Corticotropin

Corticotropin binds melanocortin-2 receptors on adrenal fasciculata cells, raising cyclic AMP and driving steroidogenesis, so plasma cortisol rises within an hour. The manufacturers and some investigators argue that its clinical effects go beyond simple steroid release: full-length ACTH also binds MC1R, MC3R and MC5R on lymphocytes, monocytes and microglia, producing steroid-independent anti-inflammatory signalling. That claim is the entire justification for using corticotropin instead of far cheaper prednisone, and the head-to-head evidence supporting it is thin. In infantile spasms, where high-dose ACTH clearly outperforms low-dose oral steroids for spasm cessation and hypsarrhythmia resolution, the case is much stronger.

Targets: MC2R on adrenal cortex, Cortisol synthesis, MC1R, MC3R and MC5R on immune cells

• · Dosed in units per body surface area: 75 units per square metre twice daily for 2 weeks, followed by a structured taper over 2 weeks.
• · 80 to 120 units daily. Used mainly when high-dose methylprednisolone has failed or is not tolerated.
• · 40 to 80 units every 24 to 72 hours, per the Cortrophin Gel label.

Work out your exact syringe units →

• very commonIrritability, insomnia and behaviour change— Very prominent in infants.
• very commonHypertension— Blood pressure must be checked at every visit in infantile spasm protocols.
• very commonWeight gain and cushingoid appearance
• commonHyperglycaemia
• commonInfection risk including serious opportunistic infection— Live vaccines must be avoided during and shortly after therapy.
• commonHypokalaemia— From mineralocorticoid stimulation.
• commonAdrenal suppression on withdrawal— Requires tapering and stress-dose planning.

• Scleroderma
• Osteoporosis
• Systemic fungal infection
• Ocular herpes simplex
• Recent surgery
• Peptic ulcer disease
• Congestive heart failure
• Uncontrolled hypertension
• Primary adrenocortical insufficiency or adrenocortical hyperfunction
• Live or live-attenuated vaccination during therapy
• Intravenous administration, which is not a licensed route

• redundantcosyntropin — Cosyntropin is the synthetic short fragment used for diagnosis rather than therapy.
• cautioninsulin-icodec — Cortisol elevation raises insulin requirements substantially during a course.

• · Blood pressure at every visit
• · Serum potassium and glucose
• · Growth and weight in children
• · Signs of infection
• · Bone health on repeated courses

Prescription drug in the US. Notorious for its price, historically tens of thousands of dollars per vial, which has driven repeated litigation and pricing investigations.

• H.P. Acthar Gel FDA prescribing information (label)
• Purified Cortrophin Gel FDA prescribing information (label)
• American Academy of Neurology and Child Neurology Society practice guideline on infantile spasms (guideline)

MC2R on adrenal fasciculata cells is the obvious mechanism: Gs coupling, cyclic AMP, PKA, phosphorylation of StAR protein, cholesterol delivered to the inner mitochondrial membrane, and steroidogenesis all the way to cortisol. It also stimulates the zona glomerulosa enough to produce a mineralocorticoid effect, which is where the hypokalaemia and hypertension come from. The contested part is everything else. Full-length ACTH(1-39) also binds MC1R, MC3R and MC5R, which are expressed on macrophages, lymphocytes, microglia and adipocytes, and the melanocortin system has documented steroid-independent anti-inflammatory effects: suppression of NF-kappaB, reduced TNF-alpha and IL-6 output, and induction of regulatory phenotypes. That is the manufacturer's argument for why corticotropin should work where prednisone does not, and it is a biologically coherent argument. What does not exist is convincing head-to-head clinical evidence for most of the labelled indications. In infantile spasms the picture is genuinely different: high-dose ACTH clearly outperforms low-dose oral steroid for spasm cessation and hypsarrhythmia resolution, the effect is rapid, and there is a plausible central mechanism involving CRH suppression in the immature brain rather than simple glucocorticoid action. Take that indication seriously and treat the rest with scepticism proportional to the price.

The behavioural effects in infants are severe and under-warned: irritability, inconsolable crying and sleep disruption are near-universal on high-dose protocols and are the main reason families struggle through a course. Second, abrupt cessation after more than about two weeks produces adrenal insufficiency, and the structured taper exists for that reason. Third, infection: serious and opportunistic infections occur, the drug masks the usual presenting signs, and by the time it looks obvious it is advanced. Fourth, the gel is viscous and needs a large-bore needle and a warmed vial, and it must never be given intravenously, which is not a licensed route. Fifth, and this is the part that deserves plain speaking: for most of its roughly 18 grandfathered labelled indications there is no modern comparative evidence that it beats prednisone, and its US price history, which has run into tens of thousands of dollars per vial and generated repeated litigation and congressional scrutiny, means the burden of proof should sit heavily on anyone prescribing it outside infantile spasms.

1. —Weeks 1-2, infantile spasms — Dosed in units per square metre, not micrograms: 75 units per square metre intramuscularly twice daily for 2 weeks.
2. —Weeks 3-4, infantile spasms taper — Structured taper over 2 weeks, typically 30 units per square metre in the morning for 3 days, then 15 for 3 days, then 10 for 3 days, then 10 every other morning for 6 days. Tapering is not optional; the adrenals have been driven hard.
3. —Multiple sclerosis relapse, 2-3 weeks — 80 to 120 units daily intramuscularly, used mainly when high-dose methylprednisolone has failed or cannot be tolerated.
4. —Rheumatic and autoimmune flares — 40 to 80 units every 24 to 72 hours per the Cortrophin Gel label, with the interval extended as the flare settles.

• MC2R on adrenal zona fasciculata — High; MC2R is the ACTH-specific receptor and binds no other melanocortin.

  Gs-cyclic AMP-PKA signalling, StAR phosphorylation, cholesterol transport into mitochondria and cortisol synthesis. Peak cortisol at a median 8 hours after the gel depot.

• MC2R on zona glomerulosa — High

  Aldosterone and deoxycorticosterone production, producing the sodium retention, hypertension and hypokalaemia that are prominent in infantile spasm protocols.

• MC1R, MC3R and MC5R on immune cells and microglia — Full-length ACTH binds all three; cosyntropin's 1-24 fragment does not carry the same profile.

  Proposed steroid-independent anti-inflammatory signalling through NF-kappaB suppression and cytokine reduction. This is the entire justification for using corticotropin over prednisone and the head-to-head evidence for it is thin.

Cortisol begins rising within an hour and peaks at a median of 8 hours after an intramuscular gel dose, with the elevation sustained for roughly 12 to 24 hours. Spasm cessation in infantile spasms usually occurs within the first two weeks, and if it has not occurred by then it generally will not. Cushingoid change, weight gain and hypertension develop over the same two weeks. Adrenal axis recovery after a course takes weeks.

Vigabatrin is the other first-line agent in infantile spasms, particularly in tuberous sclerosis, and combination therapy has been studied and is used. Live and live-attenuated vaccines must be avoided during and shortly after a course. Potassium supplementation is routine. Insulin requirements rise substantially and need active management rather than reactive correction. Do not combine with cosyntropin, which is the diagnostic fragment of the same molecule. Anyone on a course who is also on antihypertensives will usually need those doses increased. Gastric protection is reasonable given the peptic ulcer contraindication.

Against prednisone and high-dose oral prednisolone in infantile spasms: ACTH has the better evidence for spasm cessation and hypsarrhythmia resolution, though high-dose prednisolone has narrowed the gap in several trials and is vastly cheaper. Against methylprednisolone in multiple sclerosis relapse: methylprednisolone is first-line, cheaper, and better studied; corticotropin is a fallback for patients who cannot tolerate it or have not responded. Against cosyntropin: cosyntropin is the synthetic 1-24 diagnostic fragment, not a therapy, and it lacks the C-terminal region that supports the manufacturer's melanocortin argument. Against prednisone for nephrotic syndrome, rheumatic flares and the rest of the grandfathered list: the honest answer is that nobody has run the comparison properly, and given the price difference that absence is itself informative.

Notoriously high. H.P. Acthar Gel has been reported at tens of thousands of dollars per vial in the US and its pricing has been the subject of litigation and federal investigation; Purified Cortrophin Gel was reintroduced partly as a lower-cost competitor. I did not source current figures this session and will not invent them.

• ?The ACTH(1-39) sequence given is the standard human sequence; the porcine product differs slightly and is in any case a mixture, and I did not resolve either sequence from a primary source this session, so verified is false.
• ?No pharmacokinetic parameters beyond the cortisol response are characterised for the repository gel formulation.
• ?Whether the steroid-independent melanocortin mechanism contributes meaningfully to clinical effect is genuinely unresolved and is the central controversy about this drug.
• ?The AAN infantile spasms guideline is cited as further reading; I did not confirm its identifiers.
• ?Blood-brain barrier penetration is marked partial based on the proposed central mechanism in infantile spasms, which is not firmly established.
• ?No cost figures were sourced.

• PURIFIED CORTROPHIN GEL (corticotropin) injection - FDA prescribing information ANI Pharmaceuticals, DailyMed

  Source of the median 8 hour time to peak cortisol (range 3 to 12 hours), the 34.52 mcg/dL baseline-corrected peak cortisol after 80 units, the porcine origin and the 15 percent gelatin repository vehicle.

• Evidence-based guideline update: medical treatment of infantile spasms American Academy of Neurology and Child Neurology Society, Neurology

  Further reading, not verified this session. This is where the case for ACTH as first-line therapy in infantile spasms, as opposed to its other labelled indications, is actually made.