L10 Advances in drugs targeting the parathyroid glands Flashcards

1
Q

Role of PTH

A

Maintenance of adequate levels of blood ionized calcium (free calcium)
- normal neuromuscular function
- bone mineralisation

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2
Q

What cells in the parathyroid gland secrete PTH, and in response to what?

A

Chief cells secrete PTH in response to small decreases in blood ionized calcium in order to maintain calcium homeostasis

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3
Q

Effect of PTH secretion on calcium

A
  • increased intestinal absorption of calcium
  • increased renal calcium reabsorption
  • increased bone resorption, which increases calcium since bone is a calcium store
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4
Q

How is PTH synthesised?

A

PTH is synthesised as a prepropeptide hormone comprising 115 amino acids, but only the single chain full length polypeptide is secreted. The preprohormone and prohormone have little/no biological effect and are not released.

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5
Q

Factors influencing PTH synthesis

A
  • cAMP acting via cAMP response element binding protein upregulates PTH gene transcription
  • vitamin D downregulates PTH transcription
  • low serum calcium levels upregulate PTH synthesis
  • high serum phosphate levels upregulate PTH synthesis
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6
Q

PTH is a product of a single gene located on which chromosome?

A

11

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7
Q

Why is the structure of PTH important?

A

As many as 50 amino acids can be removed from the C-terminus without compromising biological potency. However, removal of serine at the N-terminus virtually inactivates the hormone.

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8
Q

How many amino acids does PTH contain?

A

84

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9
Q

Where is parathyroid hormone-related peptide (PTHrP) found?

A

in the plasma of patients suffering from certain malignancies and accounts for the accompanying hypercalcaemia (little/no PTHrP found in normal individuals)

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10
Q

What allows PTHrP to bind PTH1R with high affinity?

A
  • similar first 13 amino acids to PTH
  • similarities in the N-terminus to PTH
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11
Q

What type of receptor is PTH receptor?

A

G-protein coupled receptor

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12
Q

Which enzymes are important in regulation of calcium levels and are a result of Gαs and Gαq stimulation, respectively?

A

PKA and PKC

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13
Q

Rapid response to PTH

A

protein phosphorylation

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14
Q

Delayed response to PTH

A

altered expression of genes regulated by cAMP response element binding protein

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15
Q

Increased PTH causes bone resorption, so how can PTH help with osteoporosis?

A

Intermittent PTH administration has anabolic effects. This results in bone formation and increased osteoblast number, which is beneficial in osteoporosis treatment.

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16
Q

How are intermittent PTH levels achieved?

A

When dosed daily because PTH is cleared within 2-3 hours of administration - intermittent increase in PTH

17
Q

What does continuous administration of PTH or high circulating PTH levels (e.g. in primary hyperparathyroidism) cause?

A

bone demineralisation and osteopenia

18
Q

Examples of human recombinant PTH (rhPTH)?

A
  • Teriparatide (PTH 1-34) - osteoporosis treatment
  • Full length recombinant PTH (1-84): Preotact (awaiting approval) and Natpar (hypoparathyroidism)
  • Ostabolin (cyclic PTH 1-35) - in development
19
Q

Example of a PTHrP synthetic analog and its clinical indication

A

Abaloparatide (Tymlos) - approved in 2017 for the treatment of osteoporosis

20
Q

How does Abaloparatide work?

A

Binds to RG conformation of PTH1R with greater selectivity and activates both cAMP and β-arrestin pathways with similar potency

21
Q

What is characteristic of hypoparathyroidism?

A
  • decreased PTH release
  • lack of control over serum calcium levels
  • chronic hypocalcaemia
22
Q

3 types of hypoparathyroidism

A
  1. Genetically-induced abnormal gland formation, impaired PTH production or altered PTH secretion
  2. Decreased parathyroid gland function due to surgery, autoimmune diseases or infiltrative conditions
  3. Resistance to PTH: pseudohypoparathyroidism
23
Q

Two examples of PTH analogs (not approved)

A
  • AZP-3601 (increased Ca levels & deemed safe in clinical trials)
  • LY627-2K (promising results regarding serum Ca levels) - repurposed for hypoparathyroidism (tolerability issues arose when trialled for osteoporosis)
24
Q

Example of a prodrug of PTH

A

Transcon-PTH

25
Q

How does Transcon-PTH work?

A

Parent drug + Transcon carrier + Transcon linker
Linker cleavage dependent upon pH & temp. When linker dissolves, active PTH is released. The linker prolongs PTH release and inhibits its binding until release.

26
Q

Why are subcutaneous preparations of PTH analogs devised to prolong the half-life of the molecules?

A

to increase their biological activity

27
Q

Hyperparathyroidism is characterised by…

A

hypercalcaemia and elevated PTH levels

28
Q

Main cause of hyperparathyroidism

A

benign overgrowth of parathyroid tissue (mainly adenoma) causing excess secretion of PTH

29
Q

What is secondary hyperparathyroidism?

A

Parathyroid glands become enlarged and hyperactive in response to a condition outside of the parathyroid gland (most commonly CKD)

30
Q

Current treatment for hyperparathyroidism

A

Surgical removal of the parathyroid gland (currently no pharmacological treatments)

31
Q

What effect does Sema3d have in hyperparathyroidism?

A

Sema3d inhibits parathyroid proliferation via inhibition of the EGFR/ErbB signalling pathway. Sema3d knockout mice develop hyperparathyroidism.