Disease & Condition Terms

FGFR3 gain-of-function mutation (G380R — glycine to arginine at position 380 in the transmembrane domain): constitutive receptor activation → sustained MAPK/ERK signalling in growth plate chondrocytes → inhibited proliferation and premature hypertrophy → shortened long bones, characteristic rhizomelic (proximal) limb shortening, macrocephaly, midface hypoplasia. Inheritance: autosomal dominant, but approximately 80% are new mutations (advanced paternal age is a risk factor). Vosoritide (Voxzogo): 39 amino acid CNP analogue, daily SC injection. Mechanism: NPR-B activation → cGMP → PKG-II → RAF-MEK-ERK pathway inhibition downstream of FGFR3 → restored chondrocyte proliferation and differentiation. Phase III results (ACH-PHITE): annualised growth velocity increased by approximately 1.57 cm/year vs placebo over 52 weeks, sustained through open-label extension. Treatment: initiated in children ≥2 months with open epiphyses, continued until growth plates close. Monitoring: growth velocity, IGF-1, blood pressure (CNP has vasodilatory effects).

Prevalence: approximately 60 per million. Caused by GH-secreting pituitary adenoma (>95% of cases). Diagnosis: elevated IGF-1 for age/sex + failure to suppress GH below 1 μg/L during 75g OGTT + pituitary MRI showing adenoma. Treatment algorithm: transsphenoidal surgery (first-line, cure rate 40-90% depending on tumour size), medical therapy for residual disease (somatostatin analogues — octreotide LAR or lanreotide autogel are first-line medical therapy, normalising IGF-1 in approximately 50-70%; pasireotide for patients resistant to first-generation SSAs; pegvisomant — GH receptor antagonist, not a peptide — for those resistant to SSAs), and radiotherapy (for refractory cases). Monitoring: serum IGF-1 (target: age/sex-normalised range) and random GH <1 μg/L indicate biochemical control. Somatostatin analogue tumour shrinkage: approximately 20-50% of patients achieve >20% tumour volume reduction, supporting their use as primary therapy in patients unsuitable for surgery.

Primary adrenal insufficiency: autoimmune adrenalitis accounts for approximately 80% in developed countries (adrenal cortex antibodies against 21-hydroxylase). Other causes: infections (tuberculosis — still common in developing countries, HIV-associated), bilateral adrenalectomy, haemorrhagic infarction (Waterhouse-Friderichsen syndrome), metastatic cancer, and genetic (congenital adrenal hyperplasia). Clinical features: fatigue, weight loss, hyperpigmentation (ACTH excess → MC1R stimulation on melanocytes), hypotension (aldosterone deficiency), hyponatraemia, hyperkalaemia, and adrenal crisis (life-threatening hypotension/shock precipitated by stress/infection). Diagnosis: morning cortisol <3 μg/dL is diagnostic; cosyntropin stimulation test (250μg IM/IV → cortisol measured at 30/60 min; peak <18-20 μg/dL confirms adrenal insufficiency). Cosyntropin (synthetic ACTH 1-24) is the standard diagnostic peptide drug for adrenal function assessment. Treatment: lifelong glucocorticoid replacement (hydrocortisone) ± mineralocorticoid (fludrocortisone).

Resistance mechanisms relevant to peptide antibiotics: glycopeptide resistance — vanA/vanB gene clusters encode enzymes that modify the D-Ala-D-Ala peptidoglycan target to D-Ala-D-Lac (1000-fold reduced vancomycin binding) in VRE (vancomycin-resistant Enterococci) and rare VRSA (vancomycin-resistant S. aureus); polymyxin resistance — mcr genes encode phosphoethanolamine transferases that modify lipid A, reducing the anionic charge that polymyxins exploit for membrane binding (plasmid-mediated, transferable between species — a major global concern); daptomycin resistance — mutations in mprF and other genes alter membrane phospholipid composition, reducing daptomycin binding; and echinocandin resistance — FKS gene mutations alter the beta-1,3-glucan synthase target (relevant to rezafungin). The WHO's priority pathogen list highlights organisms where antibiotic resistance poses the greatest threat — several require peptide antibiotics as last-resort treatments. Novel antimicrobial peptide development (engineered AMPs, lantibiotics, peptide-antibiotic conjugates) aims to address the growing resistance crisis.

ART encompasses: IVF, ICSI (intracytoplasmic sperm injection — injecting a single sperm directly into the oocyte), frozen embryo transfer (FET — thawing previously cryopreserved embryos for transfer), donor gamete procedures, and gestational surrogacy. Peptide drug involvement: GnRH agonists and antagonists (pituitary suppression — cetrorelix and ganirelix are standard), FSH/LH preparations (not peptide drugs per se but protein hormones for ovarian stimulation), and oxytocin antagonists (atosiban — used in some countries to prevent uterine contractions during embryo transfer, though evidence is mixed). ART success rates: approximately 30-40% live birth rate per cycle for women under 35, declining with age. Multiple pregnancy risk (from transferring >1 embryo) has driven the trend toward single embryo transfer, particularly with improving blastocyst culture and cryopreservation techniques.

X-linked recessive (TAFAZZIN gene, Xq28): affects males almost exclusively. TAFAZZIN encodes a transacylase that remodels cardiolipin — the signature phospholipid of the inner mitochondrial membrane. Cardiolipin remodelling deficiency → abnormal cardiolipin species (monolysocardiolipin accumulation, reduced tetralinoleoyl-cardiolipin) → disorganised mitochondrial cristae → impaired electron transport chain complex assembly → reduced ATP production + increased ROS. Clinical features: dilated cardiomyopathy (often presenting in infancy — leading cause of morbidity/mortality), skeletal myopathy (exercise intolerance, proximal weakness), neutropenia (cyclic or intermittent — increasing infection risk), and growth delay. Elamipretide (Barth syndrome approval): mitochondria-targeted tetrapeptide (D-Arg-Dmt-Lys-Phe-NH2) that binds cardiolipin → stabilises cristae structure → improves ETC complex organisation → enhanced ATP production and reduced ROS. TAZPOWER trial: improvements in functional assessments. FDA accelerated approval (2024) based on functional endpoints; confirmatory trials required.

Carcinoid syndrome occurs when functional midgut NETs (primarily ileal) metastasise to the liver — hepatic metastases release serotonin and other vasoactive substances directly into the systemic circulation (bypassing hepatic first-pass metabolism). Symptoms: flushing (85-90%, episodic facial/upper body redness), diarrhoea (80%, watery, non-bloody — serotonin stimulates intestinal secretion and motility), bronchospasm (15%), and carcinoid heart disease (20-50% — serotonin-mediated endocardial fibrosis causing right-sided valve disease, particularly tricuspid regurgitation and pulmonary stenosis). Diagnosis: elevated 24-hour urinary 5-HIAA (5-hydroxyindoleacetic acid, serotonin metabolite) and/or elevated chromogranin A. Treatment: octreotide LAR or lanreotide autogel suppress serotonin secretion and control symptoms in approximately 70-80% of patients. Telotristat ethyl (tryptophan hydroxylase inhibitor) is added for breakthrough diarrhoea. SSA therapy also slows tumour progression (antiproliferative effect demonstrated in PROMID trial for octreotide LAR and CLARINET trial for lanreotide).

Defined as: <3 spontaneous bowel movements per week for ≥3 months with additional symptoms (straining, hard stools, incomplete evacuation, sensation of blockage). Linaclotide (14 amino acids) and plecanatide (16 amino acids) are structurally related to uroguanylin (an endogenous GC-C agonist). Their local mechanism of action in the GI lumen (no clinically significant systemic absorption — peptides are degraded in the intestine) provides a favourable safety profile. Unlike osmotic or stimulant laxatives, GC-C agonists address the underlying secretory and sensory dysfunction rather than merely promoting evacuation. Linaclotide Phase III trials showed significant improvement in complete spontaneous bowel movements (CSBM), straining, abdominal pain, and global symptom relief vs placebo.

CKD is classified by GFR category (G1-G5) and albuminuria category (A1-A3). Prevalence: approximately 10-15% of adults globally. Progression: GFR declines at variable rates; reaching G5 (GFR <15 mL/min) requires renal replacement therapy (dialysis or transplantation). Peptide drug relevance: difelikefalin (IV formulation) is approved specifically for CKD-associated pruritus in haemodialysis patients — it is administered after each dialysis session via the venous line; renal dose adjustments are required for many peptide drugs because peptide fragments are renally cleared; GLP-1 RAs are being investigated for kidney protection in diabetic CKD — the semaglutide FLOW trial showed significant reduction in kidney disease progression; and dehydration from GLP-1 RA gastrointestinal side effects can precipitate acute kidney injury in CKD patients, requiring careful hydration counselling.

C. difficile is a spore-forming, toxin-producing anaerobic bacterium causing antibiotic-associated diarrhoea and colitis. Pathogenesis: broad-spectrum antibiotics disrupt normal colonic microbiota → C. difficile spore germination and vegetative cell proliferation → toxin A (enterotoxin) and toxin B (cytotoxin) production → colonocyte damage, inflammation, and pseudomembrane formation. Severity: ranges from mild diarrhoea to fulminant colitis with toxic megacolon (mortality approximately 5-10% overall, higher in elderly/immunocompromised). Recurrence: approximately 20-25% after first episode, increasing with each subsequent recurrence. Vancomycin oral formulation (125-500mg QID for 10-14 days) is first-line treatment for initial and recurrent CDI — oral vancomycin is not significantly absorbed, achieving high colonic concentrations. Fidaxomicin (a macrocyclic antibiotic, not a peptide) is an alternative with lower recurrence rates. CDI illustrates how peptide antibiotics can be used topically within the GI tract (oral vancomycin for local colonic effect) as well as systemically.

Cushing's disease accounts for approximately 70% of endogenous Cushing's syndrome. ACTH-secreting pituitary adenoma (usually microadenoma <10mm) → bilateral adrenal hyperplasia → excess cortisol. Diagnosis: confirm hypercortisolism (24h urinary free cortisol, midnight salivary cortisol, 1mg overnight dexamethasone suppression test) → confirm ACTH-dependent (plasma ACTH inappropriately normal/elevated) → localise source (pituitary MRI, inferior petrosal sinus sampling if MRI equivocal). First-line: transsphenoidal surgery (remission rate approximately 70-90% for microadenomas). Second-line medical therapy for surgical failure: pasireotide (Signifor — SC twice daily or LAR monthly) — targets SSTR5 (highly expressed on corticotroph adenomas) → suppresses ACTH secretion → cortisol reduction. Phase III PASPORT-CUSHINGS: approximately 26% of patients achieved urinary free cortisol normalisation at 6 months. Key side effect: hyperglycaemia (approximately 73% — due to SSTR5-mediated inhibition of insulin secretion), requiring glucose monitoring and management.

Cushing's syndrome (CS) — the clinical state of chronic cortisol excess regardless of cause. Causes: exogenous (iatrogenic — most common overall, from chronic glucocorticoid therapy), ACTH-dependent endogenous (Cushing's disease ~70%, ectopic ACTH ~10%), and ACTH-independent endogenous (adrenal adenoma ~15%, adrenal carcinoma ~5%). Clinical features: central obesity with proximal muscle wasting, moon face, buffalo hump, purple striae (>1cm wide), skin fragility/easy bruising, hypertension, glucose intolerance/diabetes, osteoporosis, emotional lability/depression, and immunosuppression. Screening: multiple positive screening tests required (UFC, LDSST, midnight salivary cortisol). Differential diagnosis between aetiologies uses: plasma ACTH level, high-dose dexamethasone suppression test, CRH stimulation test, and IPSS (inferior petrosal sinus sampling). Medical therapy targets vary by cause — pasireotide for pituitary, metyrapone/ketoconazole for any cause (adrenal steroidogenesis inhibition).

CTCL subtypes: mycosis fungoides (MF — patches, plaques, tumours on skin; indolent course) and Sézary syndrome (SS — erythroderma + circulating malignant T cells; aggressive). Romidepsin (Istodax): cyclic depsipeptide (bicyclic, containing a disulphide bond that is reduced intracellularly to activate the compound) that inhibits class I HDACs (histone deacetylases). HDAC inhibition → histone hyperacetylation → chromatin remodelling → reactivation of silenced tumour suppressor genes + direct pro-apoptotic effects. FDA approval: relapsed/refractory CTCL (GPI-04-0001 trial: ORR approximately 34%, complete response approximately 6%) and relapsed/refractory PTCL. Romidepsin is administered as IV infusion over 4 hours on days 1, 8, 15 of a 28-day cycle. Key toxicities: nausea, fatigue, thrombocytopenia, and ECG changes (QT prolongation monitoring required).

DVT pathophysiology (Virchow's triad): venous stasis, endothelial injury, and hypercoagulability. Anticoagulant peptide drugs: bivalirudin (direct thrombin inhibitor — binds both the catalytic site and exosite 1 of thrombin; used during PCI as an alternative to heparin, with a short half-life of ~25 minutes allowing rapid offset; the HORIZONS-AMI and EUROMAX trials established its role in acute coronary intervention) and eptifibatide (platelet glycoprotein IIb/IIIa antagonist — prevents fibrinogen-mediated platelet aggregation; used in acute coronary syndromes and PCI). While heparin (a glycosaminoglycan, not technically a peptide) remains the standard anticoagulant for DVT, the peptide-based thrombin inhibitor bivalirudin offers advantages in HIT (heparin-induced thrombocytopenia) where heparin is contraindicated.

Central DI causes: idiopathic (~30%), post-neurosurgical (pituitary/hypothalamic surgery — may be transient or permanent), head trauma, pituitary tumours, infiltrative diseases (sarcoidosis, histiocytosis), autoimmune (anti-vasopressin neuron antibodies), and genetic (rarely, mutations in AVP gene). Diagnosis: water deprivation test (restrict fluids → measure urine osmolality — failure to concentrate urine >300 mOsm/kg; then administer desmopressin → if urine concentrates >50% increase, central DI confirmed; if no response, nephrogenic DI). Desmopressin therapy: intranasal (10-40μg daily in 1-3 doses, bioavailability ~3-5%), oral tablet (100-800μg daily, bioavailability ~0.1%), oral lyophilisate/melt (60-360μg daily, sublingual absorption), and parenteral (1-4μg daily SC/IV — for acute or perioperative use). Dose titration: target adequate fluid balance (urine output 1.5-2.5 L/day) while avoiding hyponatraemia from excessive water retention. Hyponatraemia is the primary safety concern — patients must allow breakthrough polyuria periodically to prevent water intoxication.

Endometriosis affects approximately 10% of reproductive-age women (approximately 190 million globally). Pathophysiology: endometrial-like tissue outside the uterus (ovaries, peritoneum, rectovaginal septum, rarely extrapelvic) responds to cyclical oestrogen → proliferation, inflammation, fibrosis, adhesion formation → chronic pelvic pain, dysmenorrhoea, dyspareunia, and infertility. Diagnosis: definitive by laparoscopy with histological confirmation (though empirical treatment is increasingly accepted). Hormonal management aims to suppress oestrogen: combined oral contraceptives (first-line), progestins, GnRH agonists (nafarelin nasal spray, goserelin implant, leuprolide depot — effective but cause menopausal symptoms and bone loss, limiting use to 6-12 months; add-back therapy with low-dose HRT mitigates these effects), and oral GnRH antagonists (elagolix — partial oestrogen suppression, dose-dependent, with lower bone loss risk than agonists due to incomplete suppression). Surgery for visible implants/endometriomas is complementary.

FOP is an ultra-rare autosomal dominant disorder (prevalence approximately 1:1.36 million) caused by a gain-of-function mutation in ACVR1 (activin A receptor type 1, also called ALK2) — the R206H mutation accounts for approximately 97% of cases. ACVR1 is a BMP type I receptor; the mutation causes constitutive activation and aberrant response to activin A (which normally does not activate ACVR1) → ectopic endochondral ossification in soft tissues (muscle, tendons, ligaments, fascia). Hallmark: progressive heterotopic ossification forming a 'second skeleton' that immobilises joints. Clinical course: episodic flare-ups (often triggered by trauma, surgery, or intramuscular injections) leading to cumulative disability. Palovarotene (Sohonos): retinoic acid receptor gamma (RARγ) agonist that inhibits BMP-dependent chondrogenesis — blocking the endochondral ossification pathway downstream of aberrant ACVR1 signalling. FDA approved 2023 for FOP in adults and children ≥8 years (females) or ≥10 years (males), with growth plate monitoring required due to premature epiphyseal closure risk.

MGFA (Myasthenia Gravis Foundation of America) classification: Class I (ocular only), Class II (mild generalised — IIa predominantly limb/axial, IIb predominantly oropharyngeal/respiratory), Class III (moderate generalised), Class IV (severe generalised), Class V (requiring intubation ± mechanical ventilation). Approximately 85% of patients with initial ocular MG develop generalised disease within 2 years. Generalised MG significantly impacts quality of life: difficulty chewing/swallowing, dysarthria, limb weakness affecting daily activities, respiratory weakness (myasthenic crisis requiring ventilatory support occurs in approximately 15-20%). Treatment escalation: acetylcholinesterase inhibitors (pyridostigmine — symptomatic, first-line) → immunosuppressive therapy (corticosteroids, azathioprine, mycophenolate) → targeted therapies (complement inhibitors — zilucoplan, eculizumab, ravulizumab; FcRn inhibitors — efgartigimod, rozanolixizumab; anti-CD20 — rituximab). Zilucoplan's advantage: self-administered SC injection (vs IV infusion for eculizumab), lower cost, and peptide-based rather than antibody-based complement inhibition.

Gigantism occurs when GH excess begins before epiphyseal fusion (growth plate closure) in childhood/adolescence, causing excessive linear growth (heights >7 feet possible). Same underlying pathology as acromegaly (GH-secreting pituitary adenoma) but different clinical presentation due to timing. Treatment parallels acromegaly: surgery, somatostatin analogues, and radiation. Genetic causes of paediatric GH excess include: McCune-Albright syndrome (activating GNAS mutations), Carney complex (PRKAR1A mutations), X-linked acrogigantism (Xq26.3 microduplications including GPR101), and AIP gene mutations (familial isolated pituitary adenoma). Pegvisomant and somatostatin analogues can control GH excess while monitoring for continued growth until epiphyses fuse.

Paediatric GHD: diagnosed by failure to achieve expected growth velocity + low IGF-1 + failure of GH to rise above defined threshold (typically 7-10 μg/L depending on assay) during two stimulation tests (insulin tolerance test, glucagon stimulation, GHRH-arginine, or clomiphene). Treatment: daily SC somatropin injection titrated to IGF-1 levels and growth response; next-generation weekly options include somapacitan (Sogroya — albumin-binding long-acting GH) and somatrogon (Ngenla — CTP-fused long-acting GH), improving convenience from daily to weekly injection. Adult GHD: diagnosed by ITT (gold standard, GH peak <3-5 μg/L) or GHRH-arginine test; symptoms include: increased visceral fat, decreased lean mass, reduced bone density, fatigue, impaired quality of life. Adult treatment: lower somatropin doses than paediatric, titrated to mid-normal IGF-1 range. Transition period (adolescent→adult) requires re-testing to confirm persistent GHD.

CKD-associated pruritus (CKD-aP) in haemodialysis patients is often severe, chronic, and refractory to conventional antihistamines (because histamine is not the primary mediator). Pathophysiology: multifactorial — uraemic toxin accumulation (particularly protein-bound toxins not efficiently cleared by standard dialysis), systemic micro-inflammation (elevated CRP, IL-6, IL-31), peripheral neuropathy (C-fibre dysfunction), xerosis (dry skin from sweat gland atrophy), and altered endogenous opioid balance. Impact: sleep disturbance (reported in >60% of patients with moderate-severe pruritus), depression, reduced quality of life, and increased mortality risk (independent of other CKD factors). Difelikefalin dosing: 0.5μg/kg IV bolus into the venous blood line at the end of each haemodialysis session (3× weekly). This timing exploits the dialysis access for drug administration and synchronises dosing with the treatment schedule. SC difelikefalin formulation is in development for non-dialysis CKD-aP and other pruritic conditions.

HAE types: Type I (85% — reduced C1-INH levels, <50% normal), Type II (15% — normal C1-INH levels but dysfunctional protein), Type III (rare — normal C1-INH, associated with Factor XII mutations or unknown cause, primarily affects women). Pathophysiology: C1-INH deficiency → uncontrolled contact system activation → excessive bradykinin generation → bradykinin B2R activation → vascular permeability → angioedema. Attack locations: subcutaneous (face, extremities, genitalia — painful, disfiguring), abdominal (intestinal wall oedema — severe pain, mimicking surgical abdomen), and laryngeal (life-threatening airway obstruction — mortality rate approximately 25-40% if untreated). Icatibant mechanism: competitive B2R antagonist → immediate blockade of bradykinin-mediated vascular leakage. Dosing: 30mg SC into abdominal area, onset of symptom relief typically within 30-60 minutes, may repeat after 6 hours if needed. Self-administration training enables patients to treat attacks promptly. Other HAE treatments: C1-INH replacement (plasma-derived or recombinant), lanadelumab (anti-kallikrein antibody for prophylaxis).

Prevalence: approximately 40-50% of HIV patients on cART (combination antiretroviral therapy), though rates are declining with newer regimens. Risk factors: older NRTIs (stavudine, zidovudine — strongest association with lipoatrophy), protease inhibitors (associated with dyslipidaemia and insulin resistance), duration of therapy, age, and baseline BMI. Pathophysiology: multifactorial — mitochondrial toxicity (NRTIs inhibit mitochondrial DNA polymerase-γ → impaired adipocyte mitochondrial function), altered adipokine production, increased inflammation, and direct viral effects. Cardiovascular risk: excess visceral fat increases coronary artery disease risk (already elevated in HIV). Tesamorelin (Egrifta): the only approved drug specifically for HIV lipodystrophy. Dosing: 2mg daily SC injection. Phase III results: approximately 15-18% reduction in trunk fat at 26 weeks vs placebo, maintained at 52 weeks with continued treatment. Lipodystrophy severity returns to baseline within 3-6 months of discontinuation. Tesamorelin does not significantly affect limb fat (lipoatrophy), which has different underlying pathophysiology.

HSDD: persistently low sexual desire causing significant personal distress, not attributable to medical conditions, medications, or relationship factors. Affects approximately 10% of premenopausal women. Bremelanotide (Vyleesi): MC3R/MC4R agonist acting on hypothalamic melanocortin pathways involved in sexual desire and arousal. Dosing: 1.75mg SC self-injection ≥45 minutes before anticipated sexual activity, maximum 1 dose per 24 hours, maximum 8 doses per month. Phase III RECONNECT trials: statistically significant increase in satisfying sexual events and reduction in distress related to low sexual desire. Side effects: nausea (approximately 40%), flushing, headache, and transient skin hyperpigmentation (MC1R activation). Contraindication: uncontrolled hypertension (bremelanotide can transiently increase blood pressure). Bremelanotide represents a novel mechanism — unlike flibanserin (a serotonergic/dopaminergic oral agent), it acts through the melanocortin system and is used on-demand rather than daily.

IVF protocol stages: (1) controlled ovarian stimulation (COS — exogenous FSH ± LH for 8-14 days to develop multiple follicles; GnRH agonist or antagonist prevents premature ovulation), (2) trigger (hCG or GnRH agonist injection when lead follicles reach 17-18mm — initiating final oocyte maturation), (3) oocyte retrieval (transvaginal ultrasound-guided aspiration 34-36 hours after trigger), (4) fertilisation (conventional IVF or ICSI), (5) embryo culture (to day 3 cleavage stage or day 5 blastocyst), (6) embryo transfer (fresh or frozen-thawed), and (7) luteal phase support (progesterone ± oestrogen to support implantation). GnRH antagonist protocol advantages: shorter stimulation, no flare effect, lower OHSS risk (especially with GnRH agonist trigger), and flexibility in cycle start timing. GnRH agonist long protocol: provides more complete pituitary suppression but requires 2-3 weeks of down-regulation before stimulation begins.

Defined as failure to conceive after 12 months of regular unprotected intercourse (6 months if female partner >35 years). Affects approximately 10-15% of couples. Causes: female factors (ovulatory dysfunction ~25%, tubal disease ~20%, endometriosis ~10%, uterine factors ~5%), male factors (~30%), combined factors (~20%), and unexplained (~15%). Peptide drug roles in fertility: GnRH agonists (nafarelin, leuprolide, goserelin) for pituitary suppression in IVF protocols (preventing premature LH surge during controlled ovarian stimulation), GnRH antagonists (cetrorelix, ganirelix) for flexible suppression in IVF (started when follicles reach 14mm, preventing premature LH surge without the initial flare — shorter treatment duration than agonist protocols), and GnRH agonist trigger (single dose to induce LH surge for final oocyte maturation — lower OHSS risk than hCG trigger, particularly important in high-responder patients).

IBS subtypes: IBS-C (constipation-predominant), IBS-D (diarrhoea-predominant), IBS-M (mixed). Linaclotide and plecanatide act on guanylate cyclase-C (GC-C) receptors on intestinal epithelial luminal surface → increased intracellular and extracellular cGMP → CFTR chloride channel activation → intestinal fluid secretion + accelerated transit. cGMP also reduces visceral pain signalling (activating visceral afferent nerve inhibition). Linaclotide (Linzess): 290μg daily for IBS-C, 72μg for chronic constipation. Plecanatide (Trulance): 3mg daily for IBS-C and chronic constipation. Both are oral peptides that act locally in the GI tract (minimal systemic absorption). Diarrhoea is the main side effect (pharmacological — excessive secretion). These represent rare examples of orally administered peptide drugs that work without systemic absorption.

MCL arises from B cells in the mantle zone of lymph node follicles. Characterised by the t(11;14)(q13;q32) translocation → cyclin D1 overexpression → dysregulated cell cycle. MCL accounts for approximately 5-7% of NHL. Clinical course: historically aggressive (median survival 3-5 years) but newer therapies improving outcomes. Bortezomib is approved for relapsed/refractory MCL based on the PINNACLE trial (overall response rate approximately 33%, complete response approximately 8%). MCL treatment has evolved: first-line induction with R-DHAP or R-HyperCVAD including bortezomib, consolidation with ASCT in younger patients, and maintenance therapy. BTK inhibitors (ibrutinib, acalabrutinib) have become important for relapsed MCL. Bortezomib's role in MCL illustrates the broader applicability of peptide-based proteasome inhibition beyond myeloma.

MRSA carries the mecA gene encoding PBP2a (penicillin-binding protein 2a) — an altered transpeptidase with low affinity for beta-lactam antibiotics, conferring resistance to all penicillins, cephalosporins, and carbapenems. MRSA prevalence: approximately 20-50% of hospital S. aureus isolates in many countries (declining in some due to infection control programmes). Peptide antibiotic options for MRSA: vancomycin (glycopeptide — historical gold standard; trough-guided or AUC-guided dosing; nephrotoxicity limits prolonged use), daptomycin (lipopeptide — concentration-dependent bactericidal; for bacteraemia and right-sided endocarditis; NOT effective for pneumonia due to surfactant inactivation), telavancin (lipoglycopeptide — for complicated skin infections and hospital-acquired pneumonia), dalbavancin (lipoglycopeptide — ultra-long half-life enabling single or two-dose treatment), and oritavancin (lipoglycopeptide — single-dose treatment for skin infections). The availability of multiple peptide antibiotic classes provides crucial therapeutic options against this major pathogen.

Myeloma pathophysiology: malignant plasma cells accumulate in bone marrow → monoclonal protein (M-protein/paraprotein) production → organ damage (CRAB criteria: Calcium elevation, Renal insufficiency, Anaemia, Bone lesions). Treatment evolution: pre-2000 (melphalan/prednisone, median survival 3 years) → 2003+ (bortezomib/Velcade — first proteasome inhibitor, combined with immunomodulatory drugs and dexamethasone, median survival increased to 5-7 years) → current era (quadruplet combinations including anti-CD38 antibody + proteasome inhibitor + IMiD + dexamethasone, with ASCT consolidation; median survival approaching 10+ years). Bortezomib mechanism: reversible 20S proteasome inhibition → accumulation of pro-apoptotic proteins + NF-κB suppression → myeloma cell apoptosis. Carfilzomib (Kyprolis): irreversible proteasome inhibition with greater selectivity — for relapsed/refractory disease. Motixafortide's role: CXCR4 antagonist mobilising HSCs for autologous stem cell transplant, which remains a key component of myeloma therapy for eligible patients.

MS pathophysiology: autoreactive T cells (Th1 and Th17) cross the BBB → recognise myelin antigens → inflammatory cascade → demyelination, oligodendrocyte death, and axonal damage → neurological deficits. Types: relapsing-remitting (RRMS, ~85% at onset — discrete attacks with recovery), secondary progressive (SPMS — gradual worsening after initial RRMS), primary progressive (PPMS, ~15% — gradual worsening from onset), and clinically isolated syndrome (CIS — first attack). Glatiramer acetate (Copaxone/generics): 20mg daily or 40mg three-times-weekly SC injection. Mechanism (proposed): GA is a random copolymer of four amino acids (L-Glu, L-Ala, L-Tyr, L-Lys) that mimics myelin basic protein (MBP). It shifts GA-reactive T cells from Th1 (pro-inflammatory) to Th2 (anti-inflammatory) phenotype → these GA-reactive Th2 cells cross-react with myelin antigens in the CNS → local anti-inflammatory cytokine release (IL-4, IL-10, TGF-β) + BDNF secretion → reduced inflammation and potential neuroprotection (bystander suppression). Efficacy: reduces relapse rate by approximately 30% in RRMS.

MG subtypes: AChR antibody-positive (~85% — antibodies cause AChR loss through three mechanisms: complement-mediated membrane destruction/MAC formation, crosslinking-induced AChR internalisation, and direct receptor blockade), MuSK antibody-positive (~5-8% — antibodies disrupt agrin/LRP4/MuSK signalling critical for AChR clustering), LRP4 antibody-positive (~2-3%), and seronegative (~5-10%). Zilucoplan targets the complement-mediated damage mechanism specifically — it blocks C5 cleavage, preventing C5a inflammatory signalling and MAC formation at the NMJ. Approved for generalised MG in anti-AChR antibody-positive adults (the subtype where complement plays the most significant role). Dosing: 0.3mg/kg daily SC self-injection. RAISE Phase III trial: significant improvement in MG-ADL (Myasthenia Gravis Activities of Daily Living) score at week 12 vs placebo. Meningococcal vaccination is required before starting zilucoplan (complement inhibition increases meningococcal infection risk — same requirement as for eculizumab).

Nephrogenic DI: kidneys fail to respond to vasopressin despite adequate hormone levels. Causes: genetic (X-linked AVPR2 gene mutations — V2 receptor defect, 90%; autosomal AQP2 gene mutations — aquaporin-2 water channel defect, 10%), acquired (lithium — most common acquired cause, affects ~20-40% of long-term users; hypercalcaemia, hypokalaemia, chronic kidney disease, ureteral obstruction, and various drugs). Pathophysiology: V2 receptor activation normally → Gαs → cAMP → PKA → aquaporin-2 vesicle translocation to collecting duct apical membrane → water reabsorption. Nephrogenic DI disrupts this pathway. Desmopressin is INEFFECTIVE (the target V2R system is non-functional). Treatment: manage underlying cause, thiazide diuretics (paradoxically reduce urine output by increasing proximal tubule reabsorption — reducing delivery of fluid to the collecting duct), amiloride (especially for lithium-induced — blocks lithium entry into collecting duct cells via ENaC), NSAIDs (reduce prostaglandin-mediated antagonism of vasopressin), and adequate hydration.

WHO NET classification: well-differentiated NETs (Grade 1: Ki-67 <3%; Grade 2: Ki-67 3-20%; Grade 3: Ki-67 >20% but well-differentiated morphology) and poorly differentiated neuroendocrine carcinomas (NEC: Ki-67 >20%, poorly differentiated, aggressive). Functional NETs secrete hormones causing clinical syndromes: insulinoma (hypoglycaemia), gastrinoma (Zollinger-Ellison syndrome), glucagonoma, VIPoma (watery diarrhoea), carcinoid (serotonin → flushing/diarrhoea). SSTR expression: 70-90% of well-differentiated NETs express SSTR2, enabling: Ga-68 DOTATATE PET diagnostic imaging (identifying tumour location and SSTR status), somatostatin analogue therapy (octreotide LAR, lanreotide — controlling hormone secretion + antiproliferative effect in well-differentiated G1-G2 NETs — PROMID and CLARINET trials), and PRRT with Lu-177 dotatate (NETTER-1 trial: significant PFS improvement in midgut NETs progressing on octreotide LAR). Treatment sequence: surgery (cure for localised disease) → SSA (antiproliferative + symptom control) → PRRT or everolimus/sunitinib for progressive disease.

Primary nocturnal enuresis (PNE): never achieved sustained dryness. Pathophysiology: multifactorial — nocturnal polyuria (reduced nocturnal vasopressin secretion → failure to concentrate urine during sleep), detrusor overactivity (uninhibited bladder contractions), and high arousal threshold (failure to wake in response to full bladder). Desmopressin mechanism: V2 receptor activation → AQP2 insertion → water reabsorption → reduced urine volume. Available forms: oral tablet (200-400μg at bedtime), oral lyophilisate/melt (120-240μg, sublingual — preferred for children due to easier administration and more consistent absorption), and nasal spray (10-40μg — less commonly used due to variable absorption and hyponatraemia risk in children). Response: approximately 60-70% show significant response. Key safety: fluid restriction in the evening (maximum 200mL from 1 hour before to 8 hours after desmopressin) is essential to prevent dilutional hyponatraemia, which can cause seizures. Desmopressin efficacy is assessed after 1-2 weeks; treatment duration is typically 3-6 months with periodic withdrawal trials.

NASH is the progressive inflammatory form of non-alcoholic fatty liver disease (NAFLD), characterised histologically by: steatosis (fat accumulation in >5% of hepatocytes) + lobular inflammation + hepatocyte ballooning ± fibrosis. NASH can progress to cirrhosis (approximately 10-20% over 10-20 years) and hepatocellular carcinoma. Prevalence: approximately 3-5% of adults globally. Pathophysiology: insulin resistance drives hepatic lipogenesis → lipotoxicity → oxidative stress and ER stress → hepatocyte injury → inflammation → stellate cell activation → fibrosis. GLP-1 RA relevance: semaglutide Phase II NASH trial showed significant histological improvement (NASH resolution without worsening fibrosis) — the mechanism involves: reduced hepatic lipogenesis (via improved insulin sensitivity and reduced hyperinsulinaemia), weight loss reducing hepatic fat content, and potential direct anti-inflammatory effects through hepatic GLP-1R signalling. Phase III NASH trials for semaglutide are ongoing. Tirzepatide and survodutide (GLP-1/glucagon dual agonist) are also in NASH clinical development.

T-score between -1.0 and -2.5 at any measured site. Prevalence: approximately 50% of postmenopausal women. Not all osteopenia progresses to osteoporosis — rate depends on age, BMD trajectory, and risk factors. Management: lifestyle interventions (weight-bearing exercise, adequate calcium 1000-1200mg/day, vitamin D 800-1000 IU/day, fall prevention, smoking cessation), FRAX assessment to quantify fracture risk, and pharmacotherapy only if FRAX probability exceeds treatment thresholds (US: ≥3% hip fracture or ≥20% major osteoporotic fracture). Monitoring: repeat DEXA in 1-2 years if near osteoporosis threshold, otherwise every 3-5 years. Osteopenia represents the at-risk population where prevention may avoid the need for osteoporosis pharmacotherapy.

Diagnosis: DEXA T-score ≤-2.5 at lumbar spine, femoral neck, or total hip. FRAX tool integrates BMD with clinical risk factors (age, sex, BMI, prior fracture, family history, smoking, alcohol, glucocorticoid use, RA, secondary osteoporosis) to calculate 10-year fracture probability. Treatment decision: FRAX-based thresholds (country-specific) or history of fragility fracture. Drug classes: anti-resorptive (bisphosphonates — first-line; denosumab — RANKL antibody) and anabolic/bone-forming (teriparatide — PTH 1-34, daily SC, 2-year limit due to osteosarcoma signal in rats; abaloparatide — PTHrP analogue, daily SC, potentially better balance of formation/resorption; palopegteriparatide — TransCon PTH, potential for different PK profile). Anabolic agents are generally reserved for severe osteoporosis (very low T-score, multiple fractures, or anti-resorptive failure). Sequential therapy strategy: anabolic first → transition to anti-resorptive (maintains bone gains) is more effective than anti-resorptive first.

Paget's disease involves: excessive osteoclastic bone resorption → reactive excessive osteoblastic bone formation → disorganised woven bone (larger, weaker, more vascular than normal lamellar bone). Prevalence: 1-3% of adults >55 years (decreasing), often asymptomatic. Diagnosis: elevated serum alkaline phosphatase + characteristic radiographic findings (bone expansion, cortical thickening, sclerotic/lytic areas). Symptoms: bone pain, deformity (bowed tibiae, enlarged skull), fractures, hearing loss (temporal bone involvement), and rarely malignant transformation (osteosarcoma, <1%). Treatment: bisphosphonates (zoledronic acid single IV dose — now first-line). Calcitonin-salmon was a historical treatment (SC injection for 6-18 months) — it suppresses osteoclast activity and reduces alkaline phosphatase, but has been largely replaced by bisphosphonates which produce more complete and durable biochemical remission.

PCOS affects approximately 8-13% of women of reproductive age. Diagnosis (Rotterdam criteria — 2 of 3): oligo/anovulation, clinical/biochemical hyperandrogenism, and polycystic ovarian morphology on ultrasound. Pathophysiology: insulin resistance → compensatory hyperinsulinaemia → stimulates ovarian androgen production + reduces SHBG → elevated free androgens → follicular arrest, anovulation, hirsutism, acne. GLP-1 RA relevance: emerging evidence shows GLP-1 RAs improve metabolic parameters in PCOS (weight loss, insulin sensitivity, reduced androgens, improved ovulation rates) — trials are ongoing. GnRH agonists are sometimes used diagnostically (GnRH stimulation test evaluating LH/FSH response) and therapeutically (ovulation induction in IVF protocols for PCOS patients — GnRH antagonist protocols reduce ovarian hyperstimulation syndrome risk in this high-risk population).

PPH is defined as blood loss ≥500mL after vaginal delivery or ≥1000mL after caesarean section. It is the leading cause of maternal mortality worldwide (approximately 70,000 deaths annually). Causes (the 4 Ts): Tone (uterine atony — most common, 70-80%), Tissue (retained placenta), Trauma (genital tract lacerations), and Thrombin (coagulopathy). Oxytocin is the cornerstone of PPH prevention and treatment: prophylactic oxytocin (10 IU IM or 5 IU slow IV) is recommended for all deliveries (WHO recommendation — reduces PPH incidence by approximately 50%). For treatment of atony: oxytocin infusion (20-40 IU in 1L normal saline at 250mL/hour). Carbetocin (a synthetic oxytocin analogue with longer half-life ~4-10× oxytocin) is approved in some countries for PPH prevention. Heat-stable carbetocin is particularly important for low-resource settings where cold chain maintenance is challenging.

Central precocious puberty (CPP) results from premature activation of hypothalamic GnRH neurons → pulsatile GnRH → LH/FSH → sex steroid production → premature secondary sexual characteristics and accelerated bone maturation. Diagnosis: pubertal development before age 8 (girls) or 9 (boys), elevated basal or GnRH-stimulated LH levels, advanced bone age on hand X-ray. GnRH agonist therapy: histrelin implant (Supprelin LA — 12-month SC implant, most convenient), leuprolide depot (1-month or 3-month IM injection), or triptorelin depot (every 28 days). Mechanism: continuous GnRH → initial LH/FSH surge (1-2 weeks) → GnRH receptor downregulation → gonadotropin suppression → sex steroid levels fall to prepubertal range. Treatment is continued until an appropriate age for puberty (typically age 11-12 for girls, 12-13 for boys), then discontinued to allow natural pubertal progression. Monitoring: LH suppression, height velocity, bone age.

Most common non-skin cancer in men (approximately 1.4 million new cases globally per year). Androgen deprivation therapy (ADT) is the foundation of treatment for advanced/metastatic disease: GnRH agonists (goserelin — SC implant 1 or 3 months; leuprolide — IM/SC depot 1, 3, 4, or 6 months; triptorelin — IM depot 1, 3, or 6 months; histrelin — SC implant 12 months) achieve castrate testosterone (<50 ng/dL) via GnRH receptor downregulation. GnRH antagonists (degarelix — SC injection monthly; relugolix — oral tablet daily) achieve castration without flare. Choice factors: agonist flare risk (avoid in spinal cord compression, urethral obstruction — use antagonist or add anti-androgen cover), convenience (histrelin implant = annual; leuprolide 6-month depot vs degarelix monthly), and oral availability (relugolix — the only oral GnRH antagonist for prostate cancer). ADT is combined with: novel androgen receptor pathway inhibitors (enzalutamide, abiraterone, darolutamide, apalutamide) and docetaxel for metastatic disease; radiation for localised/locally advanced disease.

Pruritus is mediated by unmyelinated C-fibres (distinct from but overlapping with nociceptive C-fibres) expressing pruriceptors — receptors activated by histamine, proteases (PAR-2), cytokines (IL-31, IL-4, IL-13), neuropeptides (substance P, CGRP), bile acids, and opioids (mu-opioid agonists are pruritogenic; kappa-opioid agonists are antipruritic). Afferent signals travel via the spinothalamic tract to the thalamus and somatosensory cortex. CKD-associated pruritus affects 40-70% of haemodialysis patients and is associated with: uraemic toxin accumulation, immune dysregulation (micro-inflammation, elevated IL-31), altered opioid balance (relative mu-opioid excess/kappa-opioid deficit in skin), and neuropathy. Difelikefalin addresses the opioid imbalance mechanism: selective peripheral kappa-opioid receptor agonism restores the mu/kappa balance, reducing pruritogenic signalling without CNS effects. The KALM-1 and KALM-2 Phase III trials demonstrated significant improvement in itch intensity (Worst Itch NRS) and itch-related quality of life.

PE occurs when a thrombus (usually from lower extremity DVT) embolises to the pulmonary arterial circulation, causing ventilation-perfusion mismatch, right ventricular strain, and potentially cardiovascular collapse. Classification by severity: massive (with sustained hypotension/shock — mortality approximately 25-50%), submassive (RV dysfunction without hypotension — mortality approximately 3-15%), and low-risk (no RV dysfunction — mortality <1%). Diagnosis: CT pulmonary angiography (CTPA) is the standard; D-dimer is used to rule out PE in low-probability patients. Treatment: anticoagulation (initial parenteral followed by oral), systemic thrombolysis for massive PE, and catheter-directed therapy for selected submassive cases. Bivalirudin may be relevant in PE patients with concurrent HIT requiring anticoagulation without heparin. The complement of anticoagulant and antiplatelet peptide drugs (bivalirudin, eptifibatide) plays a role in the broader thrombotic disease management landscape.

MECP2 (methyl-CpG binding protein 2) function: binds methylated CpG dinucleotides in DNA → recruits co-repressor complexes → regulates gene expression in neurons. MECP2 loss → widespread transcriptional dysregulation affecting: BDNF expression (reduced), glutamate signalling (altered excitatory/inhibitory balance), synaptic maturation (impaired), and microglial function (inflammatory phenotype). Clinical stages: Stage I (6-18 months — developmental stagnation), Stage II (1-4 years — rapid regression, loss of hand skills and speech, onset of stereotypies), Stage III (preschool-adult — pseudo-stationary, some improvement in social interaction, seizures), Stage IV (late motor deterioration — reduced mobility, scoliosis). Trofinetide (Daybue): synthetic GPE tripeptide (Gly-Pro-Glu, N-terminal tripeptide of IGF-1), 2× daily oral solution. LAVENDER Phase III trial: significant improvement in RTTCGS (Rett Syndrome Clinician Global Impression Scale) and CSBS-DP-IT (Communication and Symbolic Behavior Scales). FDA approval March 2023 — the first drug specifically approved for Rett syndrome. Mechanism: proposed modulation of neuroinflammation, glutamate-mediated excitotoxicity, and synaptic function.

Sepsis-3 definition: life-threatening organ dysfunction caused by dysregulated host response to infection (identified by ≥2 point increase in SOFA score). Septic shock: sepsis with persistent hypotension requiring vasopressors and lactate >2 mmol/L despite adequate fluid resuscitation (mortality approximately 40%). Antimicrobial peptide roles in sepsis: vancomycin (empirical gram-positive coverage in suspected MRSA sepsis — IV loading dose followed by trough-guided dosing), daptomycin (alternative for MRSA bacteraemia — 6-10mg/kg IV daily; bactericidal, may be preferred for endocarditis), colistin/polymyxin B (last-resort treatment for multidrug-resistant gram-negative sepsis — carbapenem-resistant Enterobacteriaceae, Pseudomonas, Acinetobacter), and vasopressin (0.03 units/min IV infusion as second-line vasopressor alongside norepinephrine — V1a-mediated vasoconstriction, potentially reducing catecholamine requirements). Sepsis management emphasises early antibiotics (within 1 hour of recognition) and source control.

SBS results from extensive small bowel resection (most commonly for Crohn's disease, mesenteric ischaemia, or radiation enteritis) leaving insufficient intestinal length for adequate nutrient/fluid absorption. Classification by anatomy: end-jejunostomy (most severe — no colon, highest fluid losses), jejuno-colonic anastomosis (colon present — better fluid absorption but risk of oxalate kidney stones), and jejuno-ileal anastomosis (least severe). Intestinal adaptation occurs naturally over 1-2 years: villus hyperplasia, crypt deepening, increased absorptive surface area. Teduglutide mechanism: GLP-2R activation → increased intestinal villus height (+30-50% in animal models), crypt depth, intestinal blood flow, and nutrient transporter expression. STEPS and STEPS-2 trials: teduglutide 0.05mg/kg daily SC → significant reduction in parenteral nutrition volume (≥20% reduction in approximately 63% vs 30% placebo at 24 weeks; some patients achieved complete PN independence). Treatment duration is indefinite — benefits reverse upon discontinuation. Cost: approximately $300,000/year (justified by comparison to PN costs of $100,000-200,000/year plus PN-associated complications).

Uterine fibroids (leiomyomas) are benign smooth muscle tumours affecting approximately 70% of women by age 50. They are oestrogen- and progesterone-responsive and regress after menopause. Symptoms: heavy menstrual bleeding (HMB — the most common indication for treatment), bulk symptoms (pelvic pressure, urinary frequency), pain, and reproductive complications. Medical management: relugolix combination tablet (Myfembree — relugolix 40mg + estradiol 1mg + norethindrone acetate 0.5mg daily — GnRH antagonist with hormonal add-back to manage menopausal symptoms and bone loss) and elagolix with add-back (Oriahnn — for HMB associated with fibroids). These oral GnRH antagonists represent a significant advance over injectable GnRH agonists for fibroids — offering convenient oral administration, dose-dependent oestrogen suppression, and built-in add-back therapy. Treatment duration: up to 24 months (bone density monitoring required).

VWD is the most common inherited bleeding disorder (prevalence approximately 1% of the population, clinically significant in approximately 0.01%). Von Willebrand factor (VWF) is a large multimeric glycoprotein that mediates platelet adhesion to damaged endothelium and carries coagulation factor VIII. VWD types: Type 1 (partial quantitative deficiency, ~70-80% of cases — mild bleeding), Type 2 (qualitative defects — subtypes 2A, 2B, 2M, 2N with different functional abnormalities), Type 3 (virtually complete VWF absence — severe bleeding, rare). Desmopressin relevance: DDAVP stimulates release of stored VWF from endothelial Weibel-Palade bodies via V2 receptor activation → transient increase in plasma VWF and FVIII levels (2-5× baseline within 30-60 minutes). Desmopressin is effective for Type 1 and some Type 2 VWD, making it first-line treatment for mild-moderate bleeding episodes and surgical prophylaxis in responsive patients. A test dose with VWF/FVIII measurement confirms responsiveness before clinical use.