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Biotech / Medical : Zonagen (zona) - good buy? -- Ignore unavailable to you. Want to Upgrade?

To: Dauntless who wrote (2048)	1/26/1998 6:06:00 PM
From: Dr. Voodoo	Read Replies (1) \| Respond to of 7041

Dauntless, >>>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.<<<<<<< Since you have the paper, and this is an ongoing question, and you went to all the trouble to write such an informative post. HOW ABOUT POSTING THE BLOOD LEVELS AT .25, .5, .75, 1 and 2 hrs after administration of 20 mgs of phentolamine?

To: Dauntless who wrote (2048)	1/26/1998 6:24:00 PM
From: Dr. Voodoo	Respond to of 7041

To all interested, Pfister, B; Imhof, P. Pharm. Div., Ciba-Geigh Ltd., Basel, Switz Not exactly the same group, or authors, kind of thru me for a bit. The appropriate references in question are, Determination of the major metabolite of phentolamine in human plasma and urine by high-performance liquid chromatography. Godbillon, J.; Carnis, G. Cent. Rech. Biopharm., Ciba-Geigy, Rueil-Malmaison, 92506, Fr. J. Chromatogr. (1981), 222(3), 461-6. CODEN: JOCRAM; ISSN: 0021-9673. Journal written in English. CAN 94:185277 Gas chromatographic determination of phentolamine (Regitine) in human plasma and urine. Sioufi, Antoine; Pommier, Francoise; Mangoni, Patrick; Gauron, Sonia; Metayer, Jean Pierre. Cent. Rech. Biopharmac., Ciba-Geigy, Rueil-Malmaison, 92506, Fr. J. Chromatogr. (1981), 222(3), 429-35. CODEN: JOCRAM; ISSN: 0021-9673. Journal written in English. CAN 94:149909 Abstract A method for the detn. of unconjugated phentolamine (I) [50-60-2] at concns. down to 5 ng/mL in human plasma, and of free and total (free plus conjugated) phentolamine down to 25 ng/mL in urine is described. After addn. of 2-[N-(p-chlorophenyl)-N-(m-hydroxyphenyl)aminomethyl]-2-imidazoline as internal std., both compds. are extd. into benzene-Et acetate (1:1, vol./vol.) at pH 10, transferred into an acidic aq. soln. and back-extd. at pH 10 into benzene-Et acetate. They are then derivatized with N-heptafluorobutyrylimidazole. The derivs. are detd. by gas chromatog. using a 63Ni electron-capture detector. In urine, total (free plus conjugated) phentolamine is detd. after enzymic hydrolysis. The technique was applied for the study of the plasma concns. and urinary elimination after oral administration to man.

To: Dauntless who wrote (2048)	1/26/1998 7:44:00 PM
From: Cacaito	Read Replies (1) \| Respond to of 7041

Dauntless, I read the full article "Gas chromatographic determination of phentolamine (Regitine)in human in human plasma an urine" I read it back by the time I posted the Gwinup and Zorgniotti articles. I did not copy it, I did not post it because it did not answer my question. It is not about phentolamine pharmacokinetics, but about the validity of the measurement technique itself. There is not a description of the levels achieved after administration of 20 mg of phentolamine, neither in urine, neither in plasma. They did provided the sampling time, not the levels at each time, neither in blood, neither in urine. You are inferring that the levels were low (wrong)they are saying that they were able to measure down to 5 ng/ml in plasma, and down to 25 ng/ml in urine (they measure higher levels, not provided). They wanted to prove that the technique was correct up to those very low levels. They did not provided the actual levels at each time of sampling, probably they do have the data somewhere else. I guess nobody was interested in that data at the time and was not published (Ciba-G did not put more money on it). The numbers that Keith presented are reference nowhere. The "fast disolving pill" does not altered the bioavailability of phentolamine from the GI track (less than 20% of the active compound is absorbed from gatrointestinal track). Zorgniotti used a faster method, oral mucosa absorption and his subjects were advised to attempt coitus at 30 minutes (faster than 1.5 hours) and only 31.8% achieved a full erection vs placebo 13%. Not very good numbers. Remembers all patients with cardiovascular problems were excluded. I do not discard that there are chances (very low) of the drug to work. But, with the information available I will not be a long. I am not a short either. Phentolamine alone directly in the penis does not work (as per Joe Podolski CC ).

To: Dauntless who wrote (2048)	1/27/1998 12:14:00 AM
From: khrnyc	Read Replies (1) \| Respond to of 7041

Good evening Dauntless, Having recently reviewed the 1975 Imhof and 1981 Sioufi studies, I congratulate you on a thoughtful and eloquent assessment of the information--post # 2048--(and thank you for saving me some time tonight). By the way, for those of you who don't have access to a medical library or who are short of time, the New York Public Library has a corporate services division that may be able to obtain the articles you want. They charge $30 - $50 per article, an hourly rate if research needs to be done, and a fax/delivery charge. And no, I do not have a financial interest in the NY Public Library. As for Dauntless's post, no need to reiterate all he has written, but I'd like to emphasize a few points. I encourage you to understand post #2048 as I think it sheds light on the confusion surrounding the pharmacokinetics of standard release oral phentolamine vs. vasomax. Namely, the Imhof paper from 1975 does find that oral, commercially available (at the time) phentolamine given in doses of 20 to 40 mg did achieve maximum "unchanged drug" concentrations at 30 minutes. It states that they used both radioactively labelled carbon, and gas chromatography to obtain their results. The problem with this non-peer reviewed study is that there is no methodology, no controls, and does not explain how they differentiated free (unchanged drug) from conjugated (metabolized) drug. To my knowledge this study was never reproduced and in fact in 1978 was NOT used by Imhof to estimate plasma concentrations of phentolamine (instead using the less accurate method of measuring phentolamine plasma levels by measuring its effects on platelet aggregation). To me this study seems to be of questionable utility. On the other hand, the Sioufi study includes a meticulous description of techniques used for gas chromatography (they were familiar with gas chromatography and had been using it in their lab for eight years prior to the writing of their article in 1981). In the Sioufi study they note that "very low plasma levels (of phentolamine) were measured at all sampling times (= 0.25 hr, 0.50 hr, 0.75 hr, 1.0 hr, and 2.0 hr). Unfortunately no actual ng data is given for plasma phentolamine via time (this study was focused on methodology) . However, urine levels of free and total phentolamine are graphed and show the greatest rate of urinary excretion of drug occurred between the second and third hours post oral administration. The punch line is that in the International patent application to which I referred in post #1987, Zona repeated these studies SPECIFICALLY looking for plasma levels over time for standard release oral phentolamine, used gas chromatography (and included their methodology in detail), and found negligable (< 5.0 ng) levels of phentolamine up through 1.5 hours post oral administration. This is completely consistent with the Sioufi, but not the Imhof, study. If I understand correctly then, the shorts believe part, if not all, of the following: 1) Zona is a "fraud and a scam" 2) Schering Plough (who had full access to all the study data and prior studies noted above) was hoodwinked and will be unable to market this product effectively 3) The Imhof article is substantive 4) Asencio (who by the way failed to include the standard release vs. vasomax plasma conentration over time data in his January 13,15 newswires regarding the second Zona patent application) is fair in his reporting p.s. still waiting for an intelligent response to any of the questions raised in post # 1988