VIP

Vasoactive intestinal peptide is a real hormone the body makes, and the thing sold as VIP really is that hormone. UniProt gives the mature chain in entry P01282 as 28 amino acids, and aviptadil, the name used in trials and on prescription labels, is a synthetic copy of that sequence. The identity check comes back clean, which almost nothing else in this reference manages. The mismatch is route, population and combination rather than molecule.

The obstacle is arithmetic rather than biology. Domschke and colleagues infused the peptide into four healthy volunteers in 1978 and measured an average disappearance half-time of one minute after the drip stopped, concluding that their data did not support a role for VIP as a circulating hormone under physiological conditions. A minute is why every serious programme has either run a continuous drip or sprayed the peptide onto the tissue it is meant to act on. The one clean mechanistic human result is Prasse 2010, which treated 20 sarcoidosis patients with nebulised VIP for four weeks in an open study and found tumour necrosis factor alpha falling in cells washed out of the lungs against each patient's own starting sample, while regulatory T cells rose against the same baseline.

A compounded nasal spray, prescribed as the last step of a numbered protocol for chronic inflammatory response syndrome, and sold well beyond that. This entry is about a molecule and its evidence rather than about whether anybody is ill, and people carrying that diagnosis read this site too, so both positions are reported and attributed rather than adjudicated here. What can be said without settling that argument is what the treatment evidence consists of: two open label studies from one research group, 20 patients in 2013 and 31 of 35 enrolled in 2017, neither with a randomised comparison group and neither coming up in PubMed. The 2013 paper announced that a double blind placebo controlled trial had begun, and I could not find it published or registered in the thirteen years since.

The dose is the cleanest derivation chain in this batch and it ends at a nebuliser. An inhaled dose in eight patients in 2003 reappeared as an inhaled dose in sarcoidosis in 2010 and was carried across to the nose in 2013 unchanged, with the paper's stated reason being the 2010 study. Nobody worked it out again for the new route. Read the 2013 paper's own results and even the schedule is the protocol rather than what most patients did: 8 of the 20 used it three or four times a day consistently, 4 used it once or twice, 3 only before strenuous activity, and 5 stopped. Meanwhile the randomised version of the lung programme it all descends from ran across eight European countries and its investigators, replying in print in 2012, referred to the negative results of the acute test and of the three months of administration. The protocol document still lists pulmonary hypertension as an indication for the spray.

The best controlled human exposures to this peptide were designed to cause a headache and they succeeded. In a randomised double blind placebo controlled crossover in 21 patients with migraine without aura, 15 of 21 developed a migraine attack on the peptide against one of 21 on placebo, and that was the trial's primary endpoint. That infusion delivered about 224 micrograms into a vein over two hours for a 70 kilogram adult, against a nasal convention of 200 micrograms a day. Not an equivalent exposure, since how much of a spray reaches the blood is unknown and almost certainly a fraction, but the same order of magnitude. What excess looks like when the body does it is a VIPoma, a rare tumour that secretes the peptide at 0.05 to 0.2 cases per million person-years, producing watery diarrhoea, low blood potassium and no stomach acid; the 1978 volunteers at the top infusion rate reached plasma levels the authors compared to that syndrome, with flushing and a raised pulse. In the largest COVID-19 trial the primary safety outcome by day 5 occurred in 146 of 231 patients on the drug against 129 of 230 on placebo.