On phentolamine blood levels, assays, and filthy crooks
As I posted on Saturday I have a copy of the 1975 Imhof study that was the basis of Asensio's Jan. 15th report titled - Zonagen's Vasomax fast-acting claims proven false and fraudulent. I also have another article, published in 1981, which is one of several that appeared as a follow-up to the 1975 article & gets into some fairly technical subjects. As we have come to expect from this Harvard educated defender of the poor & downtrodden, he is a)misinformed and/or b)more than a little deceitful. In either case a reader of his report is left with a false impression.
From the Asensio report -
>>>Doctors R. Imhof, B. Garnier, L. Brunner, G. Keller and T. Roher conducted a study titled "Human Pharmacology of Orally Administered Phentolamine". The study was published as part of the Phentolamine Workshop and Symposium held in London, England in November 1975. The investigations were performed in collaboration with the Pharmacological Chemistry Section of Ciba-Geigy in Basle and Paris. The objective of this detailed human-pharmacology study was to measure the blood concentration and the excretion of orally administered phentolamine.<<<
First some comments, note that this was not a journal article, it was printed in a textbook that summarized the workshop & symposium. For those on this thread who feel (accurately) that the only valuable scientific information comes from "peer-reviewed" or otherwise accredited articles - it was not.
The main problem with this work was that it utilized an UNVALIDATED analytical technique - that means that appropriate analytical controls were lacking. Nowhere in the paper is there a description of the techniques used for measuring unconjugated (free) vs. conjugated phentolamine. This first study was understood to be flawed and led to at least three more studies (one in 1978, two in 1981) conducted by the same group at Ciba-Geigy. These additional studies were undertaken because the authors recognized the shortcomings of the 1975 work and all aimed at determining the pharmacokinetics of orally administered phentolamine.
The 1978 study was also authored by by Pfister & Imhof, and was published in the British Journal of Clinical Pharmacology, Vol. 5, 175 only attempted to ESTIMATE the plasma concentration of phentolamine utilizing a platelet aggregation technique - not very accurate. The importance of this study is simply that they still did not have an accurate, validated method of determination of phentolamine three years after the first paper - remember this was the same lab, so why were they still looking for a method?
One of the 1981 studies used HPLC techniques to measure phentolamine but was validated only down to 200 ng/ml - not sensitive enough to detect blood levels without massive doses.
The other 1981 study finally provides a VALIDATED ANALYTICAL TECHNIQUE - one that any other laboratory could read & (using the details in the article) duplicate. This article is:
>>>Gas Chromatographic Determination of Phentolamine (Regitine) in Human Plasma and Urine. Antoine Sioufi, Francoise Pommier, Patrick Mangoni, Sonia Gauron and Jean-Pierre Meteyer
Ciba-Geigy, Centre de Recherche Biopharmaceutique, B.P. 308, 92506 Rueil-Malmaison Cedex (France)
Estimation of the plasma concentration and course of action of phentolamine based on its inhibitory effect on adrenaline-induced platelet aggregation. Pfister, B; Imhof, P. Pharm. Div., Ciba-Geigh Ltd., Basel, Switz. Br. J. Clin. Pharmacol. (1978), 5(2), 175-80. CODEN: BCPHBM; ISSN: 0306-5251. Journal written in English. CAN 88:197538<<<
I welcome those with time & access to a medical library to go get it & read it. If you find this one, you should be able to find the others I've referenced. This study used the highly sensitive GAS CHROMATOGRAPHY analytical technique for the determination of free & conjugated phentolamine. It was VALIDATED down to concentrations of 5 ng/ml. The article is excruciatingly detailed in exactly how to perform this assay. In the "Application" section of the paper is the following -
>>>The technique was applied in a study of the elimination of phentolamine after oral administration to three healthy subjects. VERY LOW PLASMA LEVELS WERE MEASURED AT ALL SAMPLING TIMES.<<<
Blood samples were collected at .25, .5, .75, 1 and 2 hrs after the administration of the drug.(20 mg oral). This means less than 5 ng/ml since that's the lower limit of the sensitivity of this assay.
In addition, the fastest increase in the urinary levels of phentolamine occurred between hours 2-3. This logically implies that the highest plasma levels of the drug occurred shortly before then - or in hours 1-2.
This assay is the currently accepted measurement technique for determining levels of phentolamine in plasma. It is the assay used by Zonagen in their FDA submission - it was accepted by the FDA in the experimental design. The technique used in the 1975 study, upon which Asensio based his attack, would NEVER be accepted by the FDA because it is an UNVALIDATED technique.
SUMMARY
In the 1970's some scientists at Ciba-Geigy, who just happens to be the manufacturer of Regetine (phentolamine), were looking for an accurate way to measure very low concentrations of the drug. One of their early studies, yielding results based on an UNVALIDATED analytical technique, gets reported at a symposium & therefore is included in a textbook summarizing the entire symposium. The groups continue to refine their analytical techniques until, in 1981, they publish a study, detailing a VALIDATED technique - in a reputable journal. That technique is still the scientifically accepted method for determining plasma levels of phentolamine. That study is a key part of the Zonagen patent application, providing proof that phentolamine does not provide adequate blood levels when delivered in a standard dissolving tablet.
The Jan. 15th Asensio attack on Zonagen is COMPLETELY UNFOUNDED because he bases his argument on an out of date, interim study. Now a fair question might be, how come this big time, wall street, Harvard educated analyst missed all of this?? It's all basically there in the patent application - which, by the way, he uses for another attack on Zonagen. But that's another story - for another day - soon, I promise. |
