The adverse events profile of anti-IGF-1R monoclonal antibodies in cancer therapy

Aim(s)

Insulin-like growth factor-1 receptor (IGF-1R) targeted therapies have become one of the intriguing areas in anticancer drug development during the last decade. As one of these therapies, anti-IGF-1R monoclonal antibodies (mAbs) are also advancing further in development. Our purpose was to conduct a systematic review of the adverse events (AEs) caused by anti-IGF-1R monoclonal antibodies in cancer therapy.

Methods

We searched the term‘IGF-1R monoclonal antibody’ in the Pubmed database and found 389 related articles. After elaborate selection, 15 clinical studies that satisfied our criteria were then adopted for further analysis. We extracted all the useful information about the AEs of mAbs from the enrolled studies. Every kind of reported AE as well as corresponding incidences were summed up and calculated. We compared AE incidence differences in two age groups, and analyzed toxicities of mAbs used as a single agent or combined with chemotherapies. Finally, the differences of AE profiles between individual mAbs were also valued.

Results

AEs were more severe in the lower age group and 13 of 19 AE incidences in the single-agent group were significantly lower than in the combination group (P < 0.05). R1507 seemed to show a worse AE profile than cixutumumab and figitumumab.

Conclusions

When anti-IGF-1R mAbs are used for cancer therapy, it is essential to choose the proper drug and combined chemotherapies to reduce AE occurrences. Also, administration of these mAbs to younger patients should be more carefully supervised. Furthermore, some more frequently observed AEs for specific mAb should be paid adequate attention.     

Cannabis-related hospitalizations: unexpected serious events identified through hospital databases

AIMS

Cannabis is the most prevalent illicit drug used worldwide and can be responsible for serious health defects in users. However, the risk related to cannabis consumption is not well established. The present study aimed to assess cannabis-related adverse events leading to hospitalization, and to estimate the corresponding annual risk for consumers.

METHODS

Participants were patients admitted to the public hospitals in the Toulouse area (France) between January 2004 and December 2007 in relation to the use of cannabis. Reasons for admission and other occurring events were identified through hospital discharge summaries. We described all observed adverse events (AEs) and estimated their regional incidence on the basis of cannabis consumption data.

RESULTS

We included 200 patients, and identified a total of 619 adverse events (AEs), one of which was lethal. Psychiatric disorders involved 57.7% of patients and accounted for 18.2% of AEs. Most frequent outcomes were central and peripheral nervous system disorders (15.8% of AEs), acute intoxication (12.1%), respiratory system disorders (11.1%) and cardiovascular disorders (9.5%). We estimated that in 2007 the incidence of cannabis-related AEs in the Midi-Pyrenees region ranged from 1.2 per 1000 regular cannabis users (95% confidence interval (CI) 0.7, 1.6) to 3.2 (95% CI 2.5, 3.9).

CONCLUSIONS

Cannabis use is associated with complications, considered to be serious since they lead to hospitalization. Beyond the well-known and widely investigated psychiatric events, serious cerebro and cardiovascular complications have been identified. These findings contribute to improve the knowledge of cannabis-related adverse events.     

The Relevance of Prior Knowledge in Learning and Instructional Design

Objectives

To determine how different types of prior knowledge (declarative and procedural) impact student achievement and how prior-knowledge assessment can be used as an instructional design tool.

Methods

A questionnaire was developed based on the prior-knowledge model, which distinguishes between declarative and procedural knowledge. One hundred fifteen pharmacy students were tested prior to beginning 4 successive basic science courses and then prior to beginning a pharmaceutical chemistry course. Regression analysis was used to determine which type of knowledge was the best predictor of student achievement. The 4 course instructors were interviewed and their comments analyzed.

Results

Prior knowledge from previous courses significantly influenced student achievement. Procedural knowledge was especially related to student achievement. Instructors and students had mainly positive reactions towards the prior-knowledge tests.

Conclusions

Students'' prior knowledge should be taken into consideration in instructional design and curriculum planning. Furthermore, the results of prior-knowledge assessments may be used as a tool for student support in addressing areas of deficiency.     

Ketamine as a Potential Treatment for Suicidal Ideation: A Systematic Review of the Literature

Objective

To review the published literature on the efficacy of ketamine for the treatment of suicidal ideation (SI).

Methods

The PubMed and Cochrane databases were searched up to January 2015 for clinical trials and case reports describing therapeutic ketamine administration to patients presenting with SI/suicidality. Searches were also conducted for relevant background material regarding the pharmacological function of ketamine.

Results

Nine publications (six studies and three case reports) met the search criteria for assessing SI after administration of subanesthetic ketamine. There were no studies examining the effect on suicide attempts or death by suicide. Each study demonstrated a rapid and clinically significant reduction in SI, with results similar to previously described data on ketamine and treatment-resistant depression. A total of 137 patients with SI have been reported in the literature as receiving therapeutic ketamine. Seven studies delivered a dose of 0.5 mg/kg intravenously over 40 min, while one study administered a 0.2 mg/kg intravenous bolus and another study administered a liquid suspension. The earliest significant results were seen after 40 min, and the longest results were observed up to 10 days postinfusion.

Conclusion

Consistent with clinical research on ketamine as a rapid and effective treatment for depression, ketamine has shown early preliminary evidence of a reduction in depressive symptoms, as well as reducing SI, with minimal short-term side effects. Additional studies are needed to further investigate its mechanism of action, long-term outcomes, and long-term adverse effects (including abuse) and benefits. In addition, ketamine could potentially be used as a prototype for further development of rapid-acting antisuicidal medication with a practical route of administration and the most favorable risk/benefit ratio.     

The absolute bioavailability of racemic ketamine from a novel sublingual formulation

Aim

The principal study objective was to investigate the pharmacokinetic characteristics of a new sublingual ketamine wafer and to establish its absolute bioavailability and local tolerability.

Methods

The study was of open label, two way randomized crossover design in eight healthy male volunteers. Each participant received either a single 10 mg intravenous dose as a constant rate 30 min infusion or a 25 mg sublingual dose of ketamine wafer in two treatment periods with a 7 day wash out. Pharmacokinetic blood sampling and local tolerability and safety assessments were carried out during 24 h following both dosing occasions. Plasma concentrations were analyzed by non-compartmental methods and local tolerability was assessed using modified Likert scales.

Results

The median (90% CI lower, upper limit) absolute bioavailability of sublingual ketamine was 29% (27, 31%). The first quantifiable plasma ketamine concentration was observed within 5 min for all eight participants for both routes of administration and the median (min–max) time of the peak plasma concentration was 0.75 h (0.25–1.0 h) after sublingual administration. The ketamine wafer had very good local tolerability.

Conclusion

Sublingual administration of the ketamine wafer resulted in rapid absorption. The ketamine wafer has comparable bioavailability with other oral transmucosal formulations of ketamine but with markedly reduced inter-subject variability, warranting further evaluation as an analgesic adjunct.     

Neural Correlates of Suicidal Ideation and Its Reduction in Depression

Background:

The neural correlates of suicidal ideation and its reduction after treatment are unknown. We hypothesized that increased regional cerebral glucose metabolism in the infralimbic cortex (Brodmann area 25), amygdala, and subgenual anterior cingulate cortex would be associated with suicidal ideation and its reduction after ketamine infusion.

Methods:

Medication-free patients (n=19) with treatment-resistant major depressive disorder underwent positron emission tomography imaging at baseline and 230 minutes after an open-label ketamine infusion (0.5mg/kg for 40 minutes).

Results:

Baseline suicidal ideation and regional cerebral glucose metabolism in the infralimbic cortex were significantly correlated (r=.59, P=.007); but not overall mood scores (r=−.07, P=.79). Reductions in suicidal ideation after ketamine infusion were correlated with decreased regional cerebral glucose metabolism in the infralimbic cortex (r=.54, P=.02). Metabolism in other areas of interest was not significantly correlated with suicidal ideation or depression.

Conclusion:

The infralimbic cortex may be implicated in suicidal ideation.     

BDNF Release Is Required for the Behavioral Actions of Ketamine

Background:

Recent studies demonstrate that the rapid antidepressant ketamine increases spine number and function in the medial prefrontal cortex (mPFC), and that these effects are dependent on activation of glutamate α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors and brain-derived neurotrophic factor (BDNF). In vitro studies also show that activation of AMPA receptors stimulates BNDF release via activation of L-type voltage-dependent calcium channels (VDCC).

Methods:

Based on this evidence, we examined the role of BDNF release and the impact of L-type VDCCs on the behavioral actions of ketamine.

Results:

The results demonstrate that infusion of a neutralizing BDNF antibody into the mPFC blocks the behavioral effects of ketamine in the forced swim test (FST). In addition, we show that pretreatment with nifedipine or verapamil, two structurally-different L-type calcium channel antagonists, blocks the behavioral effects of ketamine in the FST. Finally, we show that ketamine treatment stimulates BDNF release in primary cortical neurons and that this effect is blocked by inhibition of AMPA receptors or L-type VDCCs.

Conclusions:

Taken together, these results indicate that the antidepressant effects of ketamine are mediated by activation of L-type VDCCs and the release of BDNF. They further elucidate the cellular mechanisms underlying this novel rapid-acting antidepressant.     

Medication Reconciliation Practices in Canadian Emergency Departments: A National Survey

Background:

As of 2015, Accreditation Canada’s Qmentum program expects emergency departments (EDs) to initiate medication reconciliation for 2 groups of patients: (1) those with a decision to admit and (2) those without a decision to admit who meet the criteria of a risk-based, health care organization–defined selection process. Pharmacist-led best possible medication histories (BPMHs) obtained in the ED are considered more complete and accurate than BPMHs obtained by other ED providers, with pharmacy technicians obtaining BPMHs as effectively as do pharmacists. A current assessment of the role of pharmacy in BPMH processes in Canadian EDs is lacking.

Objectives:

To identify and describe BPMH and medication reconciliation practices in Canadian EDs, including those performed by members of the ED pharmacy team.

Methods:

All Canadian hospitals with an ED and at least 50 acute care beds were contacted to identify the presence of dedicated ED pharmacy services (defined as at least a 0.5 full-time equivalent position). Different electronic surveys were then distributed to ED pharmacy team members (where available) and ED managers (all hospitals).

Results:

Survey responses were obtained from 60 (63%) of 95 ED pharmacy teams and 128 (53%) of 243 ED managers. Only 38 (30%) of the 128 ED managers believed that their current BPMH processes were adequate to obtain a BPMH for all admissions. Fifty-nine (98%) of the ED pharmacy personnel reported obtaining BPMHs (most commonly 6–10 per day), with priority given to admitted patients. Only 14 (23%) of the 60 ED pharmacy teams reported that their EDs had adequate staffing to comply with Accreditation Canada’s requirements for obtaining BPMHs. This result is supported by the 104 (81%) out of 128 ED managers who reported that additional ED staffing would be needed to comply with the requirements. Numerous ED managers identified the need to expand ED pharmacy services and improve information technology support.

Conclusions:

BPMH processes in Canadian EDs were variable and inadequately supported. Survey responses suggested that additional staff and significant improvements in structured processes would be required to meet Accreditation Canada standards.     

Ketamine-Induced Modulation of the Thalamo-Cortical Network in Healthy Volunteers As a Model for Schizophrenia

Background:

Schizophrenia has been associated with disturbances of thalamic functioning. In light of recent evidence suggesting a significant impact of the glutamatergic system on key symptoms of schizophrenia, we assessed whether modulation of the glutamatergic system via blockage of the N-methyl-d-aspartate (NMDA)-receptor might lead to changes of thalamic functional connectivity.

Methods:

Based on the ketamine model of psychosis, we investigated changes in cortico-thalamic functional connectivity by intravenous ketamine challenge during a 55-minute resting-state scan. Thirty healthy volunteers were measured with pharmacological functional magnetic resonance imaging using a double-blind, randomized, placebo-controlled, crossover design.

Results:

Functional connectivity analysis revealed significant ketamine-specific changes within the thalamus hub network, more precisely, an increase of cortico-thalamic connectivity of the somatosensory and temporal cortex.

Conclusions:

Our results indicate that changes of thalamic functioning as described for schizophrenia can be partly mimicked by NMDA-receptor blockage. This adds substantial knowledge about the neurobiological mechanisms underlying the profound changes of perception and behavior during the application of NMDA-receptor antagonists.     

Use of methadone for prevention of opioid withdrawal in critically ill children

Background

Opioids are commonly administered to critically ill children for analgesia and sedation, but many patients experience opioid withdrawal upon discontinuation. The authors’ institution developed a protocol for using methadone to prevent opioid withdrawal in children who have received morphine by continuous IV infusion for 5 days or longer in the pediatric intensive care unit (PICU).

Objectives

The primary objectives were to determine if opioids were tapered according to the protocol and to determine the conversion ratio for IV morphine to oral methadone that was used. Secondary objectives were to describe the methadone dosage used and the clinical outcomes, to evaluate adjustments to methadone dosing, and to report the incidence of adverse effects.

Methods

A retrospective analysis of charts was conducted for pediatric patients who had received morphine by continuous IV infusion for 5 days or longer followed by methadone in the PICU between May 2008 and August 2009. Validated scoring systems (the Withdrawal Assessment Tool and the State Behavioral Scale) were used to assess symptoms of withdrawal and degree of sedation, respectively.

Results

Forty-three patients were included in the study, with median age of 8 months (range 0.25–201 months). For 31 patients (72%), the protocol was not used, and there were no patients for whom the protocol was followed to completion. The median duration of weaning was 10 days (range 0–91 days). The conversion ratio for IV morphine to oral methadone was 1:0.78 for anticipated 5-day weaning and 1:0.98 for anticipated 10-day weaning. During the first 10 days of weaning, 18 patients (42%) experienced withdrawal symptoms. The methadone dose was increased for 11 (26%) of the 43 patients. Patients were sedated for a median of 1 day (range 0–9 days), were comfortable for a median of 6.5 days (range 1–64 days), and were agitated for a median of 2.5 days (range 0–23 days). Naloxone was required for 2 patients.

Conclusions

The institution’s methadone protocol was not followed consistently during the study period, and practices for transitioning from morphine by continuous IV infusion to methadone with tapering were also inconsistent. Further studies are needed to determine the optimal conversion ratio for morphine to methadone and the optimal tapering regimen to minimize withdrawal symptoms and adverse events.     

The Mood Stabilizer Lithium Potentiates the Antidepressant-Like Effects and Ameliorates Oxidative Stress Induced by Acute Ketamine in a Mouse Model of Stress

Background:

Evidence suggests that mammalian target of rapamycin activation mediates ketamine’s rapid but transient antidepressant effects and that glycogen synthase kinase-3β inhibits this pathway. However, ketamine has associated psychotomimetic effects and a high risk of abuse. The mood stabilizer lithium is a glycogen synthase kinase-3 inhibitor with strong antisuicidal properties. Here, we used a mouse stress model to investigate whether adjunct lithium treatment would potentiate ketamine’s antidepressant-like effects.

Methods:

Mice received chronic restraint stress and long-term pre- or postketamine lithium treatment in drinking water. The effects of lithium on ketamine-induced antidepressant-like effects, activation of the mammalian target of rapamycin/brain-derived neurotrophic factor signaling pathways, oxidative stress, and dendritic spine density in the brain of mice were investigated.

Results:

Subtherapeutic (600mg/L) lithium-pretreated mice exhibited an antidepressant-like response to an ineffective ketamine (2.5mg/kg, intraperitoneally) challenge in the forced swim test. Both the antidepressant-like effects and restoration of dendritic spine density in the medial prefrontal cortex of stressed mice induced by a single ketamine (50mg/kg) injection were sustained by postketamine treatment with 1200mg/L of lithium for at least 2 weeks. These benefits of lithium treatments were associated with activation of the mammalian target of rapamycin/brain-derived neurotrophic factor signaling pathways in the prefrontal cortex. Acute ketamine (50mg/kg) injection also significantly increased lipid peroxidation, catalase activity, and oxidized glutathione levels in stressed mice. Notably, these oxidative stress markers were completely abolished by pretreatment with 1200mg/L of lithium.

Conclusions:

Our results suggest a novel therapeutic strategy and justify the use of lithium in patients who benefit from ketamine.     

Safety and Effectiveness of Dexmedetomidine in the Pediatric Intensive Care Unit (SAD–PICU)

Background:

Critically ill children require sedation for comfort and to facilitate mechanical ventilation and interventions. Dexmedetomidine is a newer sedative with little safety data in pediatrics, particularly for therapy lasting longer than 48 h.

Objective:

To quantify the frequency of adverse events and withdrawal syndromes associated with dexmedetomidine and to describe the use of this drug for continuous sedation in critically ill children.

Methods:

In this retrospective study of patients who received dexmedetomidine for sedation in the pediatric intensive care unit, adverse events were assessed with the Naranjo scale to determine the likelihood of association with dexmedetomidine. Interventions in response to adverse events were also recorded.

Results:

One hundred and forty-four patients (median age 34 months, range 0 – 17.7 years) who underwent a total of 153 treatment courses were included. The mean infusion rate of dexmedetomidine was 0.42 μg/kg per hour (standard deviation 0.17 μg/kg per hour, range 0.05–2 μg/kg per hour). The median duration of therapy was 20.50 h (range 0.75–854.75 h), and 70 infusions (46%) lasted more than 24 h. At least one adverse event was observed in 115 (75%) of the treatment courses. Hypotension (81 [53%]) and bradycardia (38 [25%]) were the most common adverse events and were deemed “probably” attributable to dexmedetomidine in 17 (11%) and 9 (6%) of the treatment courses, respectively. In 55 of the 66 treatment courses with infusions lasting longer than 24 h for which post-infusion data were available, at least one withdrawal symptom was observed; agitation (41 [62%]) and hypertension (22 [33%]) were the most common withdrawal symptoms.

Conclusions:

Dexmedetomidine was commonly administered for longer than 24 h in the authors’ institution. Dexmedetomidine was generally well tolerated; however, the majority of patients experienced withdrawal symptoms. Patients receiving dexmedetomidine for more than 24 h should be monitored for withdrawal following discontinuation, and interventions should be provided if needed. Prospective, controlled studies are needed to characterize the safety of long-term dexmedetomidine therapy in critically ill children.     

Interaction between positive allosteric modulators and trapping blockers of the NMDA receptor channel

Background and Purpose

Memantine and ketamine are clinically used, open-channel blockers of NMDA receptors exhibiting remarkable pharmacodynamic similarities despite strikingly different clinical profiles. Although NMDA channel gating constitutes an important difference between memantine and ketamine, it is unclear how positive allosteric modulators (PAMs) might affect the pharmacodynamics of these NMDA blockers.

Experimental Approach

We used two different PAMs: SGE-201, an analogue of an endogenous oxysterol, 24S-hydroxycholesterol, along with pregnenolone sulphate (PS), to test on memantine and ketamine responses in single cells (oocytes and cultured neurons) and networks (hippocampal slices), using standard electrophysiological techniques.

Key Results

SGE-201 and PS had no effect on steady-state block or voltage dependence of a channel blocker. However, both PAMs increased the actions of memantine and ketamine on phasic excitatory post-synaptic currents, but neither revealed underlying pharmacodynamic differences. SGE-201 accelerated the re-equilibration of blockers during voltage jumps. SGE-201 also unmasked differences among the blockers in neuronal networks – measured either by suppression of activity in multi-electrode arrays or by neuroprotection against a mild excitotoxic insult. Either potentiating NMDA receptors while maintaining the basal activity level or increasing activity/depolarization without potentiating NMDA receptor function is sufficient to expose pharmacodynamic blocker differences in suppressing network function and in neuroprotection.

Conclusions and Implications

Positive modulation revealed no pharmacodynamic differences between NMDA receptor blockers at a constant voltage, but did expose differences during spontaneous network activity. Endogenous modulator tone of NMDA receptors in different brain regions may underlie differences in the effects of NMDA receptor blockers on behaviour.     

A pilot study of plasma metabolomic patterns from patients treated with ketamine for bipolar depression: evidence for a response-related difference in mitochondrial networks

Background and Purpose

(R,S)-ketamine produces rapid and significant antidepressant effects in approximately 65% of patients suffering from treatment-resistant bipolar depression (BD). The genetic, pharmacological and biochemical differences between ketamine responders and non-responders have not been identified. The purpose of this study was to employ a metabolomics approach, a global, non-targeted determination of endogenous metabolic patterns, to identify potential markers of ketamine response and non-response.

Experimental Approach

Plasma samples from 22 BD patients were analyzed to produce metabolomic patterns. The patients had received ketamine in a placebo-controlled crossover study and the samples were obtained 230 min post-administration at which time the patients were categorized as responders or non-responders. Matching plasma samples from the placebo arm of the study were also analysed. During the study, the patients were maintained on either lithium or valproate.

Key Results

The metabolomic patterns were significantly different between the patients maintained on lithium and those maintained on valproate, irrespective of response to ketamine. In the patients maintained on lithium, 18 biomarkers were identified. In responders, lysophosphatidylethanolamines (4) and lysophosphatidylcholines (9) were increased relative to non-responders.

Conclusions and Implications

The results indicate that the differences between patients who respond to ketamine and those who do not are due to alterations in the mitochondrial β-oxidation of fatty acids. These differences were not produced by ketamine administration. The data indicate that pretreatment metabolomics screening may be a guide to the prediction of response and a potential approach to the individualization of ketamine therapy.

Linked Articles

This article is part of a themed issue on Mitochondrial Pharmacology: Energy, Injury & Beyond. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2014.171.issue-8     

Cannabinoid Hyperemesis Syndrome

Background:

The purpose of this review is to describe cannabinoid hyperemesis syndrome (CHS), which is thought to be induced by long-term cannabis use, and provide clinical pharmacists with information to manage the hyperemetic phase of CHS.

Method:

Published literature was searched and reviewed using PubMed.

Results:

CHS is characterized by intractable nausea and vomiting without an obvious organic cause and associated learned compulsive hot water bathing behavior. Patients often seek care in the emergency department (ED) for symptomatic relief.

Conclusion:

CHS is potentially underrecognized and underdiagnosed in the ED, and it should be considered in the differential diagnosis in long-term cannabis use patients with CHS symptoms to avoid unnecessary extensive diagnostic workup including invasive radiologic imaging. Pharmacists have an important role in CHS recognition, education, and symptom management.