Wider Reading

Question 1

What is an example of a gene therapy potentially used in the future to cure cancer?

Answer 1

A nanoparticle delivery system taht delivers FDZ4 to the pulmonary endothelium in pre-clinical models of lung cancer was seen to decrease lung tumour growth and metatasis
The FDZ4 protein stablises blood vessels in tumours and decreases hypoxia
Potential to improve therapeutic outcomes in lung cancer patients

Question 2

What condition have been treated with gene therapy in foetuses?

Answer 2

Mice with Angleman syndrome
ASOs that could activate the paternal UBE3A gene were delivered through the amniotic fluid
Mice had phenotype improvements- on the accelerating rotarod and fear conditioning
Delivering medicine through amniotic fluid is as effective as delivering it to the foetal brain via cerebrospinal fluid.
May be used in future to treat conditioms such as cyctic fibrosis. Cystic fibrosis cannot be treated by gene therapy after birth

Question 3

What is morphine indicated for?

Answer 3

• FDA-approved usage of morphine sulfate includes moderate to severe pain that may be acute or chronic
• Palliative care, cancer treatment benefit most
• In the emergency department, morphine is given for musculoskeletal pain, abdominal pain, chest pain, arthritis, and even headaches
• Also used since the 1900s to relieve MI pain

Question 4

How does morphine produce most of its analgesic effects?

Answer 4

Binds to the mu-opioid receptor

Question 5

What is aspirin and what is used for?

Answer 5

Aspirin is commonly used throughout the world as an over the counter (OTC) analgesic medication used to treat various painful conditions and to reduce fever
They reversibly inhibit cyclooxygenase (prostaglandin endoperoxide synthase), the enzyme mediating production of prostaglandins and thromboxane A2

Question 6

What are the side effects of aspirin?

Answer 6

The most commonly reported events were dizziness, drowsiness, gastric irritation, nausea, and vomiting, nearly all of which were of mild to moderate severity

Question 7

What proves aspirin works as an analgesic?

Answer 7

Post surgery a single dose of aspirin was given to patients in a non-blinded trial
Fewer participants required rescue medication with aspirin than with placebo over four to eight hours postdose

Question 8

What does cyclooxygenase produce?

Answer 8

enzyme mediates the production of prostaglandins and thromboxane A2

Question 9

What is the evidence paracetemol works through the COX pathway?

Answer 9

One theory is that acetaminophen increases the pain threshold by inhibiting two isoforms of cyclooxygenase, COX-1 and COX-2, which are involved in prostaglandin (PG) synthesis.
Studies also suggest that acetaminophen selectively blocks a variant type of the COX enzyme that is unique from the known variants COX-1 and COX-2. This enzyme has been referred to as COX-3.
However it does not inhibit other downstream moleculaes such aas pro-clotting TXAs so may act in another route

Question 10

What other routes is paracetemol posluated to act in?

Answer 10

Modulates ligands of Cannabinoid receptors
Involved in 5-HT3 receptor activation

Question 11

What evidence is there that paracetemol acts via 5-HT3 receptors?

Answer 11

• Paracetamol is effective in rat pain models after central administration. Animal data supports the contention that spinal 5-hydroxytryptamine type 3 (5-HT3) receptors are be involved in the antinociceptive effect of paracetamol
• co-administration of tropisetron or granisetron (5-HT3 receptor antagonists) with paracetamol completely blocked the analgesic effect of acetaminophen in volunteers

Question 12

What is paracetemol?

Answer 12

• Acetaminophen is often found combined with other drugs in more than 600 over the counter (OTC) allergy medications, cold medications, sleep medications, pain relievers, and other products
• the most commonly taken analgesic worldwide and is recommended as first-line therapy in pain conditions by the World Health Organization (WHO)

Question 13

How have statins been shown to be anti-inflammatory?

Answer 13

Shown to have reduced inflammation in depression patients
- Atorvastatin vs placebo in 60 patients
- Assessed by a psychiatrists using the Hamilton Depression rating scale
- Inflammatory proteins were measured
- Statin group displayed a significant decrease in HDRS- statins can be used to decrease inflammation and help with depression

Question 14

How are statins used in cancer?

Answer 14

• Danish breast cancer group- 14000 women found statins reduced the recurrence rate among women with stage I-III ER+ BC treated with aromatase inhibitors, suggesting that statins may become an additional therapeutic regime in the future.
• Statins seem to reduce metastases
• Estrogen receptor(ER) positive and HER2 negative invasive cancers had a lower risk of recurrence in statin users in Singapore. Statin users has a long term recurrance risk reduction in both Asian and European women
• These studies are retrosspective however and RCTs need to be done to confirm results
• This is also supported by in vitro studies, where statins can also attenuate the growth of triple negative breast cell lines (MDA-MB231), and reduce breast cancer cell migration.

Question 15

Why are statins effective against cancers?

Answer 15

One theory is the direct reduction of estrogen production, through the statin induced reduction of cholesterol (precursor of estrogen hormones).
However they stop migration and metastes so this suggests a more complex pathway

Question 16

What are polypills?

Answer 16

A multi-drug formation in a single pill intended to simplify the drug regime
Proven to increase patients adheration to medication

Question 17

What is contained within a CV polypill?

Answer 17

Potential pill- a β-blocker, an angiotensin-converting enzyme inhibitor (ACEI), a statin, and aspirin

Question 18

What are the negatives of a polypill?

Answer 18

Drug interactions need to be better characterised
- Also may cause unnecessary consumption of medication
- Unknown risks e.g. bleeding in health patients taking these pills as a preventative measure
- Hard to decipher which drug is causing the adverse effect
- Studies have demonstrated a significant inter-individual variability in terms of drug response, which has been mainly associated with their specific genetic profiles or genotypes of CVD-related Pharmacogenes, influencing drug metabolism, drug transport, and drug effects
- HOPE-3 study didnt find a significant difference in CV death or event

Question 19

Where are beta-1 and beta-2 receptors located?

Answer 19

Beta-1 receptors located primarily in the heart mediate cardiac activity. Beta-2 receptors, with their diverse location in many organ systems, control various aspects of metabolic activity and induce smooth muscle relaxation.

Question 20

What is a potential treatment of anxiety?

Answer 20

Beta blockers- not FDA approved but they have a potent anxiolytic effect

Question 21

How do beta blockers treat anxiety?

Answer 21

Block the sympathetic nervous system and catecholamine response- help with symptoms such as tachycardia, sweating, fear and hyperventilation

Question 22

What evidence is there that propanolol can treat anxiety?

Answer 22

• Shown to mitigate mild distressing states such as exam nerves, stage fright and preformance anxiety in musicians
• Treated anxiety- no longer first line due to SSRIs
• These meta-analyses found no statistically significant differences between the efficacy of propranolol and benzodiazepines regarding the short-term treatment of panic disorder

Question 23

What are organoids?

Answer 23

• Organoids are a three-dimensional (3D) cell culture derived from pluripotent stem cells
• Organoids reproduce the morphological structure, physiological function, gene specificity, and other characteristics of the source tissue.

Question 24

What can organoids be used for?

Answer 24

• Organoids can be a platform in screening drugs with high efficiency and sensitivity, guiding clinical precision treatment and personalized treatment
• CRISPR cas9 gene editing in organoids provide a new oppurtunity to study tumour gene mutation.
  Can create organoids in future from patients with cancer or hereditory disease to see what treatments may work

Question 25

What are the disadvantages of cell lines and organoids?

Answer 25

Cell lines- cannot receive signals like in vivo e.g. from the circulatory system. Also lose the original tissue heterogenicity
Organoids- At present, organoids are still of micron size, and a particular gap still exists between their functions and normal tissues. A significant factor is the lack of a vascular system. When organoids grow to a certain extent, the cells in the center cannot get enough nutrition, and excretion of metabolic waste in the cells is difficult, limiting the popularization and application of organoids.

Question 26

What gene therapy can help with cancer?

Answer 26

• Nanoparticle delivery of FZD4 to lung endothelial cells inhibits lung cancer progression and metastses
  
  • This protein stablises blood vessels in tumours, decreases hypoxia and prevents metasteses.
  • Dr. Kalin’s lab developed a nanoparticle delivery system to successfully deliver FZD4 to pulmonary endothelium, which decreased lung tumor growth and metastasis in pre-clinical models of lung cancer.
  • Thus, increasing levels of FZD4- either genetically or via gene therapy- shows promise to improve therapeutic outcomes in lung cancer patients.

Question 27

What is an example of a prenatal gene therapy?

Answer 27

Angleman mice- delivering ASOs through the amniotic fluid was as effective as deliverying via CSF
Injection of the ASO in a mouse model of AS also resulted in successful restoration of UBE3A and phenotypic improvements in treated mice on the accelerating rotarod and fear conditioning
The prenatal therapy achieved a broad biodistribution in the brain
May be used in future to treat conditioms such as cyctic fibrosis. Cystic fibrosis cannot be treated by gene therapy after birth

Question 28

How can AI speed up drug design and development?

Answer 28

• AI speeds up drug design for Parkinsons by 10 fold
  
  • Machine learning techniques were used in Cambridge to quickly screen a chemical library containing millions of enteries and identify 5 compounds for further investigation
  • Screening large chemical libaries is time consuming and expensive, and often unsuccessful
  • Using machine learning, the researchers were able to speed up the initial screening process by ten-fold, and reduce the cost by a thousand-fold, which could mean that potential treatments for Parkinson’s reach patients much faster.
  • Looked at proteins that could block the aggregation of alpha-syncleucin
  • “Instead of screening experimentally, we screen computationally,”

Question 29

What is the history of cannabis as a medical plant?

Answer 29

• Cannabis is thought to be one of the oldest plants cultivated for human use, with uses in the manufacturing of fibre, rope and textiles dating back as early as 12,000 BCE
• The 19th century where neurologists, J. Reynolds and W. Gowers, described case reports of treatment resistant epilepsy being successfully treated by cannabis preparations

Question 30

How is CBD thought to decrease seizure frequency?

Answer 30

Question 31

In what model does CBD help improve the phenotype?

Answer 31

• Here we show that cannabidiol (CBD) effectively reduced seizures and autistic-like social deficits in a well-validated mouse genetic model of Dravet syndrome (DS), a severe childhood epilepsy disorder caused by loss-of-function mutations in the brain voltage-gated sodium channel NaV1.1.
• Treatment with lower doses of CBD also improved autistic-like social interaction deficits in DS mice

Question 32

How does CBD help with migraines?

Answer 32

In migraines, current theory suggests that the CB system mitigates migraine through several pathways (glutamine, inflammatory, opiate, and serotonin) both centrally and peripherally
- The study reported better migraine symptom reduction, less negative headache impact, better sleep quality, and decreased medication consumption
- CB reduced the number of days of migraine after 30 days, and the frequency of migraine headaches per month.
- Serotonin imbalance is believed to play a role in migraine pathophysiology. CBD has been shown to interact with serotonin receptors (5-HT1A receptors)
- Repeated treatment with CBD (5 mg/kg/day, subcutaneously [s.c.], for 7 days) increased 5-HT firing through desensitization of 5-HT1A receptors.
- Serotonin has been directly implicated in the pathophysiology of migraine and studies on plasma and urinary levels of 5-HT and its main metabolite, 5-hydoxyindoleacetic acid suggest that between their migraine attacks, patients have decreased levels of plasma 5-HT

Question 33

How does CBD help with viral infections?

Answer 33

CB2 receptors were reported to control the functions of immune cells in inflammatory disease models. Animal models lacking CB2 receptors have shown an exacerbated inflammatory response due to an increase in immune cell function
In the later stages of SARS-CoV-2 infection, it was found that CBD and Δ-9-THC significantly restricted the release of cytokines induced by the virus and reduced the recruitment of immune cells to the tissues in vitro
CBD induces interferon expression and up-regulates its antiviral signaling pathway. A cohort of human patients previously taking CBD had significantly lower SARSCoV-2 infection incidence of up to an order of magnitude relative to matched pairs or the general population.

Question 34

How do SSRIs help with Raynaulds?

Answer 34

Fluoxitine= showed a significant improvement in the Raynaud’s condition score (RCS) and daily frequency of attacks
The involvement of the serotoninergic pathway in vascular tone is complex; serotonin causes direct vasodilation in some receptors receptors and may have been contributing to the episodic vasospasm in the extremities

Question 35

How do SSRIs help with vasomotor symptoms?

Answer 35

A form of Paroxetine is the only non-hormonal therapy approved for hot flushes within the US
The 5-HT2A receptor subtype is also thought to underlie the thermogenesis. Stimulation of this receptor may change the set point temperature thereby activating some autonomic functions to cool down the body. An increased skin temperature and sweating are the result. Thus an involvement of 5-HT2A receptors in the aetiology of the hot flushes is strongly suggested.

Question 36

What are the side effects of SSRIs?

Answer 36

the most common side effects reported included nausea, fatigue and drowsiness

Question 37

Is the Astrazenaca vaccine still available?

Answer 37

• No, the UK government is not ordering future supplies of the AstraZeneca Covid-19 vaccine.
• Evidence shows that mRNA vaccines, Pfizer and Moderna, are more effective at boosting protection from Covid-19, so these vaccines are being recommended for the seasonal booster programme.

Question 38

What two vaccines contain lipid nanoparticles?

Answer 38

The two mRNA-based vaccines namely the BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna) have been given emergency use authorization
Both contain- mRNA, which is transiently active and does not integrate into the genome and is safer than viral vectors and DNA
The mRNA encodes the SARS-COVID-19 spike protein

Question 39

What vector does the Sputnik vaccine use?

Answer 39

Sputnik V developed by the Gamaleya Research Institute (Moscow, Russia), which consists of an HAdV-5 vector boost given after priming with an adenovirus vector of human serotype 26 (HAdV-26)
Sputnik V was the first coronavirus vaccine to use a heterogeneous boosting approach based on 2 different vectors for 2 vaccine shots. This approach generates a more sustainable immunity compared to vaccines that use the same delivery mechanism for both shots.

Question 40

What type of vaccine is the astrazenecaa vaccine?

Answer 40

Recombinant, replication-deficient chimpanzee adenovirus vector encoding the SARS-CoV-2 Spike glycoprotein

Question 41

What are drugs that manage symptoms of AD?

Answer 41

Acetylcholinesterase inhibitors (AChEI) donepezil, galantamine, rivastigmine, and the N-methyl-D-aspartate receptor (NMDA) receptor allosteric modulator, memantine

Question 42

What is memantine?

Answer 42

Memantine is an uncompetitive, low-affinity, open-channel blocker that blocks the extrasynaptic NMDAR that selectively enters the receptor-associated ion channel during its open state
Cannot completely block NMDARs as they are essential for normal neuronal function
Small molecule drug

Question 43

What are the side effects of Memantine?

Answer 43

Can cause constipation, dizziness, drowsiness, dyspnoea, headache, hypersensitivity or hypertension

Question 44

What was the first Acetylcholinesterase inhibitor?

Answer 44

Tacrine was the first of the AChE inhibitors approved for the AD treatment in 1993, but its use has been abandoned because of a high incidence of side effects including hepatotoxicity

Question 45

What are the pleotrophic effects of SGLT2 inhibitors?

Answer 45

• There is evidence that SGLT2is inhibit SNS activation by suppressing renal afferent signaling to the brain and central reflex mechanisms; Dapagliflozin inhibited SNS activity in a neurogenic hypertensive mouse model
• In patients with T2D, SGLT2 inhibitors decreased pro-inflammatory markers such as CRP, TNF-alpha and IL-5
• Canagliflozin treatment showed favorable effects on the progression of albuminuria

Question 46

What are the main side effects of SGLT2 inhibitors?

Answer 46

SGLT2 inhibitors have several side effects such as urinary tract infection or genital infection

Question 47

Why is DNA methylation of CRP important?

Answer 47

Looks at CRP levels over an extented time, rather than a snapshot of blood at one time that could be influenced by that days activity

Question 48

What does digitalis do?

Answer 48

Digoxin is the compound. Strengthenes heart contractions by increasing Ca2+