General Drugs Flashcards
1
Q
What is inflammation?
A
A complex biological response to harmful stimuli such as trauma or infection
It is normally beneficial and is key to physiological processes such as tissue repair and regeneration
When it becomes chronic, can cause problems
2
Q
What are the major classes of anti-inflammatory drugs?
A
NSAIDs (aspirin and ibuprofen)
Glucocorticoids
3
Q
What immune cells are important for inflammation resolution and regeneration?
A
Neutrophils undergo opotosis during inflammation and then are rapidly cleared by macrophages- termed efferocytosis
After clearing neutrophils, macrophages change phenotype from pro to anti inflammatory
4
Q
What does effercytosis lead to?
A
Efferocytosis helps contribute to tissue repair and resolution however dysregulated efferocytosis can lead to permanent tissue damage.
5
Q
What drugs act on neutrophils to cause apoptosis?
A
CDKi
Cyclin-dependant kinase inhibitors
Stop chronic inflammation as if there to too many neutrophil this causes a ,assive influx of inflammatory molecules and chronic inflammation
5
Q
What is a current theory regarding efferocytosis and tissue resolution?
A
Driving neutrophils into apoptosis will result in faster resolution of the tissue
6
Q
What is the mechanism of action of CDKis?
A
Cyclin-dependent kinase inhibitors inhibit the production of Mcl-1, a key protein involved in inhibiting apoptosis
This induces granulocyte (neutrophil, eosinophil) apoptosis and enhances resolution of granulocyte-dependent inflammation
7
Q
What is a CDK inhibitor currently being trialled?
A
R-roscovitine
8
Q
What are survival agents of neutrophils?
A
GM-CSF and LPS, both mediators of inflammation
9
Q
How does R-Roscovitine affect GM-CSF and LPS treated neutrophils?
A
It inhibits the delay of apoptosis induced by these survival agents
I.e. it overrides pro-inflammatory factors
10
Q
What did Rossi et al 2006 discover about R-roscovitine?
A
R-roscovitine enhances the resolution of established neutrophilic-dependent inflammation of acute pleurisy via a caspase dependent mechanism
Carrageenan was given intrapleurally which is a plant that causes inflammation
11
Q
How can it be established that a drug is acting in a caspase dependent mechanism?
A
Give a caspase inhibitor i.e. zFAD and see if the drugs still produces effects
12
Q
What is ARDS?
A
Acute respiratory distress syndrome
There is no current pharmacological therapy despite many trials and mortality is > 25%
In ARDS, fluid builds up inside the tiny air sacs of the lungs, and surfactant breaks down. Causes less oxygen transfer through the lungs
13
Q
Would could potentially be used to treat ARDS?
A
CDK inhibitor
AT7519 was a potent inducer of neutrophil apoptosis and and resolution occured quicker in a mammalian model of lung inury
14
Q
What did AT7519 do to established E coli induced lung infection?
A
Accelerated the resolution of established E coli induced lung inflammation
Decreased neutrophil survival
Less E coli present after treatment- counterintuitive but hypothesised that macrophages are better at removing bugs than neutrophils
15
Q
What happens to the airway of Mcl-1 overexpressing mice?
A
Exacerbated allergic airway inflammation
Due to its protective effect stopping eosinophils from apoptosis
16
Q
How do glucocorticoids promote the clearance of granulocytes?
A
Via MER
MER deficient mice have a enhanced inflammatory response
17
Q
Why are zebrafish useful for experiments?
A
They can be genetically manipulated
Do not need a home license to handle
They have an intact immune system
Transparent so can visualise the proccesses occuring within them
18
Q
How long are you allowed to use zebrafish for before you need a license?
A
Allowed to use zebrafish for 5 days after fertilisation
19
Q
How can the immune system be studied in zebrafish?
A
Can study the immune response via dyed cells through transgenic lines
If you cut off the tail it starts to regenerate and immune cells can be visualised
20
Q
What did transgenic staining reveal about the injuries in zebrafish?
A
Injury of the zebrafish tailfind results in recruitment of neutrophils and macrophages to the injury site
Macrophages eventually dominated at the injury site
21
Q
What is wogonin?
A
A CDKi
22
Q
What does wogonin do in zebrafish inflammation?
A
- It was found by lucus et al 2013 that wogonin (a CDKi) enhances resolution of established inflammation in zebrafish
- Number of neutrophils decreased in the presence of wogonin
23
Q
What did the Rossi group find about macrophages in zebrafish tailfin regeneration and repair?
A
KO of Irf8 lead to the generation of no macrophages. In the absence of macrophages there is reduced regeneration
24
What are the different types of pain?
Nociceptive pain- pain caused in response to a noxious substance
Neuropathic pain- pain caused by disease within the PNS or CNS
Both types of pain can coexists
25
What does paracetamol do do oesteoarthritis?
It was found that in elderly patients with OA, they experianced less intense pain with paracetemol
Functional MRI studies found the pain was localised to smaller area due to the activation of neurones in sensory cortex
26
What is neuropathic pain?
Ongoing, unremitting pain or either peripheral or central origin
Due to nerve injury
Difficult to treat
27
What may cause neuropathic pain?
Stroke- causes extra electrical activity and firing
Lesions within the spinal cord
28
What is phantom limb syndrome?
Post amputation pain in the missing limb.
There is an abnormal expression of ion channels that causes spontaneous firing in the injured or severed nerves
29
How can phantom limb syndrome be treated?
Local anaesthetics can influence the firing rate of the damaged nerves by blocking Na+ channels
Systemic anaesthetics cannot be given due to effects on muscles and heart
30
Whar is nocioception?
The sensory nervous system's process of encoding noxious stimuli
31
Where do cell bodies of sensory neurones lie?
The dorsal root ganglion
32
What is referred pain?
Referred pain is pain perceived at a location other than the site of the painful stimulus It is the result of a network of interconnecting sensory nerves, that supplies many different tissues
E.g. organ pain can radiate to the skin and this makes diagnosis harder
33
What receptor is present within sensory neurones and how could these be used to treat pain?
NaV 1.7, 1.8, 1.9
If these could be selectively blocked, could stop pain firing to the dorsal root ganglion
Systemically blocking Na+ receptors would have systemic effects
34
What can happen to nociceptor Na+ channels following an injury?
Can accumulate subtype specific sodium channels
Also get a build up of clusters of these channels near the axon which may trigger the neurone to activate more readily
35
How is pain mapped within the brain?
The somatosensory cortex is a map of body
Pain awareness comes from the anterior cingulate cortex, insula and amygdala
36
How does synaptic plasticity change in chronic pain?
In short nociceptor activation, there is AMPA discharge but NMDAR are still blocked by Mg2+
After repetitive firing there is more Glutamate released, more AMPA activation and NMDA activation so more excitability and magnification of the pain
37
What limits the synpatic plasticity that occurs in pain?
Ketamine
NMDAR antagonist
Limitations to its use due to psychotropic inducing effects
38
What are MAGUK proteins?
Membrane associated gyuanylate kinase (MAGUK) proteins are scaffolding proteins that tether NMDA receptors
39
What is an example of a NMDA scaffolding protein?
PSD-95
Huge scaffold molecules- can hold onto many NMDA receptors and attach them to the synapse. Makes sure there are many receptors available for ligand
40
How are scaffolding molecules involved in pain?
When PSD-95 is deleted in mice, hypersensitive pain behviours are stoping
Therefore pain may relate to signalling molecules not just receptors
41
What are the main targets for opiod receptors?
μ-opioid receptor, mu OR; δ-opioid receptor, deltaOR; and κ-opioid receptor, kappa OR
42
What are the pros and cons of opioids?
PRO= very effective for most acute and inflammatory pain
CON= little efficacy against neuropathic pain. High risk of addiction and there is a marked tolerance and dose escalation required. Also causes severe sedation, respiratory and lower gut suppression
43
What is a potential method for achieving analgesia from opiods without the unwanted side effects?
Biased agonism
Need to find an agonist that activates the favourable G protein signalling without activting the beta-arresti pathway that causes side effects
44
What is proof of concept that biased agonism can be used to inhibit the unwanted side effects of analgesia?
Beta arrestin KO mice do not get the 'bad effects' but still get analgesia
45
How might biased signalling be induced in humans to cause analgesia without unwanted side effects?
Cannot KO the beta arrestin pathway, so instead drugs need to be found.
TRV130 and PZM21 have been identified as a potential agent that stops the beta arrestin pathway
46
What is TRV130?
Oliceridine
Clinical trials are underway
APOLLO-1 and 2 trials
sold under the brand name Olinvyk and given intraveneously
FDA approved
47
What are examples of Gabapentinoids?
Gabapentin and pregabalin
48
How do Gabapentinoids act?
Act on the Ca2+ channel in nerves.
They block calcium transport to the plasma membrane by binding to alpha2 and delta1 subunits, thereby inhibiting nociceptive inputs
49
What are Gabapentinoids used for?
Anti-convulsants and neuropathic analgesics
50
What is the problem with gabapentoids?
Calcium channels in various locations are blocked- causes dizziness, ataxia and at higher doses sedation.
11 patients have to be treated for 1 to response so not very useful
51
What are the two receptors for endocannabinoids?
CB1 mainly found in the forebrain, sensory afferents and some peripheral sites mainly found within the immune system
52
Where are endogenous CB receptor agonists derivived from and what are they useful for?
Fatty products of the body and CNS can make endogenous arachidonic acid derived agonists for CB receptors- these are effective for mild to moderate pain
53
What two types of CB receptor agonists are effective for mild to moderate pain?
Both plant derived and endogenous arachidonic acid-dervived agonists can be effective analgesics
54
Why are CB1 receptors implicated in analgesia?
- CB1 receptors predominant in nociceptors all way through pain pathway
- In CB1 KO mice, they had a heightened sense of pain
55
What are some of the cons for using cannabinoid agonists for management of pain?
Their psychotropic activity
Hyperthermia
56
How can the negative side effects of CB1 receptors be solved?
Biased agonism
Need to find a biased ligand
Peripherally selective CB1 agonists
57
What successes has biased agonism had in cannabinoid-mediated pain?
In mice with mutated CB1R, that lack GRK sites (needed for arrestin recruitment)
the analgesic effects of CB agonists is increased
Furthermore, a CB1R positive allosteric agonist, ZCZ011 produces analgesia wihout the unwanted side effects in rodents.
58
How are peripherally restricted CB1R agonists helpful in pain moderation?
Peripherally restricted CB1R agonists have been created by changing drug structure so it does not pass through the BBB
It produces analgesia without hyperthermia or psychotropic effects in mice
May stop opiod addiction
59
What is the incidence of breast cancer?
2 million new cases every year and over 600,000 peope die of breast cancer annually
In the UK: (2016-2018) there was ~56,000 new cases, ~11,500 deaths. This is a survival rate of 76%
60
What is one of the most common oncogenic driver in breast cancer?
Overexpression of hormone receptors, which accounts for approximately 2/3 of all breast cancers
61
What is often found in hormone receptor negative breast cancers?
The overexpression of HER2 kinase
Known as HER2+ cancers
62
What is the name for the breast cancer type where HER2 and hromone receptors are not over expressed?
Triple negative breast cancer TBNC
The most agressive type of breast cancer
63
What types of breast cancer have the best and worst prognosis?
Hormone receptor + have best prognosis
Hormone receptor + and HER2+ is next
Hormone receptor - and HER2 + is next
Triple negative has the most prognosis
64
What stimulates growth in hormone receptor + cancers?
Hormones- oestrogen and/or progesterone stimulate cancer growth
65
What are protein kinases?
Protein kinases are enyzmes that catalyse the transfer of a phosphate group from ATP to either tyrosine, serine or threonine residues of a substrate protein, and they are integral components of intracellular signal transduction cascades
Phosphorylation usually results in a functional change of the protein by changing its enzymatic activity, subcellular location and/or its capacity to associate with other proteins.
66
What cell functions are protein kinases involved in?
Protein kinases govern a wide range of cell functions including growth, differentiation and motility= their dysregulation is directly involved in many diseases including cancer
67
What is the HER2 receptor?
Tyrosine kinase receptor HER2
68
What is the incidence of HER2 overexpression in breast cancer?
20-30% of tumours
Also found in other solid tumours such as ovarian, lung and stomach
69
Why might resistance to anti-HER2 treatment not work in HER2+ cancers?
Resistance to anti-HER2 treatment may be due to EGFr. EGFr may overexpress and and heterodimerise with HER2 in some cancers, which drives the cancer through a different pathway
70
How is CDK4/6 implicated in cancers and how can it be targeted within cancers?
CDK4 and CDK6 drive phosphorylation of proteins that allows cells to pass the checkpoint restriction point "R" and commit to division
By inhibiting this, stops the cell from passing R and stopping the progression of the cell cycle
71
How is c-SRC involved in breast cancer?
c-SRC is overexpressed in many patients diagnosed with breast cancer
c-SRC is a multifunctional protein involved in the regulation of a variety of of normal and oncogenic processes including proliferation, differentiation, survival, motility and angiogenesis
72
Are c-SRc inhibitors used to treat breast cancers?
No- not yet approved to treat breast cancer
73
What are cold and hot tumours?
- COLD= T cell absence or exclusion within the tumour microevnironement
- HOT= T cell infiltration and molecular signatures of immune activation. Respond better to immunotherapy
74
What is an immunotherapy used to treat cancer?
Anti-PD-L1/PD-1 therapy
PD-1 and PD-L1 immune checkpoint proteins are present on the surface of cells. Their interaction is involved in the suppression of the immune system and aims to prevent autoimmune disease. Cancer cells express PD-L1 to hide from an immune attack.
Targeting these proteins with inhibitors (typically monoclonal antibodies) can restore immune cell function, i.e. T cell recognition of cancer cells as a threat.
75
What is the most common genetic mutation that leads to breast cancer?
Approximately 5-10% of all breast cancers result from germine mutations in BRCA1 or BRCA2 genes
The risk of developing breast cancer increases by ~70% in women who inherit BRCA1 or BRCA2 mutations.
76
What are BRCA1 and BRCA2?
Proteins involved in the repair of double stranded DNA breaks.
If this is mutated, can lead to DNA repair errors and accumulation of genetic mutations
77
What type of drug helps in patients with BRCA-related cancer?
PARP inhibitors
PARP proteins are involved in DNA repairs and PARP inhibitors cause double-stranded DNA breaks
In patients with BRCA mutations these mutations cannot be fixed, leading to programmed cell death which is useful in cancer
78
What is triple negative breast cancer treated with?
Currently treated with immunotherapy and PARP inhibitors if there is a BRCA mutation
79
What treatment if offered for ER+ breast cancer
Oestrogen receptor positive cancer
Tamoxifen used- its metabolite endoxifen binds to the ER and prevents oestrogen from activating it
80
What are the pros and cons of tamoxifen?
It is very cheap
Since the late 90s has been used to treat millions of patients and is considered one of the first targeted anticancer therapies
Will affect all ER expression tissue- mammary glands and gonads will be affected. Can lead to menopausal symptoms
81
What drugs were developed following Tamoxifen's success?
Drugs that target endocrine pathways were developed
Fulvestrant- binds to the ER and promotes its degradation, more efficient than tamoxifen
Letrozole- a aromatase inhibitor, prevents the production of oestrogen from androgens. Is a first-line treatment in postmenopausal women
82
What are types of PARP inhibitors?
Olaparib= first approved PARPi in 2014 for ovarian cancer
Rucaparib when approved
Both approved for HER2+ metastatic breast cancers
83
What type of cancers are PD-L1+ cancers?
PD-L1+ cancers are 'cold' cancers which were traditionally regarded as difficult to treat with immunotherapy.
This is because PD-L1 is a protein that is involved in supressing the immune system. Body's cells express it to avoid autoimmunity
Cancer cells can also express it
Programmed cell death ligand 1
84
When was the first anti-PD-L1approved?
March 2019
The FDA approved the first checkpoint inhibitor immunotherapy drug, an anti-PD-L1 antibody called atezolizumab, in combination with chemotherapy, for the treatment of triple-negative metastatic breast cancer in patients whose tumours express the PD-L1 protein.
However was withdrawn in 2021 due to 18% prevalence of serious adverse reactions
Caused increase in survival- placebo= 4.8 and atezolimumab 7.4 months
85
What were the adverse effects of atezolizumab?
18% of patients had an serious adverse effect
Included pneumonia, fever, arrhythmia, and 1.8% of these were fatal
86
What is PD-1?
PD-L1 binds to PD-1 to exert its anti-immune effects
87
What immune checkpoint inhibitor is currently approved for TNBC patients?
PEMBROLIZUMAB (blocks PD-1 instead of PD-L1) in combination with chemotherapy received approval in 2021 to treat PD-L1-positive late stage TNBC patients whose tumours have high levers of PD-L1.
Causes seven months increase in median survival comapred with chemotherapy alone
88
What was the differences between pembrolizumab and atezolizumab?
Both immune checkpoint inhibitors
P inhibited PD-1, A inhibited PD-L1
89
What is used to treat HER2+ cancers?
A monoclonal antibody known as trastuzumab (Herceptin) that blocks the HER2 receptor is one of the most common drugs. It can be used combined with chemotherapy
Trastuzumab administration in HER2+ metastatic breast cancer patients significantly prolonged overall survival (from 26 to 33 months) and led to about 50% reduction in death risk.
90
When was Trastuzumab approved for use and why is it an important medication?
Approved for medical use in the EU in 2000
It is still first line therapy for HER2 patients and is on the WHOs list of essential medicines
91
What is an example of a CDK4/6 inhibitor?
Palbociclib
An orally available small molecule inhibitor
92
What is Palbociclib?
A CDK4/6 inhibitor
20th best selling drug worldwide
Given in combination with anti-homone therapy in ER+ breast cancers
Increased survival from 10-20 months
93
What are SRC inhibitors?
SRC is a family of kinases that help to promote cell survival and promote cell proliferation
Increased activity is observed in around 50% of all tumours
SRC activity is correlated with malignancy and poor prognosis, it has a key role in metastasis
94
What are examples of SRC inhibitors?
Dastainib and bosuitinib have both been approved for the treatment of leukaemia
95
What is the next upcoming breast cancer drug?
SRC inhibitors, despite evidence of the role of SRC in breast cancers, inhibition of its kinase activity has not yet translated into clinical benefit
NXP900 is a SRC inhibitor, preclinical trials showed NXP900 caused a potent restriction of tumour growth in mice
96
Where was NXP900 developed?
Initially developed by UOE but given to Nuvectis pharma
Nuvectis, which focuses on the development of innovative precision medicines for the treatment of serious conditions of unmet medical need in oncology, has launched a Phase 1a dose escalation clinical trial of NXP900 in the US.
97
What is NXP900?
A small molecule (oral) SRC kinase inhibitor
98
What is chronic chemotherapy induced peripheral neuropathy?
14000 new cases every year in the UK alone
Causes a glove and stocking distribution of predominantly sensory problems:
Numbness, pins and needles, tingling, burning, pain, hyperalgesia and allodynia
Causes motor deficits as well which can impact on walking, driving and carrying cups of coffee
35% still have peripheral neuropathy after a year of chemotherapy
99
What are the two dominant molecules in cannabis and what do they act on?
THC and cannabidiol (CBD)
THC and CBD are thought to promote pain relief by facilitating the ligand binding on the body's endocannabinoid receptors
CBD- acts on CB2 receptors, primarily in the immune system. Causes reduced inflammation and pain
THC- binds to CB1 in the brain and causes the 'high'
100
Why is measuring pain complex in clinical trials?
Can use analogue scales of 0-10 on pain, or can use more complex scales
When using a scale measuring the physical pain but not the emotional pain- pain might not improve to a significant level but QoL might
If only look at pain as a clinical outcome the outcomes are often negative. In reality the patient is not sleeping well, is not eating well, less mobile, has a burden of side effects. Often QoL is improved on drugs
101
What is CBD prescribed for in the UK?
In the UK CBD can be given to children with seizures. Can prescribe it for multiple myeloma and a spray for patients with challenging cancer pain
102
What have studies shown for cannabinoid use in pain?
There is a huge amount of pre-clinical evidence for the effectiveness of CBD in pain
Clinical studies so far have been negative
IASP Cannabinoid taskforce looked at all evidence and found that patients felt benefits from cannabinoids but couldnt translate to clinical trials
103
What is an example of a future trial to test the effects of cannabinoids on a pain condition?
Compare patients with themselves to stop placebo response
Measure QoL outcomes such as sleep and physical activity levels
Also measure inflammation markers- cytokine assays an measure endocannabinoids at baseline and follow up
Use a sensory score rather than pain score to include features such as numbness
fMRI can be used to see changes in brain networks
104
Why is it useful to test new pain drugs on patients with chemotherapy induced peripheral neuropathy rather than cancer patients?
Useful to use patients with neuropathy as cancer patients are already on opioids and it is complex to see the effects
105
Why is placebo response particulary problematic in neuropathic pain?
Due to the centres of emotion being linked highly with the chronic neuropathic pain.
Just by engaging with patients and their pain in a trial, will get a response.
