Volume 18 Number 2, Part 1 February 1988

Recently the use of topical minoxidil, an antihyper- tensive drug, was found to induce true growth of hair in selected patients. The early successes in the control of a phenomenon that has been thought of as irreversible and not given to the influence of any known intervention generated a great deal of public enthusiasm and were reported in both medical and lay press.

Prompted by these reports we thought that diazoxide, an antihypertensive drug that, like minoxidil, acts as a direct peripheral vasodilator that might cause hypertri- chosis as a side effect, might also be used topically to reverse baldness.

Our proposal was put to the company manufacturing this drug. In accordance with their request we submitted a protocol for a small clinical experiment that would be controlled, safe, and cheap. After a period of waiting for approximately a year, the company categorically rejected our proposal and were not prepared, under any circumstances to expand on the indications for the use of this drug.

The only possible reason for this obstinate and final refusal, in our opinion, can be the fact that diazoxide has been on the market for a considerable time and is no longer patented. In the event that the experiment is successful and our hypothesis that the drag would re- store hair growth is verified, it would mean that other companies could produce it en masse and more cheaply. This would no doubt create competition and might well cause a financial loss to the company originally ap- proached by us.

This particular case illustrates, in our opinion, a wide and general problem connected with the development and research of drugs and approaches to treatments in general.

A large section of clinical research is supported by pharmaceutical companies that direct and also influence it according to their own interests and not necessarily coinciding with the interests of the doctor or of the patient.

This is what happens when expensive drugs such as retinoids, antibiotics, and topical steroids benefit from enormous investments for developing new generations of drngs and new derivatives while the less expensive drugs are neglected.

We do not wish to dispute the important contribution that pharmaceutical companies give to the progress of medicine and to clinical and basic research. One cannot deny the advantages that modem medicine derives from these companies, but it seems that the balance between what we receive from them on the one hand and what we have to pay in the form of following directives,

Correspondence 385

accepting their guidance, and having to take into con- sideration their economic interest on the other hand must always be under constant check.

Ronni Wolf, M.D. Barzilai Medical Center, Ashkelon, 78306 Israel

Reply To the Editor: Pharmaceutical companies are an im- portant source of funding for a significant proportion of clinical and laboratory research. Proposals submitted to the pharmaceutical industry are, in general, reviewed for (1) scientific content and merit as judged by sci- entists and/or physicians with knowledge or expertise in the topic area, (2) ability of the investigator to con- duct the proposed research, (3) relevance to company programs and objectives, and (4) a determination of whether they compete with ongoing studies or intended studies by company personnel. If a proposal received approval by the reviewers, a recommendation is then made to the appropriate administrative sources for fi- nancial support. When the administration accepts the recommendation, if funds are available, the proposal will be funded.

Dr. Wolf is apparently philosophically opposed to a project being evaluated for its relevance to company programs and objectives. I suspect that most investi- gators involved in pharmaceutical research have ex- perienced, at various times, a sense of frustration when an idea that they judge to be exciting and potentially of great value to patient care or the advancement of scientific knowledge is rejected because it does not co- incide with company programs and objectives. In per- spective, however, it is clear that any funding agency (e.g., Dermatology Foundation, National Institutes of Health, Psoriasis Foundation, etc.) similarly sets prior- ities for the types of projects that it will support finan- cially. The kinds of priorities and the reasons for the priorities are obviously different depending upon the institution, but the impact "in the form of following directives, accepting guidance and having to take into consideration t h e i r . . , interests" is in many respects the same. Furthermore, if a project truly has merit and if one accumulates sufficient preliminary data to sub- stantiate that fact, a follow-up proposal often meets with a much more favorable response.

Compromises in scope and direction of research are almost inevitable when one seeks funding. Compro- mises of patient welfare and ethical standards are nei- ther necessary nor acceptable. Despite the inevitable

386 Correspondence

frustrations, the progress of medical research would be significantly retarded without the important contribu- tion of the pharmaceutical industry.

Virginia C. FiedIer, M.D. University of Illinois, Chicago, 1L 60680

Skin eruption caused by fat-soluble vitamin K injection

To the Editor: We read with interest the recent article by Finkelstein et al, "Cutaneous Hypersensitivity to Vitamin K, Injection" (J AM ACaD DERMATOL 1987;16:540-5). They reported six cases of cutaneous hypersensitivity to vitamin K~ injection associated with liver dysfunction. These authors came to the conclusion that patients with any type of liver disease may be at risk for vitamin K~ hypersensitivity and that the hy- persensitivity may be a marker of liver disease. We present a different view on this subject. Although the literature in North America and Europe offered less than 40 cases of cutaneous vitamin K~ hypersensitivity, ac- cording to our survey 94 cases have been reported in Japan, mainly from 1965 to 1970. ~,2 There probably exist a number of unreported cases.

Two types of skin eruptions have been described as occurring after vitamin Kt (phytonadione) injection. The localized type shows a pruritic, eczematoid, in- durated erythema around the injected skin. ~.2 The gen- eralized type, only rarely observed, shows generalized papules, 2 to 3 mm in diameter, sometimes with lo- calized eruption after the intravenous administration of vitamin K~. ~'~ The localized type of skin eruption might be caused by a delayed hypersensitivity of vitamin KI, sometimes associated with an adjuvant effect of a vi- tamin K1 vehicle, a nonionic detergent.

Vitamin Kt injection was frequently used in Japan for liver hypofunction and postoperative or postdelivery bleeding. In sixty-three cases of all the reported cases, comment was made on the patients' background of vi- tamin K~ administration, among which only four had liver dysfunction. Although Dr. Finkelstein and col- leagues emphasized a high risk of vitamin K~ hyper- sensitivity in liver diseases, we suggest that the inci- dence is dependent on the background population and field. According to our survey, no correlation was found between vitamin KI hypersensitivity and liver disease. The occurrence of cutaneous vitamin K~ hypersensitiv- ity has diminished in Japan as a result of less-frequent vitamin K1 injection. To the contrary, however, four eases of the same kind of eczematoid lesion have re- cently been reported as having occurred after local in-

Journal of the American Academy of

Dermatology

jeetion of fat-soluble vitamin I(2 (menatetrenone). ~'5 In- tradermal skin tests were positive in all the cases for vitamin K2 but were negative for the vitamin K2 vehicle. One case occurred during treatment for liver cirrhosis.

Ryoji Tsuboi, M.D., and Hideoki Ogawa, M.D., Ph.D. Juntendo University School of Medicine Hongo 2-1-1, Bunkyo-ku, Tokyo, Japan

REFERENCES 1. Honda M, Hattori Y, Moriyama M. Skin eruptions caused

by vitamin K,. Hifuka no Rinsho 1970;12:295-301. 2. Anekoji K. Skin eruptions caused by vitamin Kt injection.

Chiryo 1970;52:1577-87. 3. Yamamoto M, Higuchi T, Ogino A. Adverse skin reaction

caused by vitamin Ks. Hifuka Kiyo 1982;77:37-40. 4. Kanno Y, Murakoshi M, Takahashi N, et al. A case of

eczematoid skin eruption caused by vitamin K: injection. Hifuka no Rinsho 1984;26:448-9.

5. Shono M, Hada S. Drug eruption caused by vitamin K2. Hifuka no Rinsho 1986;28:423-7.

Reply

To the Editor: It is with great interest that we read the letter by Tsuboi and Ogawa. It is clear that reactions to vitamin K1 injection are not limited to Europe, or North America. The description of the localized and generalized types of reactions seems to be very similar to what we have observed at our Center.

The authors correctly make the point that vitamin KI hypersensitivity will be seen most often in patients with liver disease because these are the ones who are most often receiving this drug. We are not sure why the authors, in mentioning sixty-three cases of vitamin K1 hypersensitivity, referred to only four cases as having had liver dysfunction. They claim that vitamin K1 in- jection was frequently used for liver hypofunction and surgical or obstetric bleeding. Hypofunction to us is a form of dysfunction, as this implies a metabolic ab- normality with the liver. Also, could the postoperative or delivery bleeding represent a diffuse intravascular coagulation state that can throw off liver function tests?

It is also notable that reference is made to hyper- sensitivity reactions to vitamin K2. This drug is not in clinical use in North America. The reaction to the drug and not to the vehicle when testing was done follows the pattern we found when testing vitamin K~ and its vehicle.

Although most vitamin K1 sensitivity reactions will be seen in patients already known to have liver prob- lems, we still believe that an open mind should be kept to the possibility of this type of reaction suggesting