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MINOXIDIL 'SITE OF ACTION' PHARMACODYNAMICS MEASURED USING LASER DOPPLER AT UCAL; FDA/UCAL WORKSHOP PLANNED TO DEVELOP IN VITRO PENETRATION PROTOCOL

Executive Summary

The pharmacodynamics of minoxidil have been shown at the site of action on the scalp using the laser Doppler velocimetry (LDV) technique of measuring the skin blood flow, Ronald Wester, University of California at San Francisco, told the Society for Bioengineering and the Skin at its 5th annual symposium Aug. 29-Sept. 2. Testing the theory that minoxidil stimulates hair growth by increasing blood flow to hair molecules, Wester used LDV to show that minoxidil does "stimuiate a blood flow in the balding scalp." The test was part of the work Wester is conducting for Upjohn's baldness IND. Wester pointed to the ability to look at the site of action as a novel aspect of the LDV technique. We were "able to show the pharmacodynamics of minoxidil, and I think that's important in that we were able to show it at the site of action where it is supposed to be working. We didn't do any systemic blood sampling and try to guess where things were going on. We were able to actually look at the site of intended action," he said. FDA is apparently watching the work at the University of California, San Francisco as it develops protocols for in vitro penetration. The agency and the University of California Medical Center are planning to co-sponsor a workshop on the "principles and practices of in vitro percutaneous penetration as it relates to bioavailability and bioequivalence" on March 14-15, 1986 in San Francisco. LDU Measuraments Can Be Complicated Because Of Sensitivity To Environmental Factors, Researchers Say The aim of the open workshop, according to an announcement, is to "review current knowledge and develop a protocol for in vitro penetration that may satisfy some of the bioavailability and bioequivalence aspects" which have come up as a consequence of the Waxman/Hatch law's provisions for approval of generic drugs. University of California researcher Wester said that LDV also allows for the measurement of systemic activity of drugs that alter vasoconstriction. In work he has done with nitroglycerin given sublingually, microcirculation was measured to test the hypothesis that the effect of nitroglycerin in opening blood vessels would be reflected in skin blood now. "We looked at both blood levels of nitroglycerin, and laser Doppler response to these oral preparations," Wester said. "What we found was no unchanged nitroglycerin in the blood. But we do know that it was clinically effective. In fact, what's happening is that the nitroglycerin as it is taken orally is being completely metabolized. So the laser was able to sort out the bioactivity of these oral preparations of nitroglycerin," he continued. "So you can get a pharmacodynamic response from a systemically-administered drug by putting a probe on the end of a finger; a totally noninvasive method of measuring the pharmacodynamics of a drug," Wester concluded. Wester also noted that the "probe on the end of the finger was able to distinguish between two dosing sequences of topically applied nitroglycerin." Several papers presented at the meeting, however, addressed problems with the LDV technique. The question was raised of what exactly the One problem with the LDV is that because it is so sensitive, skin blood flow measurements can be affected by physiological and environmental factors such as blood pressure, pulse rate, skin temperature, room temperature and partial pressure. Some researchers have tried to devise systems to account for the effects of such outside influences. For example, at the Skin Study Center in Philadelphia P. Ronca D. Hiller and G. Groce have assembled:'a microcomputer based system of data acquisition and management that records the internal and external conditions plus the laser Doppler velocimeter (LDV) flux values simultaneously." With the system, all of the factors can be tracked at the same time, Grove explained at the meeting. A.H. Sacks from the Veterans Administration Medical Center in Palo Alto, California, reported on a problem which has been observed with the LVD relating to pressure. The VA researchers found that the DC level of the instrument decreased when the probe was applied to the skin with pressure, and that "in turn produced artificial decreases in the output signal of the instrument," Sacks declared. In Manchester, England, Peter A. Payne is working on standardizing an ultrasound Doppler skin blood flowmeter so that "absolute skin blood flow measurements are achievable in terms of litres per minutes per unit volume of tissue." Another UCAL, San Francisco researcher, R. Guy, reported on a "potpourri of the applications" of the LDV techniques that researchers at the University of California Schools of Pharmacy and Medicine have been involved in over the last couple of years. While noting that some would argue that no one knows exactly what is being measured, Guy maintained: "I think it does allow us to make some useful insights into a number of different types of phenomenon." To try to "obtain some indications of what's going on when we absorb chemicals through the skin," the University of California researchers used the LDV to measure changes induced by the topical application of a nitroglycerin ointment, .2% Nitrobid, and from a nitroglycerin transdermal patch system. LDV Studies With Penetration Enhancer Azono Show Faster Onset Of Action Dose-related responses were measured in both cases, and Guy concluded: "Certainly none of these events take place during the absence of the drug, -- so whatever the laser is measuring, it is measuring something drug-associated and providing some nice pharmacodynamic information from which we can begin to extract useful kinetics." LDV has also been used to study the action of penetration enhancers. In the study, the skin was treated with several enhancers, such as 2-pyrrolidone and 1-dodecylazacycloheptan-2-one Nelson R&D's Azone. A faster onset of action (increased blood flow) was discovered with Azone, according to study results. The test demonstrated, Guy said, "that it is possible to, in fact, look at enhancement in vivo with this technique, and we are truly seeing the effects of the various pretreatments on the skin registered in- vivo in a way that we wouldn't otherwise be able to study these things." Two examples of clinical applications of the LDV, Guy said, are "looking at the resolution of psoriasis," and "looking at how we may assess ultraviolet effects on the skin." Guy closed the session saying: "So I would say the San Francisco prognosis of the laser Doppler is healthy. We certainly think that we can do some useful things with it, we're excited about the types of observations we can make, and we look forward to learning much more about exactly what it is were looking for."
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