Well, this is different,...some discussion,...I like this Mark.
(1)-(4)
I don't have any problems with Pennsaid for short term use on healthy individuals. Britain didn't until there was a cost problem, I don't think any regulators will on a medical basis.
I don't doubt that negotiations with all health agencies will dwell on labelling warnings for several years. If Pennsaid is used on broken skin you get a greater chance for systemic absorption which defeats the lotions purpose, so skin irritation must be closely monitored. Age of patient and chronic use should, and I'm sure will be monitored closely.
I cannot answer your question on Cox2 vs Pennsaid approval times. I'm amazed, as you are, that it has taken this long. It makes no sense unless something is wrong. I think a DMSO based topical lotion with a pain killer/anti-inflammatory agent makes sense for many patients.
I suspect, unlike some, that J&J may be more of a negative influence than a positive one,...if the FDA dicks around for another year the patent is toast, and the field is wide open. I don't buy the patent extension crap,...maybe if the company was American, but not a Canadian one, especially one based in a tax haven. Putting 2 + 2 together, it seems to me that all J&J must do is wait for another year and they get to proceed without DMX, but they have been privy to all of the research accumulated by DMX.
I think that takes care of 1-4,...now 5,...
Pharm Res 1998 Oct;15(10):1589-95 Related Articles, Links
In vivo bioavailability and metabolism of topical diclofenac lotion in human volunteers.
Hui X, Hewitt PG, Poblete N, Maibach HI, Shainhouse JZ, Wester RC.
Department of Dermatology, University of California, San Francisco, 94143, USA.
PURPOSE: The primary objective of this study was to determine the rate and extent of transdermal absorption for systemic delivery of diclofenac from Pennsaid (Dimethaid Research, Inc.) topical lotion into the systemic circulation after the lotion was applied to human volunteers, in an open treatment, non-blinded, non-vehicle controlled study. In addition, the in vivo metabolism of this topical diclofenac lotion has also been studied. METHODS: Human volunteers were dosed with topical [14C]-diclofenac sodium 1.5% lotion on the knee for 24 h. Sequential time blood and urine samples were taken to determine pharmacokinetics, bioavailability and metabolism. RESULTS: Topical absorption was 6.6% of applied dose. Peak plasma 14C occurred at 30 h after dosing, and peak urinary 14C excretion was at 24-48 h. The urinary 14C excretion pattern exhibits more elimination towards 24 h and beyond, as opposed to early urinary 14C excretion. This suggests a continuous delivery of [14C]-diclofenac sodium from the lotion into and through skin which only ceased when the dosing site was washed. Skin surface residue at 24 h was 26 +/- 9.5% dose (remainder assumed lost to clothing and bedding). Extraction of metabolites from urine amounted to 7.4-22.7% in untreated urine, suggesting substantial diclofenac metabolism to more water soluble metabolites, probably conjugates, which could not be extracted by the method employed. Two Dimensional TLC analysis of untreated urine showed minimal or no diclofenac, again emphasizing the extensive in vivo metabolism of this drug. Treatment of the same urine samples with the enzymes sulfatase and beta-glucuronidase showed a substantial increase in the extractable material. Three spots were consistently present in each sample run, namely diclofenac, 3'hydroxy diclofenac and an intermediate polar metabolite (probably a hydroxylated metabolite). Therefore, there was significant sulfation and glucuronidation of both diclofenac and numerous hydroxy metabolites of diclofenac, but many of the metabolites/conjugates remain unidentified. CONCLUSIONS; There was a continuous delivery of diclofenac sodium from the lotion into and through the skin, which ceased after the dosing site was washed. The majority of the material excreted in the urine were conjugates of hydroxylated metabolites, and not the parent chemical, although further identification is required.
Publication Types:
Clinical Trial
PMID: 9794502 [PubMed - indexed for MEDLINE]
The only thing I can add to this is diclofenac sodium in solution would be a negatively charged ion, so would likely need some transport mechanism to overcome the repulsion of the negative charge of the cell interior,...I would suggest that DMSO must continue to be present throughout the skin cell layers over this time period for the continuous transfer of diclofenac over the 24 hour period to take place. |
