Vagal afferents, the area postrema, and the anatomy of nausea
Receptor expression maps explain the effect profile better than any dose-response curve.
Delphine Ruzek
Page 3 of 7 of this archive, newest first.
Archive — page 3
121 piecesRetest date, expiry date, and the two conventions being confused
A document is only as good as the chain that connects it to the material, and most chains here are two or three links longer than the paperwork admits.
What the trial protocols permitted, and what the labels omitted
Reducing a dose is not going backwards. In a tolerability-limited class it is the mechanism by which the ceiling is found.
Do you need the top of the ladder?
What the trials measured was continuation against withdrawal. What patients want to know is continuation at a lower dose, and that study has largely not been done.
What STEP 4 and SURMOUNT-4 actually established
Weight reduction in the long programmes flattens at roughly sixty to seventy-two weeks. The timing is consistent, predictable and almost never mentioned in advance.
The limits of mechanism: why receptor data will not tell you who responds
A catalogue of open questions, with an assessment of how likely each is to be resolved.
The word “confirmed” is doing an enormous amount of work on this certificate
An intact mass measurement establishes elemental composition, at best. The number of distinct sequences consistent with a given composition is astronomically large.
Retention time is not identity
Matching a retention time against a standard is evidence of consistency, not proof of identity. Two different species can elute at the same time on one method.
Why Medutest can tell you the mass is right and not that the sequence is
The Journal’s standing position: a mass that matches is necessary evidence of identity and nowhere near sufficient.
What a batch number is supposed to mean
A document is only as good as the chain that connects it to the material, and most chains here are two or three links longer than the paperwork admits.
What the GIP receptor adds: reading orforglipron as two drugs in one sequence
The glucagon arm raises energy expenditure and also raises hepatic glucose output. Balancing those is the whole engineering problem.
The software decides what counts as a peak
Baseline placement under a tailing peak is a judgement call with a direct effect on the area. It is one of the few places where two competent analysts genuinely disagree.
The eighteenth month, and the conversation that should have happened in the third
What the trials measured was continuation against withdrawal. What patients want to know is continuation at a lower dose, and that study has largely not been done.
The imaging substudy is an afterthought in the protocol and the centrepiece of the debate
The trials measured mass. Nobody measured whether the participants got weaker.
When to stop escalating and when to stop entirely
The ceiling varies severalfold between people, and nothing measurable at baseline predicts where it sits.
What the trials counted as intolerance
Trial discontinuation figures are a floor, not an estimate: trial populations are supported in ways ordinary patients are not.
Mapping a rotation that you will actually follow
A rotation scheme that is too complicated will not be followed. We describe the simple ones that are.
Sarcopenia is a diagnosis, not a synonym for losing lean mass
A tour of the source literatures, with an assessment of how far each legitimately reaches.
Escalating onto a rising curve
The four-week step exists because four to five weeks is approximately how long a once-weekly drug takes to stop rising at a fixed dose. That is a good reason, and it is not…
Holding a dose is a decision, not a failure
Every major phase 3 protocol in this class allowed escalation to be delayed for tolerability. Almost no product label explains the mechanics of doing so.