Why so few drugs Flashcards
o McKernan et al. (2000)
generated transgenic mice with a single amino acid substitution in the alpha 1 subunit, and found that sedation was not induced by diazepam in these mice, but the anxiolytic effects remain
o There was however a caveat of this study, as the authors measured sedation by motor activity, but perhaps there was some kind of motor impairment instead of sedative effects.
o They also administered a partial agonist of the alpha 2, 3 and 5 subunits to normal mice, with an antagonist at alpha 1, and found that anxiolysis was retained, but motor activity was not reduced
TGN1412 trial
TGN1412 was a humanised anti-CD28 monoclonal antibody developed for immunological diseases (e.g. multiple sclerosis, rheumatoid arthritis) and some cancers
o In preclinical testing on animal models including mice, toxicity studies demonstrated that doses hundreds of times higher than the amount administered to humans were deemed safe, and the drugs were efficacious
o However in the first human clinical trials, the drug caused catastrophic systemic organ failure in patients.
- Seok et al. (2013)
conducted a large-scale study that highlights how poorly mouse models of inflammation reflect the human condition
o This involved analysing the gene expression profiles of leukocytes in mouse models and human subjects that were elicited by inflammatory challenges (including trauma, sepsis and endotoxemia).
o The authors found that the expression profiles amongst humans across these diverse conditions were similar, suggesting a common pathway in humans independent of the initiating stress
o However, the expression profile in the corresponding mice models differed significantly from each other, and from the human data
o In fact, the correlations of the gene changes between humans and mice was equivalent to what would be expected by random chance
o This may explain why so many of the clinical trials for these disorders fail, and emphasises the need for more human-representative models, such as the DRAG mouse model
o There were however caveats to this work, for example they did only investigate one strain of mice, different microbiotal compositions in species could have influenced the profiles, and humans received medical care that wasn’t accounted for
o Schenk et al (1999)
found that immunising the PDAPP transgenic mouse (which overexpresses mutant human APP hence develops the hallmarks of AD) with Aβ protein fragments prevented Aβ plaque formation and hence the development of AD in the young mice.
o The study also importantly showed that immunisation slowed progression and reduced extent of the disease in older mice, meaning that this method could potentially provide a treatment rather than just a prophylactic measure.
Elan Corporation trial (2000)
disaster. 6% of patients got meningeal encephalitis. Trial abandoned in 2002
Thalidomide
o Thalidomide was first marketed in the 1950s for anxiety, trouble sleeping and morning sickness
o In 1960, the FDA were reluctant to approve thalidomide for morning sickness, which had already been approved in several other countries
o Turns out the FDA was right!
o Was found that when taken by pregnant women, the drug caused life-threatening birth defects called phocomelia. An estimated 10,000 were affected by its use during pregnancy, with around 40% dying around the time of birth.
Discuss repurposing Ebselen for BPD
o Problem: lithium is currently the first line prophylactic drug for bipolar disorder, discovered by chance in the 1940s. Its mechanism of action is debated, but believed to involve inhibition of inositol 1-phosphatase. Despite its mood-stabilising effects, patients often find it intolerable, it has a very narrow therapeutic index, their blood must be monitored, and it can lead to long-term kidney damage. Thus, lithium is far from the ideal therapeutic for these patients.
o Ebselen is part of the National Institutes of Health Clinical Collection – a library of bioavailable drugs that are safe clinically but do not have a current use
o E.g. Singh et al. 2013 (Oxford department): screened a clinical collection of around 450 drugs for efficacy at inhibiting inositol monophosphatase (IMPase), identified organic molecule called ebselen able to do this, which could inhibit in vitro and in vivo with similar effects to lithium
In vitro, they used a human IMPase assay to demonstrate IMPase inhibition by ebselen
And in vivo, ebselen reduced manic-like behaviour in mice, including rearing in the open field test and amphetamine-induced hyperactivity. To confirm the importance of inositol depletion, intracerebroventricular injection of inositol reversed the behavioural effects of ebselen.
o Preliminary human data of ebselen treatment for bipolar disorder is promising, phase II clinical trial completed Sept 2019! Waiting for results!
Van’t Veer et al (2002)
“o They performed microarray analysis of 78 primary breast cancer tumours, and identified a gene expression ‘profile’ of 70 genes that could predict the risk of future distant metastasis, and so could identify in advance which patients would or would not respond to chemotherapy
o The group with a ‘good’ as opposed to a ‘poor’ prognosis did not suffer distant metastases within 5 years Computer software can now compare a patient’s mRNA profile to the gene expression profile from this study in order to predict whether they would benefit from chemotherapy”
Cardoso et al 2016
published a phase III randomised study in the NEJM involving 6693 women with early-stage breast cancer which assessed the clinical risk (by looking at conventional histology) and the genomic risk in parallel. Tgus stratified pts into two groups - both low, both high or a lack of concordance. These discordant groups were then randomised to recieve chemotherapy or not. Aim was to identify which of these predictive parameters is most accurate at identifying those that stand to benefit from chemotherapy. Found that there was v little difference between those who recieve chemotherapy and those who dont in terms of survival without metastases in both groups. This suggests that a combination of both approaches shows that aroun 40% of pts considered at a high clinical risk may not actually benefit from chemotherapy.
Faurholt-Jepsen et al. 2015
conducted a study of 61 patients ages 18-60 diagnosed with bipolar disorder (BD)
- The authors used software for smartphones (the MONARCA I system) that collects automatically generated objective data, as well as self-monitored data on illness activity
- Results:
- Over time, they found a significant positive correlations between BD scores (for both mania and depression) on different classifications and the number of incoming/outgoing calls per day, the duration of calls, as well as the number of outgoing text messages per day
- They also reported significant negative correlations between self-monitored data (i.e. mood and activity) and depressive scores, and significant positive correlations between self-monitored data (i.e. mood and activity) and mania scores
- Moreover, using the automatically-generated objective data, they were able to discriminate between affective states
- Implications:
- Data automatically generated by smartphone apps represents an easy way to monitor illness activity with real-time data in BD and may serve as an electronic biomarker of illness activity
