48 What’s New Around the World Burks

WHAT’S N E W AROUND THE WORLD

Jcrmes W . BzrrksJic Scu Orlc~ans, La., U.S.A.

Ominous clouds seen last year on the therapeutic horizon in the form of gov- ernment restrictions account, as was predicted, for an apparent state of doldrums in the advance of dermato- logic treatment. To those of you who come hurriedly from the temples of the basic sciences, with the genetic concept of the origin of most derma- toses fresh in your minds, to your right- ful place a t the bedside of the patient, I must confess that there will be no revelation of cures by alteration of DNA. However, for those of you who do not adhere to this popular concept of etiology for all dermatoses and for those who do not limit their practices to the genodermatoses this review con- tains some practical “take-home” treat- ments for humans rather than for rats. Admittedly, i t is almost impossible to

report anything new in the face of the ever-increasing flood of paper commu- nications which cross our desks, many of them quasi-scientific reports, some containing news items leaked by drug houses even before publication in our specialty journals and others giving Dr. Kildare-type headlines to uncon- firmed therapeutic breakthroughs or to trivial contributions, depending upon the availability of material. For the most part, the material for this review was obtained, as in previous years, by direct communication with dermatologists from various parts of the world. That responses to my re- quests this year were woefully lacking in new treatments abroad as well as in this country indicates that govern- ment restrictions were not solely re- sponsible. There did appear to be

* Division of Dermatology. Dent. of Medicine, Tulane University School of Medicine, New Orleans, La.. U.S.A. Based upon What’s New Here and Abroad, presented at the Symposium in Therapy, Annual Meeting of the Ameri- can Academy of Dermatology, Chicago, Ill., U.S.A., Nov. 30-Dec. 5, 1963.

Dermatologia Tropica January-March 1964 48

reluctance on the par t of some institu- tional investigators and medical direc- tors of pharmaceutical companies to re- lease information of advances. Even individual investigators who are “going i t alone” with “off-the-shelf” material were uncommunicative, possibly be- cause of medicolegal complications. In the interim between the thalidomide catastrophe and the publication of re- sults obtained from government-con- trolled and subsidized work and the resumption of normal development work on new drugs by private enter- prise, clinicians in private practice must confine their studies to new ap- plications of available drugs. Admit- tedly, much remains to be done in this field because, for the past fifteen years or so, we have had such a wealth of new modalities that we hardly had time to master them before new ones ap- peared. Thus, there is a tremendous backlog of old “new” treatments to in- vestigate thoroughly. Food and Drug Administration activi- ties are not without some good. Some new drugs of widely heralded curative qualities but questionable validity will be withdrawn because of failure to meet efficacy requirements. Those who consider the invasion of their privacy by Food and Drug inspectors to re- trieve a forbidden or recalled drug a Gestapo tactic may find consolation in the avoidance of a possible medicolegal catastrophe. Others may be relieved of the pressure from drug companies to complicate their office routine with investigational drug studies. Having failed to uncover any outstand- ing new treatments from the usual sources, and hesitant to give you yes- terday’s bread, I have gone to the grass roots” local and sectional meet-

ings to learn what seems to help pa- tients currently.

Antibiotics Penicillin, because of its sensitizing potential, is still not favored by derma- tologists, in spite of the availability of less allergenic forms and two much- heralded newer sensitivity tests. A decline in the widespread use of pen- icillin, according to Pillsbury (U.S.A.) , may play a substantial role in the rise of syphilis. Only last year i t was emphasized here that the tetracyclines

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were the preferred antibiotics, since they were relatively harmless, as shown by their wide usage for over ten years. Now we have been alerted to the pos- sibility of serious side effects (Fan- coni’s syndrome) as well as milder ones (discoloration of developing teeth) ; the more serious reactions have been attributed to the formation of epi- anhydrotetracycline as a degradation product. The lesson for the drug com- panies is that more emphasis is needed on instructions regarding storage and expiration dates and that lactose is a better buffer ; the lesson for the physi- cian is that he should not pass out stale antibiotics and that he should advise patients not to take old, hoarded cap- sules containing dark-brown, gummy substances. Now that we have learned these lessons, let us forget the scare and simply remember that all drugs, if used long enough, will produce some adverse reactions ; aspirin, boric acid, penicillin, erythromycin, phenacetin and griseofulvin are but a few out- standing examples. In spite of the availability of newer, more effective and less toxic sulfona- mides, these drugs just are not as effective for general dermatologic use as the broad-spectrum antibiotics. The fact that the tetracyclines are so highly beneficial in the treatment of acne while the sulfas and penicillin are not, suggests a specific effect other than bac- teriocidal action since these agents, even when given in accepted therapeu- tic amounts, do not penetrate the patho- logic locus (the cyst) in sizeable amounts, and since most dermatologic usage approaches homeopathic dosage. A new antibiotic, aminosidine, chem- ically related to streptomycin, neo- mycin and kanamycin, was found by Gardenghi (Italy) to be highly effec- tive in controlling resistant staphilo- coccal infections without adverse side effects. Oral absorption is poor and the drug must be given intramuscularly. Local antibiotic preparations contain- ing neomycin and polymyxin have proved so successful in the treatment o€ pyodermas that there have been few additions to this group other than changes in the vehicle. A new anti- biotic, gentamycin (Schering) , pro- duced by Micromonospoi a p u r p u r a , has a wide spectrum and is active against

so What’s New Around the World Burks -

many gram-positive and gram-negative bacteria, including E. coli, Aero bacter, Kle bsiella, Pseudornonas, Proteus, pen- icillin-sensitive and resistant Staph- ylococcus and Streptococcus. Claims are that it appears to be comparable or superior to presently available prepa- rations ; however, some toxic reactions have been reported.

Steroids Faced with a lack of new corticoste- roids, we seem to have concentrated on new applications of those we have had. Whereas for the last two years we have been told how to increase the effectiveness of topical steroids by oc- clusion, utilizing everything from Bag- gies@ (Colgate-Palmolive Co.) to scro- tal supports lined with Saran WrapT M.

(Dow Chemical Co.) now, because of local and systemic effects, we are en- couraged to take off the wraps. Scog- gins’ (U.S.A.) report of the systemic absorption of corticosteroids applied to large body surfaces with occlusions has been confirmed. March and Kerbel, (U.S.A.) co-workers of Baer, found that as long as only 50% to 60% of the body surface is covered with Saran Wrap’ over triamcinolone or fluoci- nolone preparations there is no signifi- cant effect on the adrenals. Justifica- tion for the almost exclusive use of fluocinolone under occlusive dressings has been questioned by the work of Orentreich and Berger (U.S.A.) , who found in a double-blind study that fluocinolone was not superior to tri- amcinolone ; similar results were ob- tained by Irving Shapiro (U.S.A.) . A new local steroid preparation con- taining 0.2 % betamethasone has been tried in Great Britain and Ireland; Mitchell (Dublin) found it about equi- potent to fluocinolone and predicts that it may be marketed at a lower price, at least in his country. In the United States a cream containing betametha- sone and neomycin (Celestone, Scher- ing) was approved by the Food and Drug Administration. Those who favor betamethasone will be glad to learn that a new injectable form (Cele- stone Soluspan, Schering) is now at the Food and Drug Administration for approval. Ray Noojin (U.S.A.) found that these preparations were unique in offering, in a single injection, both a

soluble and insoluble corticosteroid for rapid and prolonged activity. The pres- ence of very small particulate matter in the insoluble part and the prompt anti-inflammatory action of the soluble fraction apparently account for the lack of causation of sterile abscesses, which are not uncommon with other intralesional steroids. A combination of dexamethasone and lidocaine, used as the local anesthetic for minor derma- tologic surgery, according to Wesly Wilson (U.S.A.), is worthwhile in the prophylaxis of hypertrophic or keloidal scars. Similar results were noted by William Dobes (U.S.A.) . Systemic steroid therapy of keloids within six months of onset will cause complete subsidence in 95% of cases, according t o H a r 01 d Bernstein’s (U.S.A.) seven-year follow-up report on 125 patients. Even “old” keloids were reduced by 25 % to 50 ”/. . Post-zoster neuralgia may be relieved by subcutaneous injection of triamcino- lone acetonide and lidocaine. Rees B. Rees (U.S.A.) used a mixture of 9 cc. of triamcinolone acetonide aqueous (Kenalog Parenteral, Squibb) sus- pension and 1 cc. of lidocaine (Xylo- caine, Astra) with convincing results.

S u p e rfic ia 1 Jfycosc~.s As the thoughtful evaluation of griseo- fulvin continues, both here and abroad, we have become more conscious of its limitations. Its striking benefit in the control of certain types of endemic tinea capitis may account for the fact that today we have few of these pa- tients, according to Beare (North Ire- land). Whereas for the past three years we have been trying to learn what type of tinea to treat and what form and dosage of the drug to use, now, even without influence from the Food and Drug Administration, we weigh the justification for its use. In addition to the relatively mild toxic reactions (urticaria, gastrointestinal manifestations, headache, drowsiness and vertigo) recently more serious side effects, such as lupus erythematosus- like reactions, leukopenia, proteinuria and photosensitivity, have been re- ported. Recent reports of liver damage and disturbances in porphyrin metab- olism in English mice (not guinea pigs, cats or rabbits) fed griseofulvin have

Dermatologia Tropica January-March 1964 51

resulted in a deterrent McCarthyism- like reaction to its use in humans, par- ticularly those with porphyria or liver damage and pregnant subjects. That the photosensitivity from ingestion of griseofulvin may be based on insidious liver damage with elevation of blood serum protoporphyrins was suggested as late as September 1963 by Bronow (U.S.A.). Harvey Blank (U.S.A.), in a re-examination of a number of his pa- tients who had received massive doses of griseofulvin, more than 2 Gm./day of the microcrystalline material for one to four years, found no abnormalities of liver function, uroporphyrins and cop- roporphyrins. He feels that the subject requires further study and clarification and, a t the present time, he finds no evidence to suggest that griseofulvin should be abandoned in clinical medi- cine. That side effects of drugs may not always be undesirable toxic mani- festations is exemplified by the seren- dipitous discovery of certain beneficial effects of griseofulvin on cardiovascu- lar disease a t Tulane University. Fur- ther experiences confirm our original report on the usefulness of this anti- fungal agent in the treatment of angina pectoris. Confirmation of our results by other workers is anxiously awaited. For those who are averse to prescribing griseofulvin for athlete’s foot and for the patient whose onychomycosis of the great toe may have one chance out of ten of being cured by US $1200 to US $1500 worth of griseofulvin, the new topical fungicide, Tolnaflate (un- der investigation by Schering Corpora- tion), is eagerly anticipated. Harry Robinson (U.S.A.) reports it to be curative in certain types of tinea pedis and tinea corporis within two to three weeks, without adverse reactions. In New Delhi, India, a reportedly highly potent and safe antifungal anti- biotic, hamycin, has been released. A chemosurgical technique for the re- moval of onychomycotic substance was brought back from Russia by Belisario (Australia). Ureaplast (urea 20.0, Water 10.0, cerae flav. 5.0, lanolin 20.0, emplastrum plumbi 45.0) is applied to the nails two or three times over four O r five days. After each application the softened nail is removed by shaving knife or curette. After removal is ac- complished, a fungicidal paste is ap-

plied. Griseofulvin is given a t the on- set of treatment. The average period for cure is said to be one and one-half to two months.

Of illice, Not Mm, and Psoriusis The controversy over the use of the antifolic acid drugs for psoriasis con- tinues. In the light of the dangers of this type of agents to the physician as well as to the patient, one cannot but Ice amazed a t their popularity and their reported safety and lack of serious con- sequences. Since the apparent safety of these drugs must be related to the way in which dermatologists use them, the current method of Rees B. Rees (U.S.A.) , the pioneer in their applica- tion, is presented here : “2.5 mg. Metho- trexate daily by mouth for six days, fol- lowed by three days rest, then repeti- tion. After one week’s rest, if the blood count and urinalysis show normal findings, but if there has not been an adequate response, we give one tablet daily for twelve days. If this in turn is ineffective after a week’s rest, we use Aminopterin on a tablet for tablet basis in the two schedules mentioned above. Rarely, we will give more than one tablet a day to a very large individ- ual or one who fails to respond other- wise. At the very first sign of any toxic effect whatsoever, the patient is in- structed to stop the medication and to contact us immediately. We are still very cautious in using Aminopterin in elderly people, very frail and debili- tated people, persons who have serious associated illness, people with extensive intertriginous or stasis involvement. Of course, it cannot ever be used during pregnancy. If a person is well-estab- lished on Methotrexate and Aminop- terin and has to take i t from time to time, after the first few blood counts we merely insist on a complete blood count at least every three months. In our opinion and apparently now in the opinion of many very competent men who have used these compounds, they are safer for long-term therapy than, say, steroids internally.” There is a new technique for the treat- ment of psoriasis which I have been advised not to mention here because this might encourage indiscriminate use. Since the code of the press is to print all the news, since the original

52 What’s New Around the World Burks

work with this technique has been re- ported in press, since several institu- tions are using it and, finally, since I cannot keep a secret, I must present it here. It is the intermittent intravenous use of Methotrexate in doses of 1-3 mg./Kg. of body weight a t intervals of seven to ten days. Might not this method of administration of a danger- ous drug, with rigid clinical and labo- ratory control, be the choice over its oral administration, where safety de- pends to a great extent on patient co- operation? A further advantage is that this method allows tailor-made doses for the individual patient to obtain op- timal effect. As a word of caution, of the 23 patients treated at Bethesda (U.S.A.) , according to a recent report, two have died, one from a gastroin- testinal hemorrhage during treatment and another from a cerebral thrombosis one week after treatment. Res ipsa loquitur! Mycosis fungoides, exfolia- tive erythrodermas and exfoliative psoriasis have been treated by John Fromer (U.S.A.) with intravenous in- fusions of 5 mg. of Methotrexate in a 24-hour period for one week, admin- istered to some patients on an out-pa- tient basis utilizing a new, portable pump (the Watson Infusor) . For those who are brave enough to use drugs with extreme toxicity and no known antidote, according to Demis of the Walter Reed Hospital (U.S.A.) the antimetabolite, 6-thioguanine, has a fa- vorable effect in psoriasis, dermatomyo- sitis, necrotizing angiitis and delayed cutaneous hypersensitivity responses. For the timid, the antiserotonin com- pound KB-95 (Sandoz) mentioned here last year, but still not available, is ef- fective in generalized scleroderma, lupus erythematosus and atopic derma- titis, according to a follow-up report from Leon Goldman (U.S.A.) . Ligh t - S e r i s i t i i ~ e Diseases It is in the group of light-sensitive dis- eases that the greatest advances have been made. The development of the concept of protoporphyria has led some to believe that genetic disturbances in porphyrin metabolism may explain, in part a t least, the cause of polymorphic light eruptions, eczematous contact dermatitis, hydroa estivale and solar urticaria. Unfortunately, according to

Bronow and Redeker (U.S.A.) there is no simple screening test which eliminates the necessity of examining heparinized blood and the stool for pro- toporphyrins. The possible role of griseofulvin in the production of liver damage and disturbances in porphyrin metabolism already mentioned in this presentation is another example of this trend of thought. Chloroquinc, discredited because of its toxic effect on the retina, may have a safe replacement for the prevention of sun damage in the form of an antihista- mine, triprolidine ( Actidil, Burroughs Wellcome & Co.), a drug with a for- mula similar to that of chloroquine and amodiaquin. Lowenthal reported in 1963 that this agent had proved capable of providing protection against certain actinic effects in a small series of pa- tients. In a subsequent report, he con- firmed his findings in additional pa- tients, according to which triprolidine not only protected normal skin from sunburn and was useful in the treat- ment of vitiligo, but also may prevent the development of solar keratoses and light-induced cancers. The recom- mended dosage is two 2.5 mg. tablets the night before and the morning of exposure. A long-acting form of the drug, in a strength of 10 mg., is avail- able in some countries. Equally exciting but less publicized is the treatment of photosensitive skin eruptions with massive amounts of ri- boflavin, recently reported by Mandel (U.S.A.) . Pyridoxine hydrochloride, in doses of 150 mg. to 200 mg. taken one-half hour prior to sun exposure, proved adequate to prevent certain im- mediate reactions. In another group of photosensitive patients, 100 mg. of vitamin B-6 every hour for nine to ten hours a day were required for protec- tion. Treatment with 1000 mg. of vita- min B-6 taken in one day was found to afford protection from one to two weeks. The mechanism of protection is thought to be based on a corrective effect of vitamin B-6 on a functional deficiency of pyridoxine phosphate, with subsequent restoration of normal tryptophan metabolism. After having been unable for years to develop a truly effective local sun screen through customary research efforts in- volving laboratory studies on mice, we

Dermatologia Tropica January-March 1964 53

have been provided by Jillson (U.S.A.) with one of the most satisfactory prep- arations to date from the forgotten survival kits of World War 11, namely, Red Veterinary Petrolatum. Not only is it a superb screen, but it is a suitable ointment base for treatment of sun- exposed areas or photosensitive skin, after it has been fortified with our most effective topical steroids. Last but not least, and most unusual these days, it is very inexpensive. We are also in- debted to Jillson for calling our atten- tion to the photosensitizing properties of bithionol, an antibacterial found in a number of preparations used by dermatologists as well as in over-the- counter products and cosmetics. Im- pressive as was the rapidity of removal of bithionol from these products, we cannot but be chagrined by the explana- tion of these drug companies that re- moval of this heretofore creditable in- gredient in their products in no way alters its effectiveness.

~ U i s c c l l ~ n r o ~ . t s Conditions Clinical investigation of a herpes sim- plex antigen (Lilly) has been halted for an evaluation of clinical experi- ences. From a biologic point of view, this treatment of recurrent herpes does not appear sound because patients with herpes have a high titer of neutralizing antibodies in their circulating blood. Furthermore, theoretical pessimism seems justified because of the demon- stration of 13 strains of herpes simplex virus from four individuals by Ashe and Scherp of the NIH (U.S.A.) . Cutaneous sarcoidosis, according to Daniel Lane (U.S.A.), was found to respond very well to the antimalarials ; this investigator and his co-workers a t M i c h i g a n gave hydroxychloroquine (Plaquenil, Winthrop) in a dosage of 200 mg. twice a day for two to three Weeks, and then 200 mg. daily as a maintenance dose. Cutaneous lesions of Seven patients involuted considerably Within three months and completely Within six. Previous reports by New York dermatologists in the Archives o f Dermatology had indicated that these drugs were not effective in sarcoidosis. The treatment of sarcoid in Hawaii is no problem, according to Harry Arnold (U.S.A.) , because the disease does not Occur there.

New treatments of warts appear as rapidly as we become disgusted with those which have failed us. If the formaldehyde measures I reported last year a re not working, I suggest this year you t ry the podophyllin-linseed oil method reported by Carslaw in the British Journal of Dermatology this year. Massing’s and Epstein’s (U.S.A.) finding of spontaneous involution of 67% of warts should be encouraging to any therapist who wishes to treat or not to treat warts. The experiences of 0 r e n t r e i c h (U.S.A.) with hair transplantation have resulted in two outstanding con- tributions; he has first, shown in a decisive, clear-cut fashion through a relatively simple office experiment that male-pattern type of baldness is a gene- determined and androgen-triggered de- fect and, second, during the past seven years, he has developed a technique and an instrument for the satisfactory cor- rection of a most distressing condition. To those who consider such a procedure impractical and unnecessary, I suggest you observe and talk with some of the enthusiastic patients so treated. Let us remember that in all treatments there are the subjective and objective results to be evaluated; so it is with correction of cosmetic defects, except that here i t is only the subjective eval- uation which really counts. Trial of the silicone-latex liquid com- bination, which has been used in Japan since 1948 and in the U. S. A. for a year or more, was stopped abruptly and officially early last spring. The only news regarding i t is based on un- confirmed rumors. Apparently, it is being used widely in the eastern and western parts of the U.S.A. by otorhinolaryngologists and plastic sur- geons. Granulomatous reactions ap- parently do occur, but they are micro- scopic and not out of proportion when compared to those seen with other in- jectables (sesame, peanut oil, etc.) . Those who wish to “go i t alone’’ may obtain the material #360 from the Dow Corning Company. A new, extremely effective systemic anthelmintic for the treatment of creeping eruption was reported at the meeting of the Southern Medical Asso- ciation at New Orleans, La., U. S. A., in 1963, by Fred Mullins. The effect

sa What’s New Around the World Burks

of this drug, thiabendazole (Merck, Sharp & Dohme) is most apparent in those patients who have had creeping eruption for at least two weeks. Other workers have found it effective for trichinosis. The pessimism of pioneer workers who are accustomed to fail- ures of new cures for this disease seems justified until the drug is evaluated on a large scale under well-controlled conditions. The chemotherapeutic agent, 5-Flu- rouracil 20 % with 5-10 % glucose added to enhance cell penetration and reduce toxicity, according to Leon Goldman (U.S.A.) , is still showing definite effect in the treatment of warts. Dillaha, Jansen and H o n e y c u t t (U.S.A.) found it of value in superficial malignancies, keratoacanthoma and solar keratoses, but have had to curtail further investigations with weaker dilutions, which they think may be as effective as the more potent one, be- cause of Food and Drug Administra- tion restrictions. In conclusion, lest you think otherwise, the FDA had nothing to do with my half-face planings, which I believe show conclusively that dermabrasion has a place in the treatment of precan- cerous skin.

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Occlusive treatment may be en- hanced by a ) water-wet sheeting over Auocinolone (Tye and Schiff, U.S.A.), b) damp cloth plus hot water bottle - 45°C (Kligman, U.S.A.), c) 25% aqueous glyc- erine packs over steroid under Saran WrapT nr. (Appel, U.S.A.) , and d) 1000 micrograms of vita- min DI2 to the gram of fluocinolone under wraps for discoid lupus erythematosus. Localized myxedema responds to fluocinolone under Saran WrapT.”. (George Skipworth, U.S.A.) . Nonspecific onychodystrophy may respond to triamcinolone (Desai, India). Necrobiosis lipoidica diabeticorum and granuloma annulare may clear up after cessation of cigarette smoking in California (Ringrose, U.S.A.), but not in Minnesota (Winkelmann, U.S.A.) .

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Dermatitis herpetiformis responds better to a combination of sulfa- pyridine and dapsone than to either drug alone (Belisario, Australia). If sulfa does not work, t ry intravenous heparin (Phil Anderson, U.S.A.) . Traumatized knees and elbows of patients with epidermolysis bul- losa may be protected by Squibb’s Rezifilm (Clinton Lane, U.S.A.) . Insect bite itch is relieved by 5% nepivacaine in collodion (Clinton Lane, U.S.A.). Vitiligo may be treated by a ) methyldopa, which may also bene- fit light eruptions and seborrheic d e r m a t i t i s (Leon Goldman, U.S.A.) , b) trimethylpsoralen, which is many times more photo- toxic than methoxsalen (Birm- ingham, U.S.A.), and c) Wren’s a i r brush (Binks Mfg. Go.) when loaded with walnut stain plus dihydroacetone ( S t e g m a i e r , U.S.A.). Tinea cruris responds imme- diately and dramatically to one or two applications of a solution of 2 % chrysarobin, 25 % mastisol and 75 70 chloroform (Nickel, U.S.A.). Seborrheic dermatitis responds to topical pyridoxine, 2.0 70, in ethyl alcohol or aquaphor, together with oral pyridoxine, 25 mg., after meals (Belisario, Australia) . Dermal burns are being treated by abrasion to prevent shock and toxicity (plastic surgeons-U.S.A. and Belgium). Healing of chronic leg ulcers is helped by ultraviolet irradiation with five to fifty times the ery- thema dose (Ingram, England). Static electricity of the Palmer House variety may be avoided by using Ionil shampoo (Owen Labo- ratories). Systemic sclerosis can be helped by E-aminocaproic acid in the early stages (Reque, U.S.A.) and by chloroquine in later stages (Korting) .

15. To keepX-ray parts from slipping when giving X-ray therapy, use Dukeplast first (Chas. Blaik, U.S.A.).