine, fluperlapine, sulpiride, flupenthixol, thiopropazate, haloperidol, levetiracetam, quetiapine, ziprasidone, sertindole, aripiprazole, buspirone, yi-gan san, biperiden discontinuation, botulinum toxin type A, electroconvulsive therapy, α-methyldopa, reserpine, and pallidal deep brain stimulation as TDS treatments (Level U). Data are insufficient to support or refute TDS treatment by withdrawing causative agents or switching from typical to atypical DRBA (Level U).

Dealing with global safety issues : was the response to QT-liability of non-cardiac drugs well coordinated?

Drug-induced torsade de pointes (TdP) is a potentially fatal iatrogenic entity. Its reporting rate in association with non-cardiac drugs increased exponentially from the early 1990s and was associated with an increasing number of new non-cardiac drugs whose proarrhythmic liability was not appreciated pre-marketing. This epidemic provoked a comprehensive global response from drug regulators, drug developers and academia, which resulted in stabilization of the reporting rate of TdP. This commentary reviews the chronology and nature of, and the reasons for, this response, examines its adequacy, and proposes future strategies for dealing with such iatrogenic epidemics more effectively. It is concluded that the response was piecemeal and lacked direction. No one entity was responsible, with the result that important contributions from regulators, industry and academia lacked coordination. While the process of dealing with QT crisis seemed to have worked reasonably well in this instance, it does not seem wise to expect the next crisis in drug development to be managed as well. Future crises will need better management and the challenge is to implement a system set up to respond globally and efficiently to a perceived drug-related hazard. In this regard, we discuss the roles of new tools the legislation has provided to the regulators and the value of an integrated expert assessment of all pre-approval data that may signal a potential safety issue in the postmarketing period. We also discuss the roles of other bodies such as the WHO Collaborating Centre for International Drug Monitoring, CIOMS and the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH).

Drotrecogin alfa (activated)...a sad final fizzle to a roller-coaster party.

Following the failure of PROWESS-SHOCK to demonstrate efficacy, Eli Lilly and Company withdrew drotrecogin alfa (activated) from the worldwide market. Drotrecogin was initially approved after the original trial, PROWESS, was stopped early for overwhelming efficacy. These events prompt consideration of both the initial approval decision and the later decision to withdraw. It is regrettable that the initial decision was made largely on a single trial that was stopped early. However, the decision to approve was within the bounds of normal regulatory practice and was made by many approval bodies around the world. Furthermore, the overall withdrawal rate of approved drugs remains very low. The decision to withdraw was a voluntary decision by Eli Lilly and Company and likely reflected key business considerations. Drotrecogin does have important biologic effects, and it is probable that we do not know how best to select patients who would benefit. Overall, there may still be a small advantage to drotrecogin alfa, even used non-selectively, but the costs of determining such an effect with adequate certainty are likely prohibitive, and the point is now moot. In the future, we should consider ways to make clinical trials easier and quicker so that more information can be available in a timely manner when considering regulatory approval. At the same time, more sophisticated selection of patients seems key if we are to most wisely test agents designed to manipulate the septic host response.

Osteoporosis in 2011: Osteoporosis therapy--dawn of the post-bisphosphonate era.

Over the past decade, investigators have actively searched for safer therapeutic approaches to replace or complement the use of bisphosphonates and/or parathyroid hormone, exploring both antiresorptive and osteoanabolic pathways. Besides marked progress in basic research, the year 2011 has seen several compounds for the treatment of osteoporosis enter or progress within clinical trials.

Different black box warning labeling for same-class drugs.

INTRODUCTION: Black box warnings (BBWs) are the strongest medication-related safety warnings in a drug's labeling information and highlight major risks. Absence of a BBW or asynchronous addition of a BBW among same-class drugs could have major implications. METHODS: We identified the 20 top-selling drugs in 2008 (10 with BBWs and 10 without BBWs on their label) that belonged to different drug classes. We collected labeling information on all drugs belonging in these 20 classes, and recorded differences in the presence and timing of acquisition of BBWs for same-class drugs. RESULTS: Across the 20 evaluated drug classes, we identified 176 different agents, of which 7 had been withdrawn for safety reasons. The reasons for the withdrawals became BBWs in other same-class agents only in two of the seven cases. Differences were identified in 9 of the 20 classes corresponding to 15 BBWs that were not present in all drugs of the same class. The information for 10 of the 15 different BBWs were included in the labels of same-class drugs as simple warnings or text, while it was absent entirely in 5 BBWs. The median interval from the time the BBW had appeared in another drug of the same class was 66 months. DISCUSSION: Differences in BBW labeling in same-class drugs are common and shape impressions about the safety of similar agents. BBW labeling needs to become more systematic.