Appendix L — Index

References are chapter.section — so 8.5 is Chapter 8, section 5. Appendix references are given by letter.

2136 entries.

"-mab" stem — 1.8
"-relin" versus "-relix" — 1.8
"-tide" stem — 1.8
*"98% / 99% purity by HPLC"* — 37.5 (science), 37.6
*"AI has revolutionized drug discovery"* — 37.6
"AI has revolutionized drug discovery" (claim form) ⚠️ — ch35 §35.8
*"disclosing all substance use to a treating clinician improves care"* — 37.5 (In the Clinic, 37.6
"Do your own research," failure of — 6.9
*"Evidence Dossier, Field 6" should be indexed under both Evidence Dossier and Field 6* — §16
"How would we know?" — 5.1
"Hunger hormone" as damaging compression — 13.6
*"I don't know"* — as one of three sentences → 39.6, professional cost of saying → 39.1
*"immune modulation"* — 37.5 (infectious)
*"it doesn't work"* — as one of three sentences → 39.6
*"it isn't on the banned list"* — 37.6, FR Tier 3
*"it's approved in [another country]"* — 37.6
*"it's FDA approved, so it's safe and effective"* — 37.6
*"it's not FDA approved, which means it's being suppressed"* — 37.6
"love hormone" nickname, rated ❌ — §21.9, ch21 §21.5
*"medical supervision reduces the risk"* — 37.6
*"my doctor had never heard of it"* — 37.6
*"my doctor prescribed it"* — 37.6
"Natural GLP-1 boosters" — 13.8
"No reported harm" vs "shown to be safe" — 17.9
*"nobody has reported any problems"* — 37.5 (science), 37.8 (safety callout), CS1
"Not for human consumption" — 6.4
"not for human consumption" — 19.2
*"nothing happened"* — 39.10, value of reporting → 39.3
"Over a hundred studies" claim — 5.CS2
"Ozempic face" — 8.8
"Ozempic face," life cycle of — 41.3, CS 41.1
*"pharmaceutical grade"* — 37.5 (science), FR Tier 3
"research use only" — 19.2
"research use only" disclaimer — 38.7
*"the next generation will be far better"* — 37.6
"the peptide is not always the drug" (named pattern) — 27.5, see also Ch 22, Ch 28
*"third-party tested"* — 37.5 (science), 37.6 (Hype Check callout), 37.6
"third-party tested," as a claim — §34.7
*"this modification makes the peptide more effective"* — 37.6
*"this peptide is a nootropic"* — 37.5 (neuropeptides)
"trust molecule" claim — ch21 §21.4
"Type 3 diabetes" framing — 10.7
"Up to" as a selection device — 9.4
*"used in animals for years"* — 37.5 (veterinary), CS2 (entry 8)
*"we don't know"* — as information → 39.6
"We make no medical claims" — 6.4
"where does it need to get to?" — ch18 §18.5
"Which is better" decomposed — 9.5
"Works with your natural systems" claim — 3.4
*14 claim-form ratings* — 37.1, 37.6, 37.8
*140 molecule/indication ratings* — 37.1, 37.5, 37.8
*154 total ratings* — 37.1, 37.8, Conclusion, KT
2018 (phage display, directed evolution) — ch35 §35.6
2024 (structure prediction, protein design) — §35.9, ch35 §35.8
32.6 → Chapter 33 (peptide design toolkit — the chapter's forward handoff)
503A and 503B — 6.CS2
503A compounding pharmacy — 12.4, 12.5
503B outsourcing facility — 12.4, 12.5
*54 ✅ / 26 ⚠️ / 50 ❌ / 10 🔬 / 10 split / 4 NOT RATED* — 37.8, Q item 10, KT

A

A1C — 8.2
A1C as surrogate — 8.2
abarelix — 27.3, case study 27.2, naming, withdrawal from US market
*absence of evidence* — distinguished from negative evidence → 39.6
Absence of glucose-dependence — 11.3, 11.4
Absolute risk reduction — 12.2, 12.8
absorption enhancers — 36.3, 36.9
Academic and philanthropic funding — 17.11
accelerated approval — 27.7, 38.3, 38.10, dossier
Accelerator and brake, endocrine architecture — 14.1, 14.9
Accusation, distinguished from description and hypothesis — 41.3
acid-labile subunit — §16.2
Acinetobacter baumannii — 25.1, 25.8
Acromegalic cardiomyopathy — 14.8
Acromegaly — 14.8
acromegaly, as high-end natural experiment — §16.9
acromegaly, as precedent for chronic growth signaling — ch18 §18.7 (→ Ch. 14)
ACTH release, vasopressin V1b and — ch21 §21.8
ACTH(1 — 24) fragment, see cosyntropin
active comparator — 36.2, 36.5
Active pharmaceutical ingredient, provenance of — 12.5
activin A — §16.3, §16.4
activin receptor type IIB (ActRIIB) P**** — §16.3
activin receptor type IIB, decoy receptors targeting — §16.3, §16.5
activity transfer as hypothesis — ch18 §18.1
adaptive immunity, contrasted with innate — 25.2
addiction / opioid use disorder — ch20 §20.6
Addiction and substance use — 10.8
addressing (peptide as delivery address) — 27.5, 27.8, case study 27.1
adeno-associated viral vector, follistatin gene therapy — §16.4
Adenylyl cyclase — 2.3
Adipose tissue as endocrine organ — 13.2, 13.CS1
adverse event reporting — forms as teaching device (further reading), 19.8, consumer reports 19.8
Advertisement, as a source in the drift log — 41 dossier
*afamelanotide* — 37.5 (neuropeptides)
affiliation, oxytocin and (vs. social salience) — §21.3, ch21 §21.5
Affinity — 2.6
Afrezza — 4.CS2
Age-adjusted versus "youthful" reference ranges — 14.4, 14.6
Age-related decline, ~14% per decade — 14.4
Aggregation — 6.CS1
aggregation — risk profile vs potency 19.3, and handling history 19.6, 19.3, and immunogenicity 19.3
Aggregation and immunogenic risk — 4.7
Agonist — 2.5
*agouti-related peptide (AgRP)* — 22.2, co-release with NPY
AgRP/NPY neurons — 13.4
Aib — 4.5
Aib (2-aminoisobutyric acid) — §33.2, §33.8
Aib, position 8 — 8.1
Akt/mTOR signaling, myostatin damping of — §16.3
albiglutide — §33.6
albumin — §33.4, §33.6
Albumin binding — 4.5
albumin binding — §33.4
Albumin binding, as half-life strategy — 15.2
albumin fusion — §33.6
Allocation during shortage — 12.3, 12.8
Alpha carbon — 1.2
Alpha helix — 1.4
alpha helix, as an interaction surface — §33.3
Alpha-MSH — 13.4
AlphaFold — case study 35.2, key terms, ch35 §35.8
*AlphaFold-class structure prediction* — 37.5 (science)
AlphaFold-class structure prediction as research tool ✅ — ch35 §35.8
*alternatives, including doing nothing* — in, as comparator question → 39.4 (question 3)
Alzheimer's disease trials — 10.7
amidation, C-terminal — ch21 §21.1
amino acid analysis — §34.6, §34.4 (as content method)
amino acid analysis, artifacts of acid hydrolysis — §34.6
amino acid availability, in protein balance — §16.1
Amino acid families (nonpolar, polar, acidic, basic) — 1.2
Amino acids, twenty proteinogenic — 1.2
amphipathic structure — 25.3, 25.5, 25.8, 25.2
Amplification — 2.4
Amplification, receptor signaling — 1.7
Amylin — 13.3
Amylin analog — 9.7
*amylin analogs, long-acting* — 37.5 (metabolic)
anabolic-androgenic steroids, as confounder in self-report — §16.8
androgen deprivation therapy — 27.1, 27.2, 27.9
Anecdote and testimonial — 5.2
*anesthesia — sedation, see* peri-operative considerations
angiogenesis requirement — ch18 §18.7
Angiogenic activity, open safety question — 17.9
Animal literature, four model families — 17.3
Animal model versus disease — 5.3
animal repair literature — ch18 §18.2
Animal studies, five failure modes — 5.3
Animal study publication pressure — 5.3, 5.CS2
Animal-sourced insulin — 11.6
ANP and BNP — 3.8
Antagonist — 2.5
antagonist experiment, as causal test — case-study-01, §20.5, §20.7, ch20 §20.4
Anterior pituitary — 14.1, 14.3, 14.8
Anti-aging industry, origins — 14.6
anti-doping — 19.9, strict liability 19.9, non-approved substances category 19.9
Anti-drug antibodies — 4.7
anti-drug antibodies — 19.7, cross-reactivity with endogenous peptide 19.3, 19.3, misread as tolerance 19.3
Anti-inflammatory claims, weakness of — 10.9
anti-inflammatory, as umbrella term — §18.6 (→ Ch. 10 §10.9), ch18 §18.5
Anti-obesity drug history — 3.7
anti-PEG antibodies — §33.5
antiandrogen cover — 27.2, case study 27.2
Antiarrhythmic suppression — 5.CS1
antibodies, as non-peptide candidates — 36.6
*antimicrobial peptides* — 37.5 (infectious), EX J, Q
antimicrobial stewardship — 25.6
antiproliferative effect vs symptom control — 27.4, 27.9
Apnea-hypopnea index — 10.6
apoptosis, IGF-1 inhibition of P**** — §16.2, §16.9
Apoptosis, inhibition by IGF-1 — 14.2, 14.7
Appetite network, redundancy of — 13.1, 13.7
Appetite stimulation, ghrelin receptor agonists — 15.3, 15.4
*appointment length* — as structural pressure → 39.1, asking for a longer one → 39.5
Approval as a regulatory decision — 5.4
approval, 2005 — ch35 §35.3
approval, definition of — 38.1
approval, indication-specific — 38.1, 38.4
approval, jurisdiction-specific — 38.1, 38.9
Approval, meaning and limits of — 15.5, case study 15.1
approval, what it is not — 38.1, 38.10
approved for pruritus, not pain — ch20 §20.9
Approved indication, narrowness of — 12.6
Approved indications beyond deficiency — 14.3
*approved pharmacopeia* — 37.5
*aprepitant — 22.5, 22.5*, case study 22.1, approved indication
aquaporin-2 — ch21 §21.8
Arcuate nucleus — 7.7, 13.4
area percent purity — §34.3, §34.7, §34.4
Area postrema — 7.7
arginine, position 8 of vasopressin — ch21 §21.1
ARNI (angiotensin receptor — 28.7, guideline position, definition, 28.7, neprilysin inhibitor)
Arnold, Frances — ch35 §35.6
Arthralgia and myalgia — 14.7
Arthropathy — 14.8
as non-opioid — ch20 §20.9
as repair mechanism — ch18 §18.7
as selection rather than design — ch35 §35.6
as standard behavioral research route — ch21 §21.6
as structural impostor — ch20 §20.1
as systemic antibiotics, rating — 25.9
as tumor requirement — ch18 §18.7
as unfalsifiable claim — ch18 §18.6
Aseptic fill-finish — 4.8
Aseptic fill-finish constraint — 6.CS2
Aseptic processing — 12.3
aseptic processing — 19.3, Case Study 34.2, §34.10, §34.9
*aspiration risk* — GLP-1 receptor agonists and → 39.2, CS 39.1, under sedation → 39.2
Aspiration under anesthesia — 8.7
Aspirin, as completed genericide — 41.1, CS 41.2
assay validity, plasma oxytocin — ch21 §21.6
assembly, dossier → §40.2, Dossier checkpoint (Steps 1 — 2)
associated deaths, definition — 25.1
Association versus causation — 14.7, 14.8
Asymmetric institutional skepticism — 6.9
Asymmetry of defense against loss versus gain — 13.1
atosiban — ch21 §21.2
attachment anxiety, as moderator of oxytocin effects — ch21 §21.5
attachment isomers — §33.8
attributable deaths, definition — 25.1
attributable vs. associated deaths — 25.1
attribution error — both directions dangerous 19.7, requires a record 19.8, 19.7
Attrition at Phase 2/3 transition — 9.CS2
Attrition in drug development — 2.9
attrition in drug development — 38.3
Attrition, administrative — 12.2, 12.8
authenticity, of documents — §34.7, §34.10
Autocrine signaling — 2.1
*automated insulin delivery* — 37.5 (metabolic)
Autophosphorylation — 11.3
average mass (vs monoisotopic) — §34.2
Axis-reading checklist — 3.9

B

bacitracin — 25.7, 25.8
Backbone rigidity and planarity — 1.3
bacterial endotoxins test — 19.3
Baker, David — ch35 §35.8, §35.9
Banting, Frederick — 11.1
Bariatric surgery, metabolic effects — 7.CS2
baroreceptors, vasopressin release and — ch21 §21.8
barrel-stave model — 25.3
Base rate, and false positives in visual identification — 41.3
base rate, drug attrition — 36.2, 36.10
baseline assessment — irreproducible after the fact 19.7, 19.7
Baseline risk and absolute benefit — 5.8
batch records — §34.10
batch release — 19.8, and recall path 19.1, 19.1
batch-to-batch variation — §34.10, §34.9
Bayer Co. v. United Drug Co. (1921) — CS 41.2, further reading
Bayliss and Starling — 3.CS1
Becker muscular dystrophy — §16.5
Belgian Blue cattle P**** — Case Study 16.2, §16.3
Benign intracranial hypertension — 14.7
Best, Charles — 11.1
Best-dose selection — 9.CS2
Beta sheet — 1.4
Beta-adrenergic receptor — 2.CS1
Beta-arrestin — 2.5, 2.7
Biased agonism — 2.5, 2.CS2
biased agonism at (see ch2 case study 2) — ch20 §20.3, §20.9
bicalutamide (antiandrogen cover) — 27.2, case study 27.2
bimagrumab — 36.6
Binding as equilibrium — 2.2
Binding versus activation — 2.2, 2.5
Binge eating disorder — 12.10
Bioavailability — 4.6
bioavailability, oral peptide — 36.3, 36.9
bioequivalence — 38.2
biological product — 38.2
Biologics and antibodies — 1.6
Biologics License Application (BLA) — 38.2
Biopsy endpoint problem — 10.4
biosimilar — 38.2
Biosimilar insulin — 11.9
bleeding disorders, desmopressin for — ch29, ch21 §21.8
Blinding, imperfect in practice — 5.5
Blinding, in diagnostic accuracy studies — 41.3
Blood glucose, secretagogue effects on — 15.4
Blood pressure reduction — 8.6
blood versus brain pools — case-study-02, ch20 §20.5
blood-brain barrier — ch20 §20.5, §20.9 (owned by ch22), §20.8
*blood-brain barrier — 22.8, structure, 22.8*, exceptions, as first-pass filter on CNS
blood-brain barrier, crossing — 36.8
blood-brain barrier, oxytocin and — ch4, ch22, ch21 §21.6
*BNP / NT-proBNP* — 37.5 (cardiovascular), CS1
bone mineral density loss (ADT) — 27.2
bone morphogenetic proteins, follistatin binding of — §16.4
Bothrops jararaca (Brazilian pit viper) — ch35 §35.4
Bottleneck, pipeline — ch35 §35.10, key takeaways
Botulinum toxin products, non-interchangeable units — 41.2, CS 41.2
*botulinum toxin type A* — 37.2 (rule 4), 37.5 (cosmetic), CS2 (entry 5)
box six (the empty functional category) → 29.10, 29.11 n/a — see Dossier section
Boxed warning — 8.7
BPC-157 — 19.2 (laundering example), dossier Field 10 worked entry (dossier), Ch 17 cross-ref 19.10
*BPC-157* — 37.3, 37.5 (growth ×2, metabolic-adjacent), KT, CS1, EX C, CS2 (entry 2)
BPC-157 for tendon healing, rating — 5.12
BPC-157, comparison with TB-500 — §18.8 (→ Ch. 17), ch18 §18.2
BPC-157, gastric juice origin story — 17.2
BPC-157, hype analysis — 6.8
BPC-157, molecular weight — 17.2
BPC-157, regulatory status — 38.4, 38.7
BPC-157, sequence and structure — 17.2
BPC-157, sequence of — 1.4
BPC-157, WADA S0 listing — 38.8
*braced arrivals* — patient and clinician → 39.1 (diagram)
Bradykinin-potentiating peptides — ch35 §35.4
brain-penetrant oxytocin receptor agonists (🔬) — ch21 §21.6, §21.9
Brand name, as container for non-drug products — 41.2, 41.8
Brand name, versus generic name — 41.1, 41.2, 41.9
Brand versus generic names — 1.8
Brazeau, Roger (somatostatin isolation, 1973) — 27.4
Breadth of indications, suspicion of — 10.1
*bremelanotide* — 37.5 (neuropeptides ×2)
bremelanotide, intranasal formulation discontinued — 38.4
brilacidin / defensin mimetics — 25.7
Brush-border peptidases — 4.1
burden estimate, 2019 — 25.1

C

Cadaver-derived growth hormone — 14.1, 3.CS2
cadaver-derived growth hormone — 19.10, as standing precedent 19.8, 19.8, case study 19.2
Cagrilintide — 9.7, 13.3
cagrilintide — 36.5, §33.9
CagriSema — 9.7, 13.3, 36.5, §33.9
*calcitonin* — 22.7, shared gene with CGRP
*calcitonin (salmon)* — 37.2 (split), 37.5 (approved pharmacopeia), 37.9
*calcitonin gene-related peptide (CGRP) — 22.7, as target not, 22.7*, structure and origin
calving difficulty, in double-muscled cattle — §16.3
cAMP — 2.3
can generate safety hypotheses — ch18 §18.7
Cancer question, GH and IGF-1 — 14.7, 14.8
cancer risk, and IGF-1 signaling P**** — §16.9
Candidate mechanisms for cardiovascular benefit — 8.CS1
cannot upgrade a rating — ch18 §18.1, §18.7
Captopril — ch35 §35.1, key terms, §35.4
carbetocin — ch21 §21.2
carcinoid crisis — 27.4
carcinoid syndrome — 27.4, 27.9
cardiac repair, thymosin β4 animal models — ch18 §18.2
*cardiovascular* — 37.5
Cardiovascular outcome trial requirement — 8.2, 8.CS2
cardiovascular risk on ADT — 27.2, 27.9
Carpal tunnel syndrome — 14.7, 14.8
carpet model — 25.3
Case report and case series — 5.2, 17.6
Case-control study — 5.2
Cash price — 12.1
CASP — case study 35.2, key terms, ch35 §35.8
CASP14 result (2020) — ch35 §35.8
CAST case study, parallel to — 17.11
CAST trial — 5.CS1
castrate level — 27.1, 27.2
Category blurring, endocrine/paracrine — 3.1
*category dismissal* — cost to future, defined → 39.7, contrasted with engaging a claim → 39.7
cathelicidin — ch18 §18.4 (→ Ch. 25)
cationic peptides — 25.3, 25.5, 25.2
cattle, double-muscled — Case Study 16.2, §16.3
CB1 receptor — ch20 §20.5
celiac disease, larazotide investigation — ch18 §18.5
cell-culture reagent, IGF-1 LR3 provenance as — §16.2
cell-penetrating peptides, fixation artifact — §33.3
central delivery controversy — case study 2, ch21 §21.6
Central GLP-1 neurons — 7.7
*central sensitization* — 22.4
*Cerebrolysin* — 37.5 (neuropeptides)
cerebrospinal fluid, oxytocin measurement in — ch21 §21.6
certificate of analysis — 19.4, §34.7, Case Study 34.1, 19.3, rating 19.4, as claim about a sample 19.3
certificate of analysis, four limitations of — §34.7
Certificate of analysis, limits — 6.CS1
certificate of analysis, six things it can establish — §34.7
cetrorelix — 27.3, §33.2
*CGRP receptor* — 22.7
*CGRP-targeting therapies* — 37.5 (neuropeptides)
ch13 (α-MSH, POMC, three-joint test) — §20.8, cited in ch20 §20.2
ch2 case study 2 (biased agonism, oliceridine) — §20.9 — **referenced, cited in ch20 §20.3, not
ch2 §2.7 — 2.8 (desensitization/downregulation) — cited in ch20 §20.6
ch21 (oxytocin/vasopressin) — forward reference in ch20 conclusion and dossier
ch22 (blood-brain barrier) — §20.8, §20.9, forward reference in ch20 §20.5
ch3 (pulsatile vs sustained) — §20.8, cited in ch20 §20.6
ch4 (five barriers, oral delivery) — cited in ch20 §20.8
ch5 (rating rules) — §20.8, §20.7, cited in ch20 §20.1
chain of custody — §34.7, §34.9
*chain of custody — see also* Ch 34, clinician's inability to verify a vial → 39.9
chair-stand test — §16.7
change control — §34.10
*changing clinicians* — warned against → 39.7, legitimate reasons → 39.7, shopping for agreement
Chapter 1 (structure, size, proteolysis) — 25.2, 25.3, 25.4
Chapter 1 §1.2 (lysine as attachment handle) — §33.2, §33.8
Chapter 1 §1.6 (intracellular targets ruled out) — §33.3
Chapter 1 §1.6 (size / route of administration) — 27.3
Chapter 1 §1.8 (drug naming) — 27.3
Chapter 10, clinical attrition — ch35 §35.10
Chapter 11 (insulin replacement) — contrasted 22.6
Chapter 11 (insulins; disulfides) — §33.4, §33.3
Chapter 11, five features of lethal rationing — 12.8
Chapter 12 (cost and access) — Dossier, §33.6
Chapter 13 (arcuate circuitry, three-joint test) — 22.3, invoked 22.2
Chapter 13 (CagriSema) — §33.9
Chapter 14 (growth hormone, acromegaly) — 27.4
Chapter 16 (surrogate endpoints) — §33.10
Chapter 16, surrogate endpoints — ch35 §35.10
Chapter 18 (LL-37 immunomodulation, vitamin D) — 25.4
Chapter 19 (unregulated market) — 25.5
Chapter 2 (receptors and amplification) — 25.2
Chapter 2 §2.7 (four termination mechanisms) — §33.10
Chapter 2 §2.9 (mechanism is not evidence) — 22.9, invoked 22.5
Chapter 20 (measuring peptides in blood) — spaced review
Chapter 21 (intranasal delivery) — spaced review, invoked 22.6
Chapter 22 (CGRP, peptide as target) — 27.5
Chapter 22 (substance P) — §33.10
Chapter 22, substance P antagonists — ch35 §35.8, §35.10
Chapter 25, antimicrobial peptides — ch35 §35.4
Chapter 26 (next chapter pointer) — Conclusion
Chapter 27 (octreotide, somatostatin analogs) — §33.3
Chapter 27 (peptide as delivery address) — forward pointer 22.7
Chapter 28 (neprilysin inhibition) — forward pointer 22.7
Chapter 28 (neprilysin, peptide as substrate) — 27.5, conclusion
Chapter 29 (cyclosporine, oral peptides) — §33.2, §33.3
Chapter 29 is the natural index hub for the phrase "approved peptide drugs"**** — recommend the
Chapter 3 (flat vs. patterned exposure) — invoked 22.3
Chapter 3 (pulsatile vs sustained signaling) — §33.10
Chapter 3 §3.3 (somatostatin as GH brake) — 27.4
Chapter 3 §3.5 (pulsatility) — 27.2
Chapter 30 (cosmetic claims) — learning paths
Chapter 30 (cosmetic peptides, "palmitoyl") — §33.2 (via Learning Paths)
Chapter 30 (cosmetic/topical peptides) — 25.7, Learning Paths
Chapter 30 (topical barrier logic) — forward pointer, learning paths
Chapter 31, veterinary use as substitute for evidence — ch35 dossier
Chapter 32 (manufacturing) — 25.6
Chapter 32 (synthesis, biologics manufacturing, batch release) — §33.2, §33.8, §33.6
Chapter 33 (peptide engineering, peptidomimetics) — 25.7
Chapter 33 (stabilization toolkit) — 27.4
Chapter 33, engineering toolkit / orforglipron arc / §33.9 ratio problem — §35.4, §35.7, ch35 §35.3
Chapter 34 (vial contents, purity) — 25.5
Chapter 34 (what is in the vial) — Conclusion
Chapter 36 (frontier) — 27.7
Chapter 37 (master rating table) — 27.8, conclusion
Chapter 39 (clinician conversation) — invoked 22.6
Chapter 4 (delivery, site of action) — 25.5, 25.8
Chapter 4 (peptide pharmacology / clearance) — 27.2, 27.4
Chapter 4 (two exits; formulation) — §33.1, §33.8
Chapter 4, delivery problem — extreme form in ziconotide — ch35 §35.4
Chapter 5 (rating rules) — 25.3, 25.9, 27.4, 27.9
Chapter 5 standard, applied to cultural claims — 41.1, 41.5, 41.9
Chapter 6, three compounded-semaglutide users — 12.4, 12.11
Chapter 7 (area postrema) — 22.5, 22.8, invoked 22.4
Chapter 7, publicly funded incretin program — 12.1
Chapter 8 (semaglutide) — §33.8
Chapter 8 (semaglutide, two-layer engineering) — 27.2
Chapter 9 (liraglutide, tirzepatide, orforglipron) — §33.4, §33.7, §33.9
Chapter 9, Phase 2 optimism — ch35 §35.10
*chapters issuing no ratings (37, 40)* — 37.1, Key Terms, KT
chelator (DOTA) — 27.5
*chemotherapy-induced nausea and vomiting — 22.5*
Cholecystokinin — 3.7
cholesterol, in membrane selectivity — 25.5
chromatogram, reading a — §34.3
Chronic exposure, uncharacterized — 17.9
Chronic kidney disease — 10.3
*chronic pain* — 22.5, 22.9, NK1 antagonist failure, heterogeneity as trial problem
Chronic therapy — 8.9
Chronic therapy, GLP-1 as — 12.2, 12.9
Circumventricular organ — 7.7
*circumventricular organs* — 22.4, 22.5, 22.8, area postrema
circumventricular organs — 36.8
Citation chain — 6.6
Citation checking — 5.10
CJC-1295 (with and without DAC) — 15.2, 15.6, 15.8, dossier
*CJC-1295 + ipamorelin* — 37.5 (growth), CS2 (entry 10)
*claim form ratings* — 37.5 (veterinary block), 37.6 (full table), KT, CS2 (entry 8)
claim form, "modification makes it more effective," ❌ — §33.10
*claim forms, rated* — "doctor prescribed it" → 39.8, "doctor never heard of it" → 39.6
*claim, as the unit of rating* — 37.1, 37.2 (rule 1), 37.5 (column note), 37.7, KT
claim, context as part of — ch21 §21.9, Dossier
CLARINET — 27.4, 27.9
class A vs class B GPCRs — §33.7
Class B GPCR — 7.3
Class B GPCR, small-molecule activation — 9.8
Class B GPCRs, structural difficulty — ch35 §35.7
Clearance — 4.3
Clinical attrition, causes of — ch35 §35.10
clinical endpoint, versus biochemical and surrogate — §18.6 (→ Ch. 6), ch18 §18.1, §18.2
*clinical judgment — prescription as → 39.8, see also* Ch 38 §38.10, not a demonstration → 39.8
clinical trial phases — 36.2
clinical trial status — 25.7
clinical trials — ch21 §21.7
ClinicalTrials.gov — 5.CS2
ClinicalTrials.gov status field — 17.6
Closed-loop system — 11.7
*CNP analog (vosoritide-class)* — 37.5 (cardiovascular)
co-elution — §34.3, §34.7
Co-intervention — 6.3
Co-intervention confound — 17.7, CS2
*co-transmission — 22.1*
coformulation — §33.9
Cohort study — 5.2
Cold chain — 4.8
*colistin* — 37.5 (infectious), 37.8 (safety callout), EX J
colistin (polymyxin E) — 25.3, 25.8, Case Study 25.1
Collagen peptides — 1.CS2
collecting duct, renal — ch21 §21.8
Collip, James — 11.1
Colonic polyps — 14.8
*colonoscopy* — CS 39.1, as sedated procedure → 39.2
colorectal neoplasia, in acromegaly — §16.9
Combination approaches, future — 13.9
Combination therapy risk — 7.4
Comment threads, deflation in — 41 dossier
Commercial interest, and scrutiny of claims — 41.4, 41.8
Comparator dose fairness — 9.5
Comparator, placebo versus active — 5.5
Comparison worksheet — 9 dossier
compartment error — §20.8, case-study-02, ch20 §20.5
compartmentalization, as a selectivity strategy — 25.5
Composite endpoints — 5.10
Composite study, methodological use of — CS1, CS2
composition vs sequence — §34.6, §34.2
compounded drugs, not approved products — 38.6
Compounded preparations, absorbed by brand name — 41.2, 41.8
Compounded semaglutide — 6.CS2
*compounded semaglutide* — 37.5 (metabolic), 37.7
compounding — 38.6, 503A 19.5, 19.5, 503B 19.5, not FDA-approved 19.5, shortage provision 19.5
compounding, 503A — 38.6
compounding, 503B outsourcing facility — 38.6
Compounding, general prohibition and shortage exception — 12.4, 12.5
compounding, shortage mechanism — 38.6
Compression ladder, joke rung added — 41.6
Concealed allocation — 5.5
concentration-dependent selectivity — ch21 §21.1, ch2 §2.2
Condensation reaction — 1.3
Cone snails — §35.4, ch35 §35.2
Conference abstract, evidentiary weight — 17.6
Conference abstracts that never publish — 5.10
Confidence interval — 5.7
confidence scores and disorder — ch35 §35.8
confirmatory trials — 38.3, 38.10
*conflict of interest* — a reason to check evidence, not evidence of dishonesty → 39.8, CS 39.2
Confounding — 14.7
Confounding by indication — 10.7, 10.CS2
confounding, in IGF-1 cancer epidemiology P**** — §16.9
Congenital leptin deficiency — 13.2, 13.CS1
consensus definitions, sarcopenia — §16.7
*constraints, institutional and licensing* — misread as personality → 39.9
Contempt as communication failure — 6.5
content (peptide) — nonlinearity of error 19.3, vs purity 19.3, 19.3
content, peptide — §34.4, §34.7, §34.6
context-dependence — ch21 §21.5
context-dependence of oxytocin effects — Dossier, §21.9, ch21 §21.5
*continuity of care* — diagnostic value of → 39.10
Continuous glucose monitor — 11.7
Continuous versus pulsatile delivery — 3.5
contract manufacturers — 19.1
Conus magus — ch35 §35.4
corneal healing, thymosin β4 animal models — ch18 §18.2
Corticosteroid withdrawal and tapering — 3.4
Cortisol and prolactin, secretagogue effects on — 15.3
cortisol, "stress hormone" nickname — ch21 §21.9
*cosmetic and topical* — 37.5
cosmetic ingredient, regulatory category — 38.4, 38.7
Cost of goods versus price — 12.1, 12.3
cost of goods, peptide manufacturing — 25.6
Cost of peptide drugs — 4.8
Counter-regulation — 3.6
Counter-regulation in energy balance — 13.1
Counterfeit and unregulated supply — 14.7
counterion — §34.4, §34.7
counterion, trifluoroacetate — §34.4
Coverage discontinuity — 11.CS2
Coverage, confusion caused by naming — 41.2, 41.8
Coverage, framing effects on — 41.8
Creutzfeldt-Jakob disease — 19.8, case study 19.2
Creutzfeldt-Jakob disease, iatrogenic — 3.CS2
Creutzfeldt-Jakob disease, prion transmission — 14.1
critical care, vasopressin in — ch21 §21.8
Cross-reaction with endogenous peptide — 4.7
crossfire (beta particle range) — 27.5, 27.6
Cryo-electron microscopy — key terms, ch35 §35.7
Cultural claims, rated with the book's discipline — 41.2, 41.3, 41.7
Cultural Drift Log — 41 dossier
Cushman, David — ch35 §35.4
Cyclization — 4.2
cyclization — §33.3
cyclization (as stabilization strategy) — 27.4
cyclosporine — §33.2, §33.3
Cysteine and disulfide bonds — 1.2, 1.4
cysteine, disulfide ring in nonapeptides — ch1 §1.2, ch21 §21.1

D

D-alanylation of teichoic acids — 25.3
D-amino acid substitution — 27.2, 27.4
D-amino acid substitution, invisibility to MS — §34.2
D-amino acids — §33.2
D-amino acids as protease defense — 4.2
DAC (Drug Affinity Complex) — 15.2
Dalton — 1.6
daptomycin — 25.8
*daptomycin* — 37.5 (infectious)
*daridorexant* — 22.6
Data monitoring committee — 10.3, 10.CS1
*date-stamping of ratings* — 37.1, 37.2 (rule 5), 37.9
db/db mouse — 13.CS1
DCCT — 11.CS1
De novo design — key terms, ch35 §35.9
De novo designed peptide binders as therapeutics 🔬 — ch35 §35.9
decline of — §33.5
deconvolution, of charge-state envelope — §34.2
decoy receptor, ActRIIB-based — §16.3, §16.5
defensins (α and β) — 25.5, 25.4
definition and size range — 25.2
Degarelix — 3.9
degarelix — 27.1 (table), 27.3, 27.9, §33.2, case study 27.2
Degludec and multihexamer chains — 11.6
degradation, rapid — §20.8, ch20 §20.6
deletion sequences — 19.3
deletion sequences, and purity assays — §34.3, §34.4
delinkage models — 25.6
Delivery filter, five questions — 4.9
Delivery routes, comparison — 4.4
delta receptor (OPRD1) — ch20 §20.3
Denervated loop experiment — 3.CS1
Denial, read as confirmation — 41.5
Denominator, absence of — 17.5, CS2
*dense-core vesicles* — 22.1
depot formulation — 27.2, 27.4
Depot formulations — 4.4
*depression, major depressive disorder — 22.9, 22.5*, NK1 antagonist failure, heterogeneity
depyrogenation — §34.5
derived from POMC — ch20 §20.2
descending facilitation — ch20 §20.4
descending inhibition — ch20 §20.4
Desensitization — 2.7
desensitization / downregulation — 27.2
desensitization and downregulation — 36.4
desensitization, not engineerable — §33.10
desmopressin — ch29, §33.2, ch21 §21.8
*desmopressin* — 37.2 (rule 6), 37.5 (neuropeptides, approved pharmacopeia ×2)
desmopressin and — ch29, ch21 §21.8
detector wavelength, effect on purity — §34.3, §34.7
Detemir and albumin binding — 11.6
DEXA, as surrogate — 36.6
diabetes insipidus, central (arginine vasopressin deficiency) — ch29, ch21 §21.8
Diabetic ketoacidosis — 11.4, 11.CS2
diacid, fatty — §33.4, §33.8
Diagnosis of GH deficiency — 14.3
Diagnostic accuracy, requirements for — 41.3
Diagnostic infrastructure as part of treatment — 13.CS2
dietary ingredient, qualification as — 38.7
dietary supplement category — 38.7
difelikefalin — ch20 §20.9
Different biology — 17.5
Different disease, model captures a piece — 17.5
Different dose, allometric scaling — 17.5
Different endpoint, animals cannot report — 17.5
Different publication pressure — 17.5
differential diagnosis — vs attribution 19.7, 19.7, gallstones/pancreatitis example 19.7
*differential diagnosis* — CS 39.1, effect of incomplete history on → 39.2
differential rates by effect — ch20 §20.3, §20.6
*Dihexa / P21* — 37.5 (neuropeptides)
Direct-to-consumer telehealth — 12.7
Directed evolution — ch35 §35.6, key terms
direction of error* — §31.5
*directional bias* — 37.10, EX §E, CS2, KT
disanalogy argument, disease versus healthy populations — §16.8
*disclosure* — fears surrounding → 39.2, clinical reasons for → 39.2, moral framing as obstacle →
Disclosure to clinician — 17.7, 17.9
Disclosure, arguments against — 41.4
Disclosure, arguments for — 41.4
Disclosure, book's refusal to impose a duty — 41.4
Discontinuation and weight regain — 8.9
Discontinuation conversation, pre-treatment — 12.11
Discontinuation rates in trials — 8.6
Discontinuation, cost-driven — 12.8, 12.11
discontinued programs, myostatin pathway P**** — §16.5
Discovery routes, four — ch35 §35.1, §35.9, key takeaways
*dismissal, clinician* — when correct → 39.7, when reflexive → 39.7, repair move → 39.7
*dispensing practices* — structural question about → 39.8, CS 39.2
displacement by engineered analogs — ch35 §35.3
Display technologies — ch35 §35.6
distinguished from addiction — ch20 §20.6
distinguished from thymosin β4 — ch18 §18.1
distribution across multicellular life — 25.2
*distribution by therapeutic block* — 37.8 (table)
disulfide — §33.3
Disulfide bonds — 11.2
Disulfide-stapled architecture — ch35 §35.2
divergence between jurisdictions — ch18 §18.3
DL-phenylalanine — ch20 §20.8
dogs, myostatin mutation in whippets — Case Study 16.2, §16.3
*doing nothing* — as a real trial arm → 39.4, absent from a recommendation → CS 39.2
dopamine, "pleasure chemical" nickname — ch21 §21.9
doping control — 38.8
dorsal horn — ch20 §20.4, §20.9
Dose accuracy, importance of — 2.4
Dose scaling across species — 5.3
dose-limiting organ (kidney, PRRT) — 27.5, 27.6
Dose-response curve — 2.6
dose-response, growth-signaling axis — §16.9
dosing errors, compounded products — 19.5, delivery-device substitution 19.5, case study 19.1
Dosing errors, vial and syringe — 12.5
Dosing errors, vial versus pen — 6.CS2
Dosing interval and half-life — 4.3
*dossier, evidence* — Field 11 as a conversation → Dossier §, verdict-to-question conversion →
*dossier, evidence (project)* — 37.1 (callout), EX AE–AI, Dossier section (5 steps), CS2
dossier, Field 5 (human evidence) when literature is thin — ch18 Dossier
dossier, Field 6 (Evidence and Rating) — ch21 Dossier
double muscling P**** — §16.3
Downregulation — 2.7, 2.8
Downregulation of receptors — 15.6, 15.7
downregulation, not engineerable — §33.10
Downward compression — 10.10
DPP-4 — 4.2, 4.5, 7.6
DPP-4 inhibitors (gliptins) — 7.6
DPP-4, as an engineering target — §33.2, §33.8
DPP-4, GLP-1 degradation by — 2.7
*drift audit* — Dossier section, EX AE–AH, CS2
drug economics and unstudied compounds — 38.10
Drug nomenclature stems — 1.8
Drug shortage list — 6.CS2
drug shortage list — 38.6
dry mouth (PSMA RLT) — 27.6
DSHEA (1994) — 38.7
du Vigneaud, Vincent — ch21 §21.1
dual antimicrobial and immunomodulatory activity — ch18 §18.4
dual enkephalinase inhibition (stated in prose, not a formal callout) — 🔬 — ch20 §20.9
Duchenne muscular dystrophy — Case Study 16.1, §16.5
dulaglutide — §33.6
Durability of replacement therapy — 11.8
duration of action, trajectory — 36.4
DXA (dual-energy X-ray absorptiometry), lean mass measurement P**** — §16.6
Dynamic stimulation testing — 14.3
dynorphin A — ch20 §20.2, §20.3
dysphoria — ch20 §20.3

E

Eating disorders, screening gap — 12.7, 12.10
Eating disorders, trial exclusion of — 12.10
EC50 — 2.6
Edema and fluid retention — 14.7, 14.8
Edman degradation — §34.6
Effect magnitude inflation — 10.CS1
Efficacy — 2.6
Efficacy estimand — 5.9, 9.4
efflux, as AMP resistance — 25.3
*eight-minute appointment — see* appointment length
electrospray ionization — §34.2
Elixir Sulfanilamide (1937) — 19.10, epigraph, case study 19.2
*emergencies* — undisclosed exposure in → 39.2
endocannabinoids / anandamide — ch20 §20.5, case-study-02
Endocrine gland, classical list — 3.1
Endocrine organs, non-classical — 3.1
Endocrine signaling — 2.1
Endogenous ligand, inherited selectivity profile — ch35 §35.5
endomorphins — ch20 §20.3 (receptor table note)
*endorphins / endogenous opioid peptides* — 37.5 (neuropeptides ×3)
endorphins cause the runner's high — ⚠️ — ch20 §20.5
endosomal escape — §33.3
Endotoxin — 6.CS1
endotoxin — 19.8, misattribution 19.3, separate from sterility 19.3, survives sterilization 19.3, §34.7, §34.5, 19.3, §34.9
endotoxin testing, absence outside regulated manufacture — §34.7, §34.5
endotoxin, absence of visual signature — §34.5
endotoxin, gray-market product concerns — §16.4
endotoxin, survival of sterilization — §34.5
endpoint mismatch, animal to human — ch18 §18.2
endpoints, hard — 27.1 (overview), 27.8
Eng, John — ch35 §35.3
enkephalins (met- and leu-) — §20.8, ch20 §20.1, §20.2, §20.6
Enteroendocrine cell — 7.2
*enthusiasm, clinician* — not a stronger signal than refusal → 39.8, five questions applied
environmental monitoring — Case Study 34.2, §34.10
envy and gloating, oxytocin and — ch21 §21.5
epidemiology, IGF-1 and cancer — §16.9
Epinephrine auto-injectors, device differences — CS 41.2
Epistemic laundering — 6.4, CS2
epistemic laundering — 19.2, diagram 19.2
*eptinezumab* — 22.7
*erenumab* — 22.7, as antibody not peptide
Escalating-dose pattern — 2.8
Escherichia coli — 25.1
essentially a copy — 38.6
Estimand — 5.9
Estimands, two — 9.4
European Medicines Agency (EMA) — 38.1, 38.9
*evidence absent (❌ type 1)* — 37.3, CS1, Q items 3–4, KT
Evidence Dossier Field 9 (Risks) — Dossier
evidence dossier, Field 10 — § Dossier
Evidence Dossier, Field 10 (Status) — Dossier section
Evidence Dossier, Field 3 (indirect mechanisms) — dossier
Evidence ladder — 5.2
*evidence present and negative (❌ type 2)* — 37.3, 37.5 ((N) marker), KT, CS1, 5, Q items 3
evidence rating (market claims) — third-party testing 19.4, absence of reports 19.8
Evidence Rating format, introduced — 2.9
Evidence rating system, introduced — 1.9
evidence versus regulatory status — 38.10
Evidence without randomization — 11.1
evidence, absent vs. present-and-negative — §21.9, ch21 §21.7
*evidence, present and negative vs. absent — 22.5, 22.5*, contrasted ❌ ratings, key takeaways
excipients — 19.3
Exclusivity, patent — 12.1
Exenatide — 4.CS1, ch35 §35.3, key terms, dossier, §35.4
exenatide / exendin-4 — §33.2
Exendin-4 — 4.CS1, §35.3, key terms, ch35 §35.1, dossier, §35.9
existence proof argument — ch20 §20.8
expectancy effect, in training — §16.8
Expectation effects — 6.3
expectation versus conditioning — case-study-01, ch20 §20.7
expectation, as neurochemical event — ch20 §20.7
Expert opinion as evidence — 5.2
Externality, speculation as — 41.5
extrapolation, cross-species — ch21 §21.3, ch5 §5.3
Exubera — 4.CS2

F

Facial fat compartments — 41.3, CS 41.1
Facial volume loss, causes other than drugs — 41.3
factor VIII, desmopressin release of — ch21 §21.8
FAERS — 19.8
failure modes and artifacts — ch35 §35.6 (Read the Study)
failure rate, why none is defensible — §34.8
falsifiability — 36.1, 36.2, 36.10
*falsifiability of a rating* — 37.2 (rule 5), 37.9 (update procedure)
Falsifier as fastest disqualifier — 6.10
Falsifier, specifying — 17.11
Fatty acid conjugation — 4.5
Fatty acid conjugation, position 26 — 8.1
*fatty-acid acylation* — 37.5 (science), 37.7 (callout)
Fc fusion — §33.6
FcRn salvage pathway — §33.6
FDA, non-approval of thymosin alpha-1 — ch18 §18.3
Feedback suppression of endogenous production — 14.3, 14.9
Fenfluramine-phentermine — 8.CS2
Fermentable fiber and GLP-1 secretion — 13.8
fiber number, developmental determination of — §16.1, §16.3
Field 11 (Verdict) under uncertainty — Dossier
Field 12, sharpened into a specification — ch35 dossier
Field 3 (mechanism), writing "not established" — 17.2, Dossier
fill-finish bottleneck — 36.9
Fill-finish capacity — 12.3
First-in-class drugs, judging — 4.CS1
First-pass hepatic extraction — 7.6
First-pass metabolism — 4.1
Five barriers to oral peptide delivery — 17.8
five channels (market structure) — diagram 19.1, 19.1
five meanings of "not FDA approved" — 38.4
five mechanisms of failure* — §31.5
Five reasons animal results fail to transfer — 17.5
five required specifications — ch18 §18.6
five translation problems applied — ch18 §18.2 (→ Ch. 5 §5.3)
five-link assumption chain — ch18 §18.1
Fixed receptor activity ratio — 9.1
flare — 27.2, 27.3, 27.9, case study 27.2
Flare phenomenon, GnRH agonists — case study 15.2
FLOW — 10.3, 10.CS1
Fluid retention, GH axis stimulation — 15.4, 15.7
follistatin gene therapy trials — §16.4
follistatin P**** — §16.4
follistatin, binding promiscuity — §16.4
follistatin, glycosylation of — §16.4
*follistatin-344* — 37.5 (growth)
follistatin-344 P**** — §16.8, §16.4
Food and Drug Administration (FDA) — 38.1, 38.9
Food environment position — 12.9
Food noise — 7.7, 12.10
Food noise, connection to addiction — 10.8
forecast versus prediction — 36.1, 36.10
Formulary — 12.2, 12.8
Formulary, organized by product and indication — 41.2, 41.9
forty-amino-acid line — 38.2
Four candidate explanations — 10.1
four goals of peptide engineering — §33.1
four limitations — ch35 §35.8, key takeaways
four questions* — §31.6
Four vials — 6.CS1
Four-tier rating system — 5.11
fragmentation, peptide (b/y ladder) — §34.2
Fragments of human proteins, as a discovery route — ch35 §35.5, dossier
*fremanezumab* — 22.7
*frequency coding of transmitter identity* — 22.1
Frozen accident hypothesis — 1.2
Frozen rating rules, applied — 14.9
functional co-primary endpoints, regulatory requirement P**** — §16.7, §16.6
functional endpoint P**** — §16.7, §16.6
Funding and evidence weight — 6.7
*funding of trials, as determinant of evidence distribution* — 37.8, CS1, Conclusion, KT

G

G protein — 2.3
G-actin, thymosin β4 binding of — ch18 §18.1
G-protein-coupled receptor (GPCR) — 2.3
gait speed — §16.7
*galcanezumab* — 22.7
Gallbladder disease — 8.7
ganirelix — 27.3
Gastric bypass rerouting — 7.CS2
*gastric emptying* — GLP-1 receptor agonists and → 39.2, variation across the class → 39.2
Gastric emptying, slowing of — 7.3
Gastrointestinal adverse effects — 8.7
Gastrointestinal protection models — 17.3, Fig 17.1
Gastroparesis — 8.7
gate, pain as regulated rather than transmitted — ch20 §20.4
GDF-11 — §16.3, §16.4
gene therapy, follistatin — §16.4
generic drugs — 38.2
generic entry and access — 36.9
generic name, absence as regulatory-history evidence — ch18 §18.1 (→ Ch. 1 §1.8)
Generic names, practice of using — 41.9
Genericide — 41.1, CS 41.2
Genericization, ladder of — 41.1
Genericization, medical consequences — 41.2
generous drift — 37.10, CS2
GH axis — 3.3
GH axis, overall architecture — 14.1
GHK-Cu — 6.8
*GHK-Cu (copper tripeptide-1)* — 37.2 (split example), 37.5 (cosmetic ×2), CS2 (entry 3)
Ghrelin — 13.6, 15.3
Ghrelin receptor (GHS-R) — 15.1, 15.3, 15.4
Ghrelin receptor agonists for cachexia — 13.6
ghrelin, "hunger hormone" nickname (parallel case) — §21.9, ch21 §21.5, ch13 §13.6
Ghrelin, introduced — 3.7
GHRH (growth hormone releasing hormone) — 14.1
GHRH (growth hormone-releasing hormone) — 15.1, 15.2
GHRH receptor — 15.1, 15.2, 15.5
GHRH(1-29) — 15.2
GHRP-2 (pralmorelin) — 15.3, 15.8, 15.9
GHRP-6 — 15.3, 15.8, 15.9
Gigantism — 14.8
Gila monster — 4.CS1
Gila monster (Heloderma suspectum) — ch35 §35.1, dossier, §35.3
GIP — 7.5
GIP agonist versus antagonist paradox — 7.5
GIP and fat storage — 7.5
GIP antagonist approaches — 9.9
GIP blunted in type 2 diabetes — 7.5
GIP, introduced — 3.7
GIP-based sequence — 9.1
Glargine and isoelectric point — 11.6
Global Burden of Disease estimate (2019) — 25.1
GLP-1 (7-36 amide), numbering convention — 7.3
GLP-1 drugs, compounded market — 38.6
GLP-1 infusion studies — 7.CS1
*GLP-1 receptor agonists* — CS 39.1, guidance evolution, peri-operative considerations → 39.2
*GLP-1 receptor agonists (class)* — 37.5 (metabolic ×2, 37.7, society)
GLP-1 receptor agonists, societal effects of, §44.1 — 44.9 (whole chapter)
GLP-1, alignment with exendin-4 — ch35 §35.3
GLP-1, four actions — 7.3
GLP-1, human (7-37) — §33.8, §33.2
GLP-1, introduced — 3.7
*GLP-1, native* — 37.3, 37.5 (metabolic)
GLP-2 — §33.2
*glucagon* — 37.5 (approved pharmacopeia)
Glucagon receptor agonism — 9.6
Glucagon suppression — 7.3
Glucose-dependence — 7.4
Glucose-dependence of incretin action — 3.6
GLUT4 — 11.3
*glutamate* — 22.1, 22.4, co-release with substance P
Glycemic improvement before weight loss — 7.CS2
Glycemic target as negotiated position — 11.4
Glycemic variability — 8.2
Glycine, flexibility of — 1.2
glycosylation, and product identity — §16.4
GMP — §34.10, §34.9
GMP, verification by inspection — §34.10
GnRH agonist suppression paradox — 3.5
*GnRH agonists / antagonists* — 37.5 (oncology ×2, veterinary)
GnRH precedent (continuous stimulation producing suppression) — 15.6, case study 15.2
GnRH pulse frequency — 3.5
goserelin — 27.1 (table), 27.2, 27.8
GPCRs as drug targets — 2.3
GPCRs, inhibitory coupling — ch20 §20.3 (see also ch2)
Gram-negative outer membrane — 25.3, 25.5, 25.8
Gram-positive cell wall — 25.3, 25.5
gramicidin — 25.3, 25.7, 25.8
*gray market — structural inability to produce evidence → 39.10, see also* Ch 19 §19.8
Gray market, cultural demand and — 41.2, 41.8
gray market, structure of — five channels 19.1, 19.1
grip strength — §16.7
*growth hormone* — 37.5 (growth ×2), KT, Q item 18, EX B
Growth hormone axis, structure of — 15.1, 15.6
Growth hormone deficiency, adult — 14.3, 14.4
Growth hormone deficiency, childhood — 14.3
growth hormone receptor deficiency — §16.9
Growth hormone, generic name (somatotropin) — 14.1
Growth hormone, nocturnal pulses — 3.5
growth hormone, off-label marketing — 38.4
Growth hormone, structure and molecular weight — 14.1
growth hormone, WADA S2 — 38.8
Growth plate, longitudinal bone growth — 14.2, 14.3, 14.8
growth signaling, dilemma of — §16.9
*growth, repair, and performance* — 37.5
*growth-hormone-releasing peptides* — 37.5 (veterinary)
Guillemin, Roger — 27.2, 27.4
Gut as endocrine organ — 3.7
gut lumen, as drug target — ch18 §18.5
Gut-brain axis — 7.7
Gynecomastia — 14.7

H

Half-life — 4.3
*hard clinical outcome, durability of* — 37.7, 37.9, KT
Hard endpoint — 5.6
Hard endpoint versus surrogate — 8.5, 8.CS1
hard outcomes — 36.2, 36.5, 36.6
harmonization, pharmacopeial — §34.10
harms of conflating dependence with addiction — ch20 §20.6
Hassabis, Demis — ch35 §35.8
Hazard ratio — 5.7
Head-to-head trials — 9.5
head-to-tail — §33.3
Healthy adherer effect — 10.CS2
Heart as endocrine organ — 3.8
Hedges, probabilistic ("just saying it's likely") — 41.5
helical wheel — 25.2
hemolysis — 25.5
hepatitis B, thymosin alpha-1 indication — ch18 §18.3
Heritability, misuse of — 12.9
HERO (relugolix) — 27.3, 27.9
Heroin, as former trademark — 41.1
Hexamer — 11.2, 11.6
*hexapeptide-8, acetyl (Argireline)* — 37.5 (cosmetic), CS2 (entry 11)
HFpEF — 10.5
histamine release (antagonist design problem) — 27.3, case study 27.2
HIV-associated lipodystrophy — 15.5, case study 15.1
Honest ❌, why hard to write — 17.10
Hormone, coining of the term — 3.CS1
host defense peptides (term) — 25.2
How Peptides Are Made — Recombinant Production, and Why Peptide Drugs Cost, Solid-Phase Synthesis
HPA axis — 3.3
HPG axis — 3.3
HPLC — §34.3, §34.7, §34.4
HPLC, reversed-phase — §34.3, §34.4
HPT axis — 3.3
Huggins, Charles — 27.2, case study 27.2, epigraph
Human evidence situation, one-sentence statement — 17.6
*hydrocarbon stapling* — 37.5 (science)
hydrodynamic radius — §33.5
Hydrolysis — 1.3
hydrolysis, acid (in AAA) — §34.6
hype check, "supports and modulates immune function" — ch18 §18.6
Hype pipeline applied to BPC-157 — CS2
Hype pipeline, five stages — 6.1
Hype: "medically supervised" — 12.7
Hype: "same drug, tenth of the price" — 12.4
hyperplasia P**** — §16.1, §16.3
hypertrophy, muscle P**** — §16.1
*hypocretin — see* orexin
Hypoglycemia — 11.4
Hypoglycemia unawareness — 11.4
hypoglycemia, and IGF-1 — §16.2, §16.9
Hypoglycemia, mechanism of — 3.6
Hypoglycemia, why largely absent — 7.4
Hypothalamus — 3.2
Hypothalamus as integrator — 3.2
hypothalamus, oxytocin/vasopressin synthesis in — ch21 §21.1

I

icatibant — §33.2
*icatibant* — 37.5 (approved pharmacopeia)
ICMJE registration policy — 5.CS2
identity claims, hierarchy of strength — §34.6
identity failure — oxytocin/vasopressin 19.3, salt forms 19.5, 19.3
identity, as one of three questions — §34.2, §34.4
Identity, purity, potency, sterility, endotoxin — 17.9
Idiopathic short stature — 14.3
IGF binding proteins (IGFBP-3) — 14.2
IGF binding proteins (IGFBPs) P**** — §16.2
IGF-1 — 14.1, 14.2, 14.3, 14.7
*IGF-1 / IGF-1 LR3* — 37.5 (growth)
IGF-1 binding proteins — 15.7
IGF-1 LR3 P**** — §16.2, §16.8
IGF-1 receptor — §16.2, §16.9
IGF-1, as downstream messenger — 15.1, 15.7
IGF-1, as feedback signal — 15.1, 15.6
IGF-1, as precedent for growth-signal risk — ch18 §18.7 (→ Ch. 16)
IGF-1, introduced — 3.3
IGF-1R inhibitors, oncology programs — §16.9
IGFBP-3 — §16.2
Ileal brake — 7.2, 7.CS2
imaging corroboration — ch20 §20.7
Immortal time bias — 10.CS2
immune response, to administered proteins — §16.4
immune system, independence of arms — ch18 §18.6
Immunogenicity — 1.6, 1.7, 4.7
immunogenicity — 19.3, and related substances 19.3, and aggregation 19.3
Immunogenicity, unassessed — 17.9
immunomodulatory roles — 25.2, 25.4
import — 19.9
import and possession rules, not advised on — 38.9
impurity profile, of synthetic peptides — §34.3
In vitro studies, limits of — 5.2
in-group favoritism — ch21 §21.5
Incentive structure of the pipeline — 6.7
INCI names — 1.8
inclusion body myositis — §16.4
Incretin effect — 3.7
Incretin effect reduced in type 2 diabetes — 7.1
Incretin effect, experiment — 7.1
Incretin research timeline — 7.CS1
Incretin, origin of the term — 7.1
independence, as outcome — §16.7, §16.6
Independent replication, information value of — 17.5
Index test, defined — 41.3
indication — 38.1
indication as part of — ch18 §18.3
Indication, versus molecule — 41.2, 41.9
Indirect mechanism, counting steps — dossier
Induced fit — 2.2
Inelastic demand — 11.CS2
*infectious disease and immunity* — 37.5
Inflammation as common thread — 10.1, 10.9
Inflammatory markers — 8.6, 8.CS1
Information loss, compounding — 6.1
Inhaled insulin — 4.CS2
Injector-pen assembly — 12.3
innate immunity — 25.4, 25.2
*insomnia — 22.6*, orexin antagonists
insulin — 19.10 (peptide, not the risk word)
Insulin analogs — 11.6
*insulin analogs* — 37.2 (split example), 37.5 (metabolic)
Insulin and glucagon — 3.6
Insulin antagonism (counter-regulatory action) — 14.2, 14.7, 14.8
insulin degludec — see continuity note), (cut from final text
insulin detemir — §33.4
insulin glargine — §33.4
Insulin pricing — 11.9, 11.CS2
Insulin pump — 11.7
Insulin rationing — 11.CS2
Insulin receptor as tyrosine kinase — 11.3
insulin receptor, IGF-1 cross-reactivity — §16.2
Insulin resistance and hyperglycemia — 14.7, 14.8
Insulin resistance, GH axis and — 15.4, 15.5
Insulin sequencing — 1.CS1
Insulin structure, two chains — 11.2
Insulin tolerance test — 14.3
Insulin, as reverse genericization failure — CS 41.2
insulin, deemed a biological product — 38.2
insulin, residue count — 38.2
insulin-like growth factor 1 (IGF-1) P**** — §16.2
Intake questionnaires, design of — 12.7
Intelligent readers as vector — 6.9
Intensive lifestyle support in obesity trials — 5.5
Intensive versus conventional control — 11.CS1
interaction checking — 19.7
*interactions, drug* — cannot be checked against an undisclosed compound → 39.2
interchangeability — 38.2
intergroup conflict, oxytocin experiments on — ch21 §21.5
Interim analysis boundary — 10.CS1
Intestinal epithelium as barrier — 4.1
Intranasal delivery — 4.4
intranasal delivery question — ch21 §21.6
intranasal oxytocin trials — ch21 §21.7
Intrathecal administration — ch35 §35.4
intrathecal requirement — ch20 §20.9
intrathecal ziconotide, severe chronic pain, refractory — ✅ — ch20 §20.9
Intrinsically disordered peptides — key terms, ch35 §35.8
Inverse agonist — 2.5
Inverse care law — 12.8
Investigational New Drug application (IND) — 38.3
Ipamorelin — 15.1, 15.3, 15.8, dossier
isomers, indistinguishable by mass — §34.2
isotopic pattern, as compositional information — §34.2

J

Joke, as information vector — 41.6
Joke, immunity from evaluation — 41.6
Jumper, John — ch35 §35.8
Justification tax — 41.8

K

K cell — 7.5
kappa receptor (OPRK1) — §20.9, ch20 §20.3
keeps all of its consequences — ch18 §18.7
Kinase — 2.3
*kisspeptin* — 37.5 (neuropeptides)
Klebsiella pneumoniae — 25.1, 25.8
Kobilka, Brian — 2.CS1
KPV — ch18 §18.5
*KPV / larazotide* — 37.5 (infectious)
KPV as C-terminal fragment of — ch18 §18.5
KPV studied under its own name — ch18 §18.5

L

L cell — 7.2
Label clause, "as an adjunct to a reduced-calorie diet" — 12.6
label, approved — 38.1, 38.5
labor augmentation — ch21 §21.2
labor induction — ch21 §21.2
Laboratory code vs generic name — 17.2
lanreotide — 27.1 (table), 27.4, 27.9, dossier (Field 7 worked example)
larazotide — ch18 §18.5
Laron syndrome — 14.8, §16.9
Laughter, as receipt for a shared premise — 41.6
Lean mass loss — 8.8
lean mass loss during weight loss — 36.5, 36.6
Lean mass measurement, confounded by fluid — 15.4, 15.7
lean mass P**** — §16.6
lean mass, as surrogate endpoint P**** — §16.6
Lefkowitz, Robert — 2.CS1
legal advice, disclaimer of — 38.1, 38.6, 38.9
Legal fiction — 6.4
legality — verify locally 19.9, 19.9, six questions diagram 19.9, jurisdictional variation 19.9
*lemborexant* — 22.6
length (31 residues) — ch20 §20.2
Leptin — 13.2
*leptin / metreleptin* — 37.5 (metabolic ×2)
Leptin receptor deficiency — 13.4, 13.5
Leptin resistance — 13.2
leucine/isoleucine, identical residue mass — §34.2
Leuprolide — 3.9
leuprolide (leuprorelin) — 27.1 (table), 27.2, 27.8, 27.9, case study 27.2
Lever versus diagnosis — 12.9
Lifestyle support in trials — 8.3
Ligand — 2.2
Limitations paragraph — 6.2
limits of — ch20 §20.7
Limits of the incretin explanation — 7.9
*linaclotide* — 37.5 (approved pharmacopeia)
line of therapy — 27.5, 27.6, dossier
lipid A — 25.3, 25.8
Lipid changes — 8.6
lipidation — §33.4, §33.8
lipidation / albumin binding, ✅ — §33.4
Lipidation as a general strategy — 4.5
Lipolysis — 14.2
lipopolysaccharide (LPS) — 25.3, 25.4, 25.5, 25.8
liraglutide — §33.4, §33.8
Liraglutide, as engineered successor — ch35 §35.3
List price (WAC) — 12.1
List price versus net price — 11.9, 11.CS2
livestock research* — §31.3, case study 1
LL-37 — 25.3 (as efflux substrate), ch18 §18.4 (→ Ch. 25), 25.4
loading, mechanical P**** — §16.1
Local gut action vs systemic delivery — 17.8
Local versus systemic GLP-1 action — 7.6, 7.7
local-action defense, limits of — ch18 §18.5 (→ Ch. 4)
Locally acting oral peptides — 4.4
Lock-and-key model, limits of — 2.2
Long half-life, reversibility problem — 4.3
Long-term safety surveillance — 14.7
Longevity and reduced GH/IGF-1 signaling — 14.4, 14.8
losartan / angiotensin receptor blockers — §33.7
lot number, as unverifiable hinge — Case Study 34.1, §34.7
low abuse liability — ch20 §20.3
lutetium Lu 177 dotatate — 27.1 (table), 27.5, 27.9, case study 27.1, dossier
*lutetium Lu 177 dotatate (PRRT)* — 37.5 (oncology)
lutetium Lu 177 vipivotide tetraxetan — 27.6, 27.9
lutetium-177 dotatate — 36.7
Lysine as attachment point — 1.2, 1.4

M

MACE — 8.5
Macleod, J.J.R. — 11.1
macrocycles — §33.7, §33.3
magainins — 25.7, 25.4
Magainins — key terms, ch35 §35.4
magnocellular neurons — ch21 §21.1, §21.2
manufacturing capacity, peptide — 36.3, 36.9
Marker versus cause — 5.CS1
market entry rewards — 25.6
market failure, antibiotics — 25.6
marketing authorization — 38.9
Marketing language, phrase-by-phrase analysis — 14.6
marrow suppression — 27.5, 27.6
MASLD and MASH — 10.4
mass spectrometry — §34.7, §34.2
*mass spectrometry, identity by* — 37.5 (science)
mass spectrometry, tandem (MS/MS) — §34.2, §34.6
mass versus function P**** — §16.6
mass-to-charge ratio — §34.2
*master table* — 37.5 (all ten blocks)
MC4R — 13.4, 13.5
mcr / *mcr-1 — 25.8, Case Study 25.1, 25.3*
*mecasermin* — 37.5 (growth)
mecasermin P**** — §16.2
Mechanical versus metabolic explanation — 10.5, 10.6
mechanism of membrane disruption — 25.3
Mechanism versus outcome — 2.9
Mechanism, inferred from downstream observation — 17.2
Mechanism, insufficiency of — 14.6, 14.9
*mechanism, limits of reasoning from — 22.5, 22.5, 22.9*, and Chapter 2 §2.9
*mechanism, prohibition on upgrading with* — 37.2 (rule 3), 37.5 (oncology, 37.7 (callout)
Mechanistic knowledge and susceptibility — 6.9
mechanotransduction — §16.1
Media, menace register — 6.5
Media, miracle register — 6.5
Medication history, accuracy of — 41.2
Medullary thyroid carcinoma — 8.7
MedWatch — 19.8, further reading
Melanocortin pathway — 13.4
*Melanotan II* — 37.5 (cosmetic, pointer from neuropeptides)
melphalan flufenamide — 27.7, dossier
membrane disruption — 25.3
membrane selectivity problem — ch18 §18.4
MEN2 — 8.7
meningitis outbreak (2012) — 19.5, 19.6, 19.10, case study 19.2
message-address concept — ch20 §20.2
Meta-analysis — 5.2
Metabolic adaptation — 12.9
*metabolic and weight* — 37.5
Metabolic memory / EDIC — 11.CS1
Metreleptin — 13.2
mice, myostatin-null — Case Study 16.2, §16.3
Microvascular complications — 11.CS1
*migraine — 22.9, as well-defined indication, 22.7*, CGRP
milk ejection — ch21 §21.2
milk ejection reflex — ch21 §21.2
Minimal clinically important difference — 17.11
minimum inhibitory concentration (MIC) — 25.5
Miracle and menace registers — CS2
Misattribution, versus silence — 41.4
MK-677 (ibutamoren) — 15.4, 15.8, 15.9
*MK-677 (ibutamoren)* — 37.2 (rule 4), 37.5 (growth), CS2 (entry 4)
MK-677, not a peptide — 15.4
model artificiality, animal injury — ch18 §18.2
moderators of oxytocin effects — Dossier, ch21 §21.5
Modified GRF(1-29) — 15.2, 15.6
*monitoring* — what supervision adds → 39.9, unavailable for undisclosed exposure → 39.2
Monitoring, what a clinician adds — 14.9
Monogenic obesity — 13.4, 13.5
monograph, pharmacopeial — §34.10
monoisotopic mass — §34.2
Monopsony — 12.1
morphine — §33.7, ch20 §20.1, §20.3
Mortality gradient with biochemical control — 14.8
Motivated reasoning — 6.9
Mounjaro — 9.2
MRI muscle volume — §16.6, §16.5
mRNA display — ch35 §35.6, key terms
mTOR pathway — §16.1
mu receptor (OPRM1) — §20.9, §20.6, ch20 §20.3
Mu-opioid receptor — 2.CS2
multi-agonist design — §33.9
multi-agonists — 36.5
murepavadin — 25.5, 25.7
muscle protein breakdown — §16.1
muscle protein synthesis — §16.1
muscular dystrophy trials P**** — Case Study 16.1, §16.5
myelodysplastic syndrome / acute leukemia after PRRT — 27.5, case study 27.1
myoepithelial cells — ch21 §21.2
myometrium, oxytocin receptor density in — ch21 §21.2
myonuclear domain — §16.1
myostatin (GDF-8) P**** — §16.3
*myostatin / follistatin inhibitors* — 37.5 (growth)
myostatin and activin type II receptors — 36.6
myostatin inhibitors, performance claims — §16.8
myostatin, human loss-of-function case report — Case Study 16.2, §16.3

N

N-methylation — §33.7, §33.3
N-terminus and C-terminus — 1.3
N-terminus as activating region — 7.3
N-type calcium channel block — ch20 §20.9
NAD+ precursors — 6.8
NAFLD and NASH, renaming — 10.4
naloxone — ch20 §20.1, case-study-01, §20.4, §20.7
naloxone reversal — case-study-01, ch20 §20.7
Naloxone, genericization in progress — CS 41.2
naltrexone — ch20 §20.5
naming conventions (-relin / -relix) — 27.3, case study 27.2, see also Ch 1 §1.8
naming, "TB-500 (Thymosin Beta-4)" construction — ch18 §18.1
Naming: laboratory codes versus generic names — 15.2, 15.8
*narcolepsy type 1 — 22.6, treatment gap, cataplexy, CSF orexin-A, 22.6*
Narrative review, citation drift through — 17.6, CS2
Narrow indication, informational value of — 15.5, case study 15.1
Natural experiment, reasoning from — 14.8
Natural history — 6.3
Nausea, mechanism of — 7.3, 7.7
Negative feedback — 3.4
Negative feedback, GH axis — 14.1, 14.3, 15.1, 15.6
Negative reports, dismissal of — 6.3
Neisseria gonorrhoeae — 25.3
*neoantigen vaccines, individualized* — 37.5 (oncology)
Neovascularization, aberrant, in tendinopathy — 17.7
nephrotoxicity — 25.5, 25.8
nephrotoxicity and renal-protective amino acid infusion — 27.5, dossier
Neprilysin inhibition — 3.8
Nesiritide — 3.8
*nesiritide — 37.3, 37.5 (cardiovascular), 37.9, as instance of "it doesn't work" → 39.6, KT, see also* Ch 28, CS1
nesiritide, approval and outcome trial — 38.10
Net price — 12.1
net protein balance P**** — §16.1
NETTER-1 — 27.5, 27.9, case study 27.1
NETTER-2 — 27.5, case study 27.1
neurodiversity — ch21 §21.7
neurodiversity framing — ch21 §21.7
*neurokinin A* — 22.4
*neurokinin B* — 22.4
*neuromodulation — 22.1*
Neuromodulator — 2.1
*neuropeptide Y* — 37.5 (neuropeptides)
*neuropeptide Y (NPY) — 22.2, structure, 22.2, appetite role, abundance, 22.3*
*neuropeptides and behavior* — 37.5
Neuroprotection models — 17.3
neurotoxicity — 25.8
Neurotransmission — 2.1
nicknames, hormone — ch21 §21.9, ch13 §13.6, §21.5
Nicotinamide riboside — 6.8
Nine in ten attrition rate — 17.1, 17.5
nisin — 25.7
nitrogen determination, for content — §34.4
Nitrogen retention and protein sparing — 14.2
*NK1 receptor — 22.4, 22.5*, species differences in, antagonist programs
*NK1 receptor antagonists* — 37.3, 37.5 (neuropeptides ×2), KT, CS2 (entry 9)
*NK2, NK3 receptors* — 22.4
no established link to chapter compounds — ch18 §18.7
Nobel Prize 1923 — 11.1
Nobel Prize 1966 (Physiology or Medicine) — 27.2
Nobel Prize 1977 (Physiology or Medicine) — 27.2
Nobel Prize in Chemistry (1955) — ch21 §21.1
nocebo — ch20 §20.7
nociceptin / orphanin FQ — ch20 §20.2, §20.3
nociception versus pain — ch20 §20.4
Nocturnal secretion and slow-wave sleep — 14.1, 14.4
non-absorption as design specification — ch18 §18.5
non-approval as proof of absence, error of — 38.10
non-approved substances (WADA S0) — 19.9
*non-disclosure* — consequences worked through → CS 39.1, documented pattern → 39.2
non-opioid placebo effects (dopamine, CCK) — ch20 §20.7
non-proteinogenic residues — §33.2
nonapeptide — ch21 §21.1
NOP receptor (OPRL1) — ch20 §20.2, §20.3
*norepinephrine* — 22.2, co-storage with NPY
nose-to-brain transport — ch22, ch21 §21.6
nosebleeds, as class safety signal — §16.5
*NOT RATED* — 37.4 (table and discussion), 37.5 (society block), 37.8 (distribution), KT
NOT RATED, as a rating outcome — 41.4
NPH and protamine — 11.6
NT-proBNP as biomarker — 3.8
nucleus accumbens, vole receptor distribution — ch21 §21.3
Nucleus tractus solitarius — 7.7
null results, weight of — ch20 §20.5, exercises D4
Number needed to treat — 5.7, 12.2
Number transmission chain — 9.CS1
Nutrient-triggered release — 7.2

O

ob/ob mouse — 13.2, 13.CS1
*obesity* — 22.2, NPY antagonist programs
Obesity as behavior — 12.9
Obesity as disease — 12.9
Observational data, benefit versus harm asymmetry — 10.CS2
obstetric use (✅) — ch21 §21.2
Obstructive sleep apnea — 10.6
occurs with appropriate therapeutic use — ch20 §20.6
octreotate — 27.5
octreotide — 27.1 (table), 27.4, 27.5, 27.9, §33.3
Off-label legitimacy spectrum — 12.6
Off-label prescribing — 12.6
off-label prescribing — 38.5
off-label promotion, prohibition of — 38.5
olfactory pathway, drug transport via — ch21 §21.6
Oliceridine — 2.CS2
Oligopeptide — 1.5
omapatrilat program (combined neprilysin — Case Study 28.2, 28.6, ACE inhibition)
omiganan — 25.7
*oncology* — 37.5
Ondetti, Miguel — ch35 §35.4
One molecule versus two drugs — 9.1
One molecule, many ratings — 10.10, 14.9
one system, many ratings — dossier, ch20 §20.7
One-dollar patent — 11.1, 11.9
opioid receptors, discovery of — ch20 §20.1
opioid-induced hyperalgesia — §20.6, ch20 §20.4
opiorphin — ch20 §20.9
Oral activity of non-peptide secretagogues — 15.4
Oral bioavailability — 8.4
Oral bioavailability of peptides — 1.6
oral endorphin-boosting supplements / DL-phenylalanine — ❌ — ch20 §20.8
Oral gauntlet, five barriers — 4.1
oral peptide problem — 36.3
Oral semaglutide — 4.6
oral semaglutide — 36.3, 36.9
Oral semaglutide, 1% bioavailability as benchmark — 17.8
Oral semaglutide, bioavailability of — 1.6
*orexin (hypocretin) — 22.6, 22.6*, discovery and dual naming, wakefulness stabilization
*orexin receptor antagonists, dual* — 37.5 (neuropeptides)
Orforglipron — 9.8
orforglipron — 36.3, 36.10, §33.7
*orforglipron* — 37.5 (metabolic)
Origin coda — ch35 dossier
Origin, evidentiary weight of — §35.3 (In the Clinic), ch35 dossier
Orphan compound problem — 17.11
Orphan drug incentives — 13.CS2
orthogonal methods — §34.3, §34.6
osmoreceptors — ch21 §21.8
out-group hostility/defensiveness — ch21 §21.5
Out-of-pocket cost — 12.1
Outcome switching — 5.10
Outcome-evidence gap, by compound — 15.8
overall survival vs progression-free survival — 27.4, 27.5, 27.9, case study 27.1
Override versus replace — 8.9
oversight, why analysis does not substitute — §34.9
*OX1R, OX2R (orexin receptors)* — 22.6
*oxytocin* — 37.5 (neuropeptides ×4), 37.9, CS2 (entry 7)
Oxytocin and vasopressin receptor cross-reactivity — 2.2
oxytocin infusion and — ch21 §21.1, §21.7
oxytocin receptor (OXTR) — ch21 §21.1, §21.2
Ozempic — 8.2

P

P-value — 5.7
package-deal effects — ch20 §20.3
pair bond — ch21 §21.3
*palmitoyl pentapeptide-4 (Matrixyl)* — 37.5 (cosmetic)
Pancreatic islet, delta cells — 3.6
*pancreatic polypeptide (PP)* — 22.2, NPY family
Pancreatitis signal — 8.7
Panning cycle — key terms, ch35 §35.6
Parabiosis experiments — 13.CS1
Paracrine signaling — 2.1
Paracrine-to-systemic problem in drug design — 2.1
Partial agonist — 2.5
partner preference assay — ch21 §21.3
patchwork, international regulatory — 38.9
patent expiry, jurisdictional variation — 36.9
Patient-derived hypotheses — 10.8
Payer case against coverage — 12.2
PEGylation — §33.5
Pentadecapeptide — 17.2
Pepsin — 4.1
peptibody — §33.6
*peptide* — science), drug conjugates — 37.5 (oncology, MHC recognition** — 37.5 (infectious)
Peptide as message, not actor — 2.1
Peptide bond, formation of — 1.3
Peptide Discovery — From Venom to Artificial Intelligence*
Peptide versus protein convention — 1.5
Peptide YY — 13.6
*peptide YY (PYY)* — 22.2, opposing action, NPY family
Peptide YY, introduced — 3.7
peptide-drug conjugate — 27.7, 27.9
peptide-drug conjugates — 36.7
peptidomimetic — 27.6
Peptidomimetic — key terms, ch35 §35.4
peptidomimetics — 25.7, 36.3, §33.7
peptidomimetics at class B GPCRs, ⚠️ — §33.7
Perfusion as unifying mechanism, proposed — 17.3, 17.4
periaqueductal gray — §20.7, ch20 §20.4
peripheral restriction as design — ch20 §20.9
PET ligand for oxytocin receptor — case study 2, ch21 §21.6
pexiganan — 25.4, 25.7
Phage display — key terms, ch35 §35.6
phagosome — 25.4, 25.5
*pharmacists* — scope and limits → 39.5, as underused resource → 39.5
pharmacopeia — §34.10
pharmacovigilance — absent in gray market 19.8, 19.8
Pharmacovigilance, absence of pathway — 17.9
Pharmacy benefit manager — 12.1
Phase 1 — 38.3
Phase 2 — 38.3
Phase 2 optimism — 9.6, 9.CS2
phase 2 optimism — 36.2, 36.5
Phase 2 versus Phase 3 — 9.6, 9.CS2
Phase 3 — 38.3
Phase 4 and post-marketing surveillance — 38.3
Phase I, absence of published — 17.6, 17.9
Phase II optimism — 5.4
physical dependence — ch20 §20.6
PI3K/Akt pathway — §16.2
Picomolar concentration — 2.4
Piedmontese cattle — §16.3
PIONEER program — 8.4
Pipeline as of 2026 — 9.9
Pituitary adenoma — 14.8
Pituitary, anterior — 3.2
placebo analgesia — case-study-01, ch20 §20.7
placebo analgesia mediated by endogenous opioids (acute/postop, adults) — ✅ — ch20 §20.7
plasma oxytocin, rise after intranasal dosing — ch21 §21.6
polymerization, and cell motility — ch18 §18.1
polymyxin B — 25.7, 25.8
Polypeptide — 1.5
POMC (proopiomelanocortin) — ch20 §20.2
POMC neurons — 13.4
Population in trials — 5.5
Population swap error — 8.3
Population, comparator, measurement questions — 5.1, 5.5
Portal circulation — 3.2
Position 34 substitution — 4.5
Position 8 substitution — 4.5
post-hoc explanation, dystrophy trial results — §16.8, §16.5
Post-marketing surveillance — 5.4
*post-traumatic stress* — 22.3, NPY associations
posterior pituitary — ch21 §21.1
postpartum hemorrhage — ch21 §21.2
Potency — 2.6
Potency, picomolar — 1.7
Powering and duration — 5.5
prairie vole — ch21 §21.3, case study 1
Pramlintide — 13.3
*pramlintide* — 37.5 (metabolic)
Pre-specified endpoints — 5.5
Precision medicine, narrowness of — 13.5, 13.CS2
Preclinical package, strength of — 17.4
Preclinical paper, anatomy of — 6.2
Preclinical research, unregistered — 17.5
Predatory journals — 5.10
predictive validity* — §31.5
preparation problem — described without instruction 19.6, 19.6
Preprints — 5.10
prepronociceptin — ch20 §20.2
preregistration — ch21 §21.4
*prescription* — not evidence → 39.8, rated ❌ → 39.8, as clinical judgment
press releases, topline — 36.2, 36.5
Prevalence, versus cultural salience — 41.6
Primary prevention, not studied — 8.CS1
Primary structure — 1.4
Prions — 3.CS2
Prior authorization — 12.2
prior malignancy, clinical asymmetry — ch18 §18.7
Privacy, medical, as default — 41.4
procedural non-standardization — ch21 §21.6
*procedures with sedation* — breadth of → 39.2
process control, documented — §34.10, §34.9
process simulation — Case Study 34.2
process vs endpoint testing — Case Study 34.2, §34.9
Product risk vs molecule risk — 17.9
Productive suffix, "-face" construction — 41.3, CS 41.1
prodynorphin — ch20 §20.2
proenkephalin — ch20 §20.2
Proglucagon — 7.2
Progressive loading program — 17.7, 17.11
Prohibited List (WADA) — 38.8
prohormone convertases — ch20 §20.2
proinsulin, structural relation to IGF-1 — §16.2
prolactin, distinguished from oxytocin's role — ch21 §21.2
proliferation, cell — ch18 §18.7
Proline run, structural consequence — 17.2, 17.8
Proline, helix disruption by — 1.2, 1.4
Proline-rich protease resistance argument — 17.8
PROMID — 27.4, 27.9
Proteases and peptidases — 1.3
proteases, bacterial, as resistance — 25.3
protein intake, and resistance training — §16.7
ProteinMPNN — key terms, ch35 §35.9
Proteolysis in circulation — 4.2
proteolysis, as an exit — §33.1, §33.8
prothymosin alpha — ch18 §18.3
Protopathic bias — 10.CS2
Proven mechanism does not generalize — 13.5
*provocation study — 22.7, 22.9*
PRRT — 36.7
Pseudomonas aeruginosa — 25.1, 25.5, 25.7, 25.8
PSMA-617 — 27.6
*PSMA-targeted radioligand therapy* — 37.5 (oncology)
PTH(1 — see teriparatide, 34)
Public funding of basic science — 12.1
public structure release — ch35 §35.8
Publication bias — 5.CS2
publication bias, in testing programs — §34.8
publication filtering — ch18 §18.2
publication filtering in — ch18 §18.2
PubMed filters, RCT and Humans — 17.6
Pulmonary delivery — 4.CS2
Pulsatile secretion — 14.1, 14.3, 14.8
Pulsatile secretion of growth hormone — 15.1, 15.6
pulsatile secretion, oxytocin — ch21 §21.2, ch3
Pulsatile versus continuous stimulation — 2.8
Pulsatility — 3.5
pulsatility principle applied — 27.2, see also Ch 3 §3.5
Pulse amplitude versus frequency — 14.4
purity — related substances 19.3, 19.3, vs content 19.3
purity, as one of three questions — §34.4, §34.3
purity, four limitations of — §34.3
purity, identity, and concentration as independent questions — ch18 §18.1 (→ Ch. 34)

Q

Qualifier loss — 9.CS1
Quality of life outcomes — 8.6
Quaternary structure — 1.4

R

R group / side chain — 1.2
racehorses, veterinary use — Dossier (→ Ch. 31), ch18 §18.1
radioligand therapy — 27.5, 27.6
Random coil — 1.4
Randomized controlled trial — 5.2
Rapid-acting analogs — 11.6
Rate-limiting step — ch35 §35.10, key terms
rated ⚠️ — §18.8, ch18 §18.3
rated ❌ — §18.8, ch18 §18.2
rated ❌ as a claim form — ch18 §18.6, §18.8
rating a claim form rather than a molecule — ch18 §18.6 (→ Ch. 9)
*rating discipline* — rule 1 (claims not molecules) →, ❌ as a statement about evidence → 39.6
*rating drift* — 37.9, 37.10
Rating rules, applied — 15.9
*rating system, four tiers restated* — 37.2
Rating the comparison, not the ingredient — 13.8
Ratings attach to claims not molecules — 1.9
Reader variability — 10.4
Reading a drug label — 4.6
Reading a pipeline announcement — 9.10
Rebate structure — 12.1, 12.8
Rebound — 3.4
recall pathway — 19.1, §34.1, requires knowing who has the product 19.8, §34.9
receptor desensitization and downregulation — ch20 §20.6 (see also ch2 §2.7–2.8)
Receptor desensitization as functional antagonism — 7.5
Receptor internalization — 2.7
Receptor, absence of established — 17.2
Receptor, definition of — 2.2
receptor-mediated transcytosis — 36.8
Receptors in unexpected tissues — 10.1
Recombinant growth hormone — 3.CS2
Recombinant insulin 1982 — 11.6
Recombinant production, effect on supply — 14.1, 14.6
Red flags in studies — 5.10
*redundancy in signaling systems* — 22.2, 22.5
reference standard — §34.4
Reference standard, unavailability of — 41.3
*refusal to rate is not a rating* — 37.4, KT
Regain on discontinuation — 12.8, 12.9
regioselectivity — §33.8
Regression to the mean — 5.2, 6.3, 17.7, 9.CS2, CS2
Regulated supply chain, value of — 6.CS1
regulatory divergence — ch18 §18.3
Regulatory history vs pharmacology, distinction — 17.2
Relative risk reduction — 12.2
Relative versus absolute reduction — 8.5, 8.CS1
Relative versus absolute risk — 5.8
release (batch) — see batch release
Releasing hormone — 3.2
relugolix — 27.3 (precision note: not a peptide), 27.9
Renal clearance of peptides — 2.7
Renal filtration of peptides — 4.2
renal filtration, as an exit — §33.1, §33.4, §33.8
Replacement versus override — 11.5, 11.8, 14.3, 14.4, 14.9
replication crisis, behavioral science — ch21 §21.4
Replication, expected failures — 10.1
reporting pathway, absence of — 19.8
Research chemical designation — 6.4
Research codes as names — 1.8
Research concentration in few groups — 17.5
research-grade material, distinction from pharmaceutical — §34.1
Research-grade versus prescription product — 4.8
Residual payer — 12.1, 12.8
residual solvents and process chemicals — 19.3
Residue, definition of — 1.3
resistance mechanisms against — 25.3
resistance training and protein intake — 36.6
resistance training P**** — §16.7, §16.1
resistance training, in older adults — §16.7
resolving observation, bidirectional — 25.9, Dossier
response factor — §34.3
Retatrutide — 9.6
retatrutide — 36.5
*retatrutide* — 37.5 (metabolic ×2)
Retrospective explanation, limits of — 13.7
Reverse causation, body fat and GH — 14.4
Reverse walk, five questions — CS2
RFdiffusion — key terms, ch35 §35.9
Rhodopsin — 2.CS1
Ribosome display — ch35 §35.6, key terms
Rimonabant — 8.CS2
Rodent thyroid C-cell tumors — 8.7
romiplostim — §33.6
rostral ventromedial medulla — ch20 §20.4
route 1, find it in nature — ch35 §35.1, §35.2–§35.4
route 2, modify an endogenous ligand — ch35 §35.1, §35.5
route 3, select from a library — ch35 §35.1, §35.6
route 4, design computationally — ch35 §35.1, §35.7–§35.9
route of administration, as prior question — case study 2, ch21 §21.6
Rudman study (1990) — 14.5, 14.6
rule 3 (never upgrade with mechanism) — ch21 §21.3
Rule 3, mechanism cannot upgrade — ch18 §18.1, §18.7
rule 4 (never downgrade with distaste) — ch21 §21.5
Rule 4, distaste cannot downgrade — §18.7, ch18 §18.2
rule 5 (falsifiable) — ch21 §21.9
Rule 5, ratings must be checkable — ch18 §18.4
rule 6 (one molecule, many ratings) — ch21 §21.2, §21.9
runner's high — case-study-02, ch20 §20.5
Rybelsus — 8.4
Rybelsus, Ozempic, Wegovy — 41.2, different products — 41.1, same molecule

S

S0 (Non-Approved Substances) — 38.8
S2 (Peptide Hormones, Growth Factors) — 38.8
*sacubitril/valsartan* — 37.5 (cardiovascular)
Safety signal, misattribution of — 41.2, 41.8
Salmonella — 25.3
salt forms — 19.5, case study 19.1, semaglutide sodium/acetate 19.5
Salt forms (semaglutide sodium, semaglutide acetate) — 12.5
Salt forms, what they can and cannot change — 17.8
Sampling error in biopsy — 10.4
sampling, low power against low-level contamination — Case Study 34.2, §34.9
Sanger, Frederick — 1.CS1
Sanger, insulin sequencing (Ch 1 callback) — §34.6
sarcopenia in older adults — 36.6
sarcopenia P**** — §16.7
Sarcopenic obesity — 8.8
satellite cells P**** — §16.1
*saturable transport* — 22.8
Schally, Andrew — 27.2
schizophrenia, oxytocin trials in — ch21 §21.7
*science, technology, and society* — 37.5
Search ranking and evidence — 6.6
Second messenger — 2.3
Second-order effects — 41.8
Secondary structure — 1.4
Secretagogue rationale, origin of — 3.4, 3.CS2
Secretin — 3.7, 3.CS1
*sedation* — retained gastric contents and → 39.2
SELECT — 10.2
SELECT trial — 5.8, 8.5, 12.2, 12.8, 8.CS1
Selectivity as concentration-dependent — 2.2
selectivity index — 25.7, 25.9, 25.5
Selectivity of venom peptides, economic explanation — ch35 §35.2
selectivity problem — 25.5
Selectivity versus safety — 15.3
Selectivity, pharmacological — 15.3
self-reported evidence, limits of — §16.8
semaglutide — §33.4, §33.8, evidence attaches to product not formula 19.10, §33.2, case study 19.1, Dossier, compounded 19.5
*semaglutide — 37.5 (metabolic ×9), 37.7 (all eight distinct claims)*, CS2 (entry 1), KT
Semaglutide for weight loss, rating — 5.12
Semaglutide salt forms — 6.CS2
Semaglutide, origin — ch35 §35.1, §35.3, dossier
semaglutide, residue count and classification — 38.2
Semaglutide, three modifications — 4.5, 8.1
*Semax / Selank* — 37.5 (neuropeptides), CS2 (entry 12)
Sentence ladder — CS1
separating two confidences — ch18 Dossier
sepsis, thymosin alpha-1 trials — ch18 §18.3
sequence determination — §34.2, §34.6
Sequence reading, one- and three-letter codes — 1.4
Sequence space, searched by design vs. selection — ch35 §35.9
sequences — ch20 §20.2
Sermorelin — 15.2, 15.8, 15.9
*sermorelin / GHRP-2 / GHRP-6* — 37.5 (growth)
serotonin, "happiness chemical" nickname — ch21 §21.9
Set point — 3.4
Set point, defended — 12.9, 13.1, 13.7
Setmelanotide — 13.5, 13.CS2
*setmelanotide* — 37.5 (metabolic)
Seven steps from compound to outcome — 15.7
Seven-step gap — 2.9
Seven-transmembrane architecture — 2.3
severe drift — 37.10, CS2
severe primary IGF-1 deficiency P**** — §16.2
shared with α-MSH / appetite system — ch20 §20.2 (see also ch13)
Short Physical Performance Battery — §16.7
Shortage list, FDA — 12.4, 12.5
Shortage, distributional effects of — 41.8
Shortage, GLP-1 — 12.3, 12.4
shortages, GLP-1 drugs — 36.9
Sibutramine — 8.CS2
side-chain-to-side-chain — §33.3
Signal termination — 2.7
Signal transduction — 2.3
six components (population, endpoint, comparator, duration, size, blinding) — ch35 dossier
Six moves for writing an honest ❌ — Dossier
Six rules for ratings — 5.11
six-minute walk distance — §16.7, §16.6, §16.5
Sixty-second first response — 6.10
Size spectrum of therapeutic molecules — 1.6
Sleep apnea — 14.8
Slipped capital femoral epiphysis — 14.7
Smad2/Smad3 — §16.3
Small molecules as drugs — 1.6
Small trials, when adequate — 13.CS2
Small-molecule GLP-1 agonist — 9.8
Smart insulin — 11.7
Smith, George — ch35 §35.6
SNAC — 36.3
SNAC permeation enhancer — 4.6
*snapshot, chapter as* — 37.1, 37.9, Conclusion
social anxiety disorder, oxytocin trials — ch21 §21.7
Social fact, established by jokes — 41.6
Social prediction — Dossier, final, dossier entry
social salience hypothesis — ch21 §21.5
Sodium and water retention — 14.2, 14.7
*solid-phase peptide synthesis (Merrifield)* — 37.5 (science)
solid-phase synthesis, scale limits — 36.9
Somatopause — 14.4
Somatostatin — 14.1
somatostatin — §33.3
somatostatin (native) — 27.4
*somatostatin analogs* — 37.5 (oncology ×2)
Somatostatin as brake — 3.3, 3.6
somatostatin receptors (SSTR1 — 27.5, 5) — 27.4
Somatostatin, as brake on GH release — 15.1, 15.6
Somatotroph — 14.1
source hierarchy, pipeline claims — 36.2
spacer chemistry — §33.4, §33.8
Species specificity of growth hormone — 3.CS2
Species specificity of the GH receptor — 14.1
specific force P**** — §16.6, §16.3
specification, definition of — §34.7, §34.10
Specificity of peptide binding — 1.7
specificity, of an analytical method — §34.3
Speculation economy — 41.5
spinal cord compression (flare risk) — 27.2, case study 27.2
*split ratings* — 37.2 (three kinds), 37.5 (cosmetic block), 37.8, KT
Split ratings (⚠️→❌) — 15.8, 15.9
split regulatory status — ch18 §18.3
stability program, and expiry — Case Study 34.1, §34.7
Stability vs bioavailability — 17.8
Staphylococcus aureus — 25.1, 25.3, 25.8
stapled peptides — §33.3
stapled peptides, intracellular delivery, ⚠️ — §33.3
STARD reporting standards — 41.3, further reading
state (A) studied and disappointing — ch18 Dossier
state (B) not studied — ch18 Dossier
state (C) studied in a different molecule — ch18 Dossier
Steady state — 4.3
Steelman of the funding objection — 17.10
Stems, naming (-tide, -glutide) — 41.1, 41.9
STEP 1 and STEP 2 trials — 12.2, 12.6
*STEP 1 and STEP 2 trials — see also* Ch 8, population difference → 39.4 (🔬 callout)
STEP 1 versus STEP 2 — 8.3
STEP program — 5.12, 8.3
Step therapy — 12.2
stereochemistry, invisibility to mass — §34.2
sterility — vs endotoxin 19.3, Case Study 34.2, §34.5, 19.3, §34.9, process not appearance 19.3
sterility vs endotoxin (Ch 19 formulation) — §34.5
sterility, cannot be tested into a product — Case Study 34.2, §34.9
Stigma, reduction of, credited to public attention — 41.7
stimulation-produced analgesia — ch20 §20.4
Stopped early for efficacy — 10.3, 10.CS1
strength, distinguished from mass — §16.6
Streptococcus pneumoniae — 25.1
structure — ch21 §21.1
Structure-based design — key terms, ch35 §35.7
Study count, why uninterpretable — 17.3, 17.5
Study scope versus claim scope — 14.5
Subcutaneous administration — 1.6
Subcutaneous injection as default — 4.4
Subgroup analysis — 5.10
subgroup findings, post-hoc — ch21 §21.7
Sublingual and buccal delivery — 4.1
Sublingual and buccal routes — 17.8
subscription procurement — 25.6
*substance P — 22.4, primary afferents, 22.4, 22.5*, sequence, naming and history
Sulfonylurea comparison — 7.4
supervision, medical — seven items 19.7, 19.7, not substitutable by self-testing 19.7
*supervision, medical — rated ⚠️ → 39.9, what it adds and does not → 39.9, see also* Ch 19 §19.7
supplements, absence of premarket approval — 38.7
supply chain, regulated — §34.1, §34.9
suppression narrative, refuted — 38.4, 38.10
Suppression of endogenous production — 3.4
surface charge modification — 25.3
*surgery — see* peri-operative considerations
SURMOUNT program — 9.2
SURMOUNT-1 — 9.3
SURMOUNT-1 two figures — 5.9
SURPASS program — 9.2
SURPASS-2 — 9.5
Surrogate endpoint — 5.6, 14.5, 14.6, 14.9, 15.7, 15.8
*surrogate endpoint — CS 39.2, in optimization-oriented practice → 39.8, see also* Ch 16
surrogate endpoint in approval — 38.3, 38.10
surrogate endpoint P**** — §16.6
*surrogate endpoint, fragility of ✅ resting on* — 37.7, 37.9, FR Tier 2, CS1 (Q6)
surrogate endpoint, immune markers as — ch18 §18.6 (→ Ch. 6)
surrogate endpoint, validation of P**** — §16.6
Surrogate endpoints — 17.5, CS1
surrogate endpoints — 36.2, 36.5, 36.6, 36.7
Surrogate failure modes — 5.6
Surrogate presented as outcome — 6.8
Surrogate-to-outcome inference — 15.7, 15.8, 15.9
surveillance systems — 19.8
Survivorship bias in testimonials — 6.3
survivorship bias, in forum reporting — §16.8
SUSTAIN 6 — 8.2, 10.2
SUSTAIN program — 8.2
*suvorexant* — 22.6
symmetric risk — ch18 §18.7
Systematic optimism of unnamed estimands — 9.4
Systematic review — 5.2
Systematic review, GH in healthy elderly — 14.6

T

Tachyphylaxis — 2.8, 15.6
*target versus drug distinction — 22.7, neprilysin inhibition, radioligands (Ch 27), 22.7*
*taste, prohibition on downgrading with* — 37.2 (rule 4), 37.5 (MK-677 note), CS2 (entry 5)
TB-500 — Dossier, §18.8, ch18 §18.1, §18.2
*TB-500* — 37.5 (growth, veterinary), CS2 (entry 8)
TB-500 as marketed fragment — ch18 §18.1
teduglutide — §33.2
teichoic acids — 25.3, 25.5
teicoplanin, dalbavancin, oritavancin, telavancin — 25.8
teixobactin — 25.7
telangiectasia, as class safety signal — §16.5
Ten-minute check (PubMed / ClinicalTrials.gov) — 17.6
Tendinopathy vs tendinitis — 17.7
Tendon and ligament transection models — 17.3, 17.7, CS1
Teprotide — key terms, ch35 §35.4
*teriparatide* — 37.5 (approved pharmacopeia)
Tertiary structure — 1.4
Tesamorelin — 15.5, 15.8, 15.9, case study 15.1
*tesamorelin* — 37.5 (growth), Conclusion
Tesamorelin, approved indication — 15.5, case study 15.1
*testimonial dynamic — see also* Ch 6, inside the clinic → 39.10
Testimonial, why persuasive — 6.3
testing programs, findings of — categories not proportions 19.4, limitations 19.4, 19.4
testing programs, independent — §34.8
TGF-β superfamily P**** — §16.3
thalidomide — 19.10, case study 19.2
The access curve — the usual shape, §44.6
theranostic loop — 27.6, case study 27.1
therapeutic use exemption — 38.8
therapeutic window — 25.5
therapeutic window, not engineerable — §33.10
Therapeutic window, venom peptides and — ch35 §35.2, §35.4
third-party testing claim — 19.4
This book's own biases — 6.7, further-reading
three jobs (shut down / replace / deliver) — 27.8
three questions (identity/purity/content) — §34.4
*three-joint test ("boost your own" claims)* — 22.3, applied to NPY
three-joint test (magnitude / duration / existence proof) — ch20 §20.8 (from ch13)
Three-tier axis structure — 3.2
thymosin alpha-1 — Dossier, §18.8, ch18 §18.3
*thymosin alpha-1* — 37.5 (infectious)
thymosin alpha-1, approved elsewhere — 38.4
thymosin β4 — ch18 §18.1, §18.2
tight junction — ch18 §18.5
Tight junctions — 4.1
timed function tests — §16.6, §16.5
tirzepatide — 36.5, §33.9
*tirzepatide* — 37.5 (metabolic ×3), CS2 (entry 6)
tirzepatide, residue count — 38.2
Tirzepatide, structure — 9.1
Tirzepatide, two brand names — 41.2
tissue-specific processing — ch20 §20.2
Titration — 4.3, 8.7
to antimicrobial peptides — 25.3
Tolerance — 2.8
tolerance — ch20 §20.6
Tonic versus pulsatile stimulation — 15.6, case study 15.2
tonsillar hypertrophy, mecasermin labeling — §16.2
toroidal pore model — 25.3
Toronto 1921 — 22 — 11.1
Trademark, loss of protection — 41.1, CS 41.2
Transected tendon vs overuse injury — 17.7
transferable (plasmid-borne) — 25.3, 25.8
transmembrane potential — 25.5
Treatment-regimen estimand — 5.9, 9.4
Trial anatomy, six features — 5.5
Trial design, randomized placebo-controlled — 17.11
Trial phases — 5.4
Trial registration — 5.CS2
Trial registration vs completion vs publication — 17.6
trial registry, as evidence check — ch18 Dossier, further-reading
trifluoroacetate — §34.4
trigeminal pathway, drug transport via — ch21 §21.6
trigger sentence — ch18 Dossier
Triple agonism — 9.6
triptorelin — 27.1 (table), 27.2, 27.8, case study 27.2
Tropic hormone — 3.2
truncation to active core — 27.4
trust and generosity claims (❌) — ch21 §21.4
trust game paradigm — ch21 §21.4
Trypsin and chymotrypsin — 4.1
Twelve-field dossier entry, model — 8 dossier
two axes (evidence × preparation) — 19.10, diagram 19.10
Two exits, closing both — 4.2
Two molecules versus one — 9.7
two thresholds, upgrade and downgrade — ch35 dossier
two-in-the-morning test — 19.7
Two-lever counter-regulation argument — 11.4
Two-minute problem — 7.6
Two-molecule versus dual-agonist architecture — 13.3
Type 1 versus type 2 diabetes — 11.5

U

*ubrogepant, rimegepant, atogepant, zavegepant* — 22.7
ultraviolet detection, 214 nm and 280 nm — §34.3
Underpowered trial, moves nothing — 17.11
Unfalsifiability, of speculation about individuals — 41.5
unfalsifiable claim — ch18 §18.6
Unfalsifiable claims — 5.1, 5.10
Unimolecular dual agonist — 9.1
unnatural amino acids — §33.2
Unpatentable compound, incentive structure — 17.11
unregistered nature of — ch18 §18.2
Untreated versus placebo controls — 14.5
*update procedure, five-step* — 37.9 (callout), EX AJ
Upward compression — 10.10
US federal statute on GH distribution — 14.6
uterine atony — ch21 §21.2
uterine contraction — ch21 §21.2
uterotonic — ch21 §21.2

V

V1a antagonist program — ch21 §21.8
V1a receptor — §21.3, ch21 §21.8
V1b receptor — ch21 §21.8
V2 receptor — ch21 §21.8, §21.1
vacuolation findings — §33.5
vagal afferent signaling — 36.8
Vagal afferents — 7.7
validation, of analytical methods — §34.10, §34.3
*values question* — 37.4, 37.5 (society block)
vancomycin — 25.8
Variability versus bioavailability — 4.4
Vascular and angiogenic models — 17.3
vasoconstriction, vasopressin-mediated — ch21 §21.8
vasodilatory shock — ch21 §21.8
vasopressin — ch21 §21.1, §21.8
Vendor page infrastructure — 6.4
Venom as pre-optimized pharmacological library — ch35 §35.2, key takeaways
*venom-derived peptides* — 37.5 (science)
Venom-derived peptides as source of drug leads ✅ — ch35 §35.3
*vericiguat* — 37.5 (cardiovascular)
*veterinary* — 37.5
veterinary reproductive management* — §31.1
vials, the four (Ch 6 callback) — 19.1, 19.2 (A/B distinction), §34.1, Overview
Video content and uncertainty — 6.6
VISA-A instrument — 17.11
Visceral adipose tissue — 15.5, case study 15.1
VISION — 27.6, 27.9
vole literature — ch21 §21.3
*volume transmission* — 22.1
von Willebrand factor, desmopressin release of — ch21 §21.8

W

WADA List, verifying against → CS1 (Entries 2 — 3), FR (Tier 2)
WADA Prohibited List — 19.9
water content — §34.7, §34.4
water retention, oxytocin-induced — ch21 §21.1
Wegovy — 8.3
Weight loss as upstream cause — 10.1
*weight loss, unexplained* — misattribution under concealment → CS 39.1
Weight stigma — 12.7, 12.9
Weight-loss drug withdrawals — 8.CS2
Weight-loss drugs, withdrawn — 12.2, 12.9
Weight-mediated benefit — 10.6
Weight-neutral health position — 12.9
what it does not report — ch18 §18.3
whippets, myostatin mutation in — Case Study 16.2, §16.3
WHO ICTRP; EU Clinical Trials Register — 17.6
WHO Model List of Essential Medicines, oxytocin on — ch21 §21.2
Why GLP-1 agonists do not suppress endogenous GLP-1 — 3.9
Why incretins were a good drug target — 7.8
Why single-target appetite drugs fail — 13.7
Why 🔬 rather than ⚠️ — 10.7, 10.CS2
Wide dose range, reported — 17.4
Willpower frame, reinforced by non-disclosure — 41.4, 41.6
winner's curse — ch21 §21.4
Winter, Greg — ch35 §35.6
withdrawal — ch20 §20.6
worked demonstration, AI claim form — ch35 dossier
worked demonstration, oral collagen peptides — ch35 dossier
World Anti-Doping Agency (WADA) — 38.8
World Anti-Doping Code — §16.8
wound healing, dermal, animal models — ch18 §18.2
Wrong-pockets problem — 12.2

X

Xenopus laevis — 25.4
Xenopus laevis (African clawed frog) — ch35 §35.4

Y

*Y receptors (Y1, Y2, Y4, Y5)* — 22.2
Yellow Card scheme — 19.8, further reading

Z

Zasloff, Michael — ch35 §35.4
Zepbound — 9.2
ziconotide — ch20 §20.9
Ziconotide — ch35 §35.1, key terms, dossier, §35.4
*ziconotide* — 37.5 (neuropeptides), 37.8 (safety callout)
ziconotide, intrathecal delivery — 36.8
zwitterionic phospholipids — 25.5

Α

α-MSH (alpha-melanocyte-stimulating hormone) — ch18 §18.5

Β

β-endorphin — §20.8, ch20 §20.1, §20.2, §20.5

Ω

ω-Conotoxin MVIIA — ch35 §35.4

⚠️ defended as a positive claim — §18.8, ch18 §18.3
⚠️ Hype Check — " §44.2, "these drugs are going to collapse the snack food industry
⚠️ topical AMP applications — 25.7
*✅ CGRP-targeting therapies for migraine prevention* — 22.7
✅ colistin, last-line MDR Gram-negative — 25.8
✅ daptomycin, approved indications — 25.8
*✅ NK1 antagonists for CINV* — 22.5
*✅ Orexin receptor antagonists for insomnia* — 22.6
✅ with a poor side-effect profile — 25.8
❌ "AMPs cannot generate resistance" — 25.3
*❌ Boosting NPY for stress resilience* — 22.3
❌ describes evidence not molecule — 17.10
❌ for untested versus untestable claims — ch18 §18.6, §18.8
*❌ NK1 antagonists as analgesics or antidepressants* — 22.5
❌ vs. 🔬, distinguishing — 25.9
💊 In the Clinic — §44.3, the structural problem from an exam room
📊 Evidence Rating — §44.6, §44.2, values question (NOT RATED), food industry (🔬), price decline (⚠️), weight stigma (NOT RATED), §44.4, §44.8
📋 Your Evidence Dossier — final checkpoint, after §44.9
🔍 Check Your Understanding — §44.5, §44.1
🔬 AMPs as broad-spectrum systemic antibiotics — 25.9
🔬 as ordinary early-stage rating — §18.8, ch18 §18.5
🔬 Read the Study — the study nobody has run, §44.6
🔬, writing honestly — 25.9
🧬 The Molecule — the one participant with no opinion, §44.5
🩺 Safety and Risk — §44.4, stigma is a clinical variable