Systemic Agents in the Management
`Of Acne
`
`RONALD M. REISNER, M.D., Torrance
`
`• Topical therapy including incision of pustules and iniection of corticoste-
`roids into nodular and cystic lesions remains the mainstay of the management
`of acne.
`Systemic agents, including diuretics, corticosteroids, broad spectrum anti-
`biotics and progestin-estrogen combinations are significant and valuable ad-
`ditions to the therapy of resistant pustulocystic acne. They are, however, not
`without side effects and they should be reserved for carefully selected patients
`for whom they may, when used with discretion, produce gratifying results
`with relatively low risk.
`
`UNDERSTANDING OF THE complex interrelation-
`ship among the various factors influencing the de-
`velopment of acne has improved with increased
`study of the fundamental pathogenesis of this com-
`1non and intriguing disease. Despite this growing
`body of knowledge, therapy for acne remains to a
`great extent empiric, with the rationale for a given
`modality often following rather than preceding its
`·use. For many years, topical therapy has remained
`the mainstay of the management of acne. Topical
`measures have included cleansing of the skin with
`a variety of agents, the application of an almost
`endless series of drying and peeling lotions which
`. consist primarily of various combinations of sulfur,
`resorcin and salicylic acid, desquamation of the
`skin with carbon dioxide slush or ultra violet light,
`m~hanical extraction of closed comedones (white-
`heads), and open comedones (blackheads), inci-
`
`From tho Department of Medicine, Divlalon of Donnatolot!Y,
`Harbor General Hospital, Torranc:o, and U. C. School of Medi-
`cine, Loa Allaoles, Univomty of California Center for the Health
`Scioilcos, Loa Anaoles.
`Supported in part by a arant from the Blliott and Ruth Handler
`PounClation.
`Presented before the Section on DormatoloBY at the 9Sth Annual
`Seulon of the California Medical Aaaoclatioli, Loa Anaoles, 19 to
`23 March 1966.
`Reprint requests to: Divilion of Dormatolot!Y1 Harbor General
`Hospltal, 1000 West Carson Street, Torranc:o 9(1309.
`
`sion and drainage of pustules and fluctuant cysts
`and, more recently, the injection of various corti-
`costeroids directly into non-fluctuant cystic and
`nodular lesions.
`Such measures, although tedious and time-con-
`suming, have often provided good control of this
`eventually self-limiting disease while waiting for
`the active process to become quiescent. However,
`the more severe and disfiguring forms of pustular
`and cystic acne with their sometimes disastrous
`emotional impact on the developing teen-age boy
`or girl and their severe residual scarring, both
`physical and psychological, have often eluded con-
`trol with topical agents alone. Although the use of
`dermabrasion has been partially successful in re-
`versing the permanent scarring changes following
`upon severe pustulocystic acne, a far more prefer-
`able approach is prevention of the scarring by ade-
`quate control of the original disease process.
`The development of several newer means of
`systemic therapy has helped improve the manage-
`ment of these more severe forms of the disease.
`Most significant among them is the long-term ad-
`ministration of chemotherapeutic agents, particu-
`larly the broad spectrum antibiotics, and the use of
`
`28 JANUARY 1967 • 106 • 1
`
`Dr. Reddy's Laboratories, Ltd., et al.
`v.
`Galderma Laboratories, Inc.
`IPR2015-__
`Exhibit 1064
`Exh. 1064
`
`

`
`estrogen-progestin combinations either together or
`sequentially. Before proceeding to a more detailed
`consideration of these agents, I would like to com-
`ment briefly on the influence of other systemically
`administered agents in the management of acne.
`Diet
`In a broad sense, alterations in diet may be con-
`sidered as systemic therapy, and in the manage-
`ment of acne there is a long list of dietary restric-
`tions that have been proposed at various times,
`including such foods as chocolate, cheese, milk,
`Although
`shellfish.
`carbohydrates,
`fats,
`nuts,
`many dermatologists still incriminate chocolate32
`as an offender, there is growing acceptance for the
`view expressed by Hopkins in 195821 that "We
`have no reliable evidence that the food one eats
`.
`has anything to do with outbreaks of acne .
`and it would seem unnecessary at this time to im-
`pose dietary restrictions on most patients with
`acne.
`Vitamin A
`Although a venerable member of the anti-acne
`armamentarium, vitamin A has never been un-
`equivocally shown to be of value in the manage-
`ment of any form of acne, and a recently carefully
`controlled double-blind study' comparing the re-
`sults of vitamin A administered orally in a dose of
`150,000 units daily for 12 weeks and a lactose
`placebo, revealed no difference in effectiveness
`between the two. An important point emphasized
`in this study was the difficulty of accurately assess-
`ing the influence of treatment on the course of
`acne by clinical impression alone. The more ob-
`jective evidence provided by serial photographs
`compared by a panel of qualified observers at a
`later date proved more accurate and reliable, and
`at the same time highlights the difficulty of making
`objective reproducible clinical assessments in a
`therapeutic trial in a disease subject to spontaneous
`exacerbation and remission. There does not seem
`to be a firm place for vitamin A in the manage-
`ment of acne at this time.
`Diuretics
`Many female patients are noted to have a flaring
`of acne during five to 10 days preceding the
`onset of menses. These patients often also have a
`gain in weight during the same time.31 Since it is
`known that there is no alteration in sebum produc-
`tion during the various phases of the menstrual
`cycle,31 it would seem reasonable to postulate a
`
`possible relationship between premenstrual reten-
`tion of fluid and exacerbation of acne. And indeed
`in many such patients the administration of a diu-
`retic during a period of from five to 14 days before
`menses has proven effective in eliminating or de-
`creasing the severity of these premenstrual flares.
`The thiazide diuretics are widely used for this pur-
`pose, although any effective diuretic well tolerated
`by the patient should be equally effective. Double-
`blind studies are needed for final evaluation of this
`modality.
`Corticosteroids
`Although corticosteroids may themselves pro-
`duce a papulopustular follicular acneform erup-
`tion, they do appear to have an effective role
`in reducing the inflammatory lesions of severe cys-
`tic acne. However, double-blind studies are also
`needed here. Because of the hazardous side effects
`associated with corticosteroid administration, use
`of them should be reserved for selected severe cases
`of cystic acne with extensive involvement unre-
`sponsive to other modes of therapy. Treatment
`should be of the shortest duration possible, with a
`suggested initial daily oral dose in the range of 20
`to 30 mg of prednisone or its equivalent, with grad-
`ual withdrawal preferably within a month or so,
`although in exceptional cases long-term treatment
`may be necessary, with its concomitant increase in
`risk of side effects.
`Chemotherapeutic Agents
`Since Andrews2 reported the successful use of
`systemically administered antibiotics in the man-
`agement of acne in 1951, a number of studies*
`have been published reporting the good therapeu-
`tic results obtained in the management of pustular
`and cystic acne by use of a variety of antibiotics
`and sulfonamides. These have included several
`controlled double-blind studies.20'40'49 Such double-
`blind studies are especially important in evaluat-
`ing therapy in a disease such as acne which is sub-
`ject to repeated spontaneous exacerbations and
`remissions. Most of the recent interest in antibiotic
`therapy for pustular and cystic acne has centered
`around the tetracyclines,f and it is with this family
`of broad spectrum antibiotics that the remainder of
`this discussion will be concerned.
`Although, as noted previously, a number of un-
`controlled studies have been reported demonstrat-
`ing the value of the tetracyclines in pustular and
`cystic acne, there has been some conflict of opin-
`*Reference Nos. 4, 9, 10, 11, 20, 22, 40, 45, 46, 49.
`fReference Nos. 9, 10, 12, 16, 20, 31, 38, 39, 40, 49.
`
`CALIFORNIA MEDICINE 29
`
`Exh. 1064
`
`

`
`-ion as to their value expressed in several recent
`controlled studies.
`Hicks,20 Stewart40 and Wansker49 have all pub-
`lished double-blind controlled studies showing the
`apparently unequivocal value of orally adminis-
`tered tetracyclines in many patients with pustulo-
`cystic acne. The matched placebo-treated and
`tetracycline-treated patients studied by Freinkel
`and coworkers16 showed similar clinical results,
`and in both groups a reduction in free fatty acids
`of the surface lipids paralleled clinical improve-
`ment. On the other hand, Smith and coworkers34
`in England and Crounse12 here in the United States
`both failed to find any significant differences be-
`in controlled
`tween placebo and tetracyclines
`double-blind studies of the treatment of acne. The
`general preponderance of opinion, however, favors
`the tetracycline group of broad spectrum anti-
`biotics as active and useful agents in the manage-
`ment of pustulocystic acne.
`In view of some disagreement as to their effi-
`cacy on the one hand and, on the other, their ap-
`parent ability to control severe pustulocystic acne
`with very small doses over a long period, it is of
`interest to inquire into the mechanism by which
`the tetracyclines exert their apparently favorable
`effect. Although the precise and final answer to
`this question is not yet known, a fairly convincing
`web of circumstantial evidence has been developed
`which points strongly toward at least one probable
`mode of action.
`In general, patients with acne produce more
`sebum than do normal persons, although acne does
`not develop in all persons with high sebum lev-
`els.30 It has also been demonstrated that the injec-
`tion of whole sebum into the skin results in a pro-
`nounced lymphocytic inflammatory response and
`that sebum with the free fatty acids removed ex-
`cites only a minimal inflammatory response.41'44
`In contrast, the injection into the skin of free fatty
`acids derived from sebum results in a decided in-
`flammatory response similar to that caused by
`whole sebum, with rupture of pilosebaceous fol-
`licles and other histologic changes comparable
`with those occurring in acne.44 This strongly sug-
`gests that the free fatty acids in sebum are largely
`responsible for the inflammatory reaction in acne.
`However, the presence of free fatty acids is not
`alone sufficient to produce inflammation in acne,
`since levels of free fatty acids in surface lipids are
`essentially the same in groups with and without
`acne.16 Other factors as yet unelucidated appear
`
`30 JANUARY 1967 * 106 * 1
`
`to be necessary for free fatty acids to incite acne.
`It is further known that there is little or no free
`fatty acid in lipids of intact sebaceous cysts25
`which suggests that the lipids of freshly secreted
`sebum must undergo hydrolysis during their pas-
`sage through the follicular canal to the surface of
`the skin where sebum is found to contain up to 23
`per cent free fatty acid.19 Although there are sev-
`eral possible sources of such lipolytic activity,
`Scheimann and coworkers36 have presented evi-
`dence that skin bacteria are a major source of such
`lipolytic activity.
`Descriptions of the organisms comprising the
`cutaneous bacterial flora in acne have in part been
`somewhat conflicting; but two recent studies37'38
`have clearly demonstrated that two organisms con-
`stitute the overwhelming majority of the bacteria
`found in all forms of acne. Both are Gram-positive.
`One is an aerobe, Staphylococcus albus, and the
`other an anaerobic diptheroid, Corynebacterium
`acnes.
`It has further been shown that injection of living
`Corynebacterium acnes into sterile steatocystomas
`(intact sebaceous cysts) results in rapid prolifera-
`tion of the organism accompanied by the produc-
`tion of "products which irritated the lining, leading
`to leakage and rupture."23 This in turn gives rise
`to a pronounced inflammatory reaction resembling
`an inflamed acne cyst. In view of the predominance
`of Corynebacterium acnes among the follicular
`bacteria and its probable role in the production of
`free fatty acids by hydrolysis of the esterified fatty
`acids of sebum in the follicle and on the surface,
`it seems reasonable to speculate that the "products"
`resulting from the injection of living Corynebac-
`terium acnes into the sterile steatocystomas might
`well be free fatty acids.
`Puhvel and coworkers33 have shown that levels
`of antibody to Cornyebacterium acnes are elevated
`in the serum of patients with acne; whereas levels
`of antibody to Staphylococcus albuS34 are not; and
`this may reflect a direct involvement of C. acnes
`in the development of acne.
`Accordingly, a reasonable working hypothesis
`might suggest that the inflammatory lesions of pus-
`tulocystic acne are due in part at least to the re-
`lease of free fatty acids in the follicular ducts as a
`result of the lipolytic activity of Corynebacterium
`acnes on sebum, and that in susceptible persons
`these free fatty acids leak through the follicle wall,
`resulting in the clinical findings of pustules, cysts
`and inflammatory nodules.
`
`Exh. 1064
`
`

`
`Since Corynebacterium acnes is known to be
`highly sensitive to the broad spectrum antibiotics,
`including the tetracyclines,29 a suitable test of this
`hypothesis would be to correlate the influence of
`the tetracyclines on the clinical course of acne with
`their influence on sebum free fatty acid levels. Just
`such a critical study was undertaken by Freinkel
`and coworkers,16 and the results support the hy-
`pothesis noted above.
`They found that administration of tetracycline
`orally to adult patients resulted in a qualitative
`alteration in the composition of sebum, the total
`quantity produced remaining unchanged. The
`change observed was a reduction in the concentra-
`tion of free fatty acids, and it correlated well with
`amelioration of the inflammatory process and clin-
`ical improvement of the patient's acne. Although
`the study did not clearly demonstrate the basis for
`this activity of tetracyclines, the evidence previ-
`ously cited strongly suggests that they act by re-
`ducing the number of Corynebacterium acnes or-
`ganisms on the skin, and hence, their lipolytic
`activity.
`suppress Corynebacterium
`The tetracyclines
`acnes on the skin as long as they are administered,
`but the organisms multiply rapidly after these
`agents are discontinued, usually reaching pretreat-
`ment levels within approximately two weeks.18
`Clinical relapse of patients with pustulocystic acne
`correlated well with rising values for free fatty
`acids in sebum ater discontinuation of tetracycline
`therapy,'6 further suggesting a relationship be-
`tween the number of Corynebacterium acnes or-
`ganisms, the amounts of free fatty acids and the
`clinical manifestations of acne.
`Thus there is a rationale (developed, to be sure,
`long after the first clinical observations of its activ-
`ity) to account for the efficacy of the tetracyclines
`in pustulocystic acne; and development of this
`rationale has illuminated and been illuminated by
`a better understanding of fundamental piloseba-
`ceous pathophysiology.
`Despite their effectiveness, the tetracyclines and
`other antibiotics should not, of course, be used in
`the routine management of all patients with acne,
`but should be reserved for the more severe, exten-
`sive and recalcitrant forms of the disease which do
`not yield to conventional therapy as alluded to
`above. In such patients, gratifying results may be
`observed within two to three weeks after the ini-
`tiation of therapy and may be maintained as
`needed for months or even years, often with ex-
`
`tremely low dosages. A typical regime consists of
`the use of a tetracycline in doses of 250 mg orally
`four times daily for the first one to three weeks
`until a positive result is obtained. This is followed
`by a gradual reduction of the dose to the lowest
`dose which is sufficient to maintain control of the
`acne. In some patients this may be as little as 250
`mg every second or third day. In females who
`experience premenstrual exacerbations, uncon-
`trolled with diuretics, an increase in the tetracy-
`cline dosage during the 10 to 14 days preceding
`the onset of menses to a level greater than the
`maintenance dose may bring about improved
`control.
`Although the tetracyclines have been remark-
`ably free of serious toxicity despite prolonged us-
`age, a number of side effects are known to be asso-
`ciated with their use. Some of these side effects are
`trivial and do not ordinarily necessitate discontin-
`uation of treatment. Others are grave and even
`life-threatening and represent absolute contraindi-
`cations to tetracycline therapy for acne.
`Among the serious complications are the devel-
`opment of severe and at times fatal liver damage
`in pregnant women given large doses of tetracy-
`cline in the presence of preexisting renal disease
`such as pyelonephritis.51 The susceptibility of
`women to this complication may be further en-
`hanced during the latter half of pregnancy be-
`cause of a physiological decrease in clearance
`from the liver during this period.8 Another prob-
`lem associated with tetracycline therapy in the face
`of preexisting renal disease is the development of
`azotemia associated with decreased renal excretion
`of tetracycline, bringing about higher blood levels
`thus enhancing inhibition of protein synthesis
`and presenting the already damaged kidney with
`an increased nitrogenous load.
`Another significant problem associated with
`long continued administration of tetracycline is dis-
`coloration of both temporary and permanent
`teeth.47 This yellow-brown pigmentation may re-
`sult from tetracycline administered from the fourth
`fetal month to the twelfth year of life.24'53 Enamel
`hypoplasia has been noted in some, but not all,
`children with discoloration of the teeth due to
`tetracycline.53 Reversible
`retardation
`of bone
`growth has also been observed in prematures re-
`ceiving tetracycline.7
`Thus it is apparent that tetracycline therapy is
`completely contraindicated for the management of
`acne in pregnant women and in children below the
`
`CALIFORNIA MEDICINE 3t
`
`Exh. 1064
`
`

`
`age of 12 years, as well as in patients with pre-
`existing renal or hepatic disease, especially in view
`of the usually long-term nature of such therapy.
`Allergic reactions to tetracycline are rare27 al-
`though anaphylactoid reactions have been re-
`ported.13"15 With the exception of demethylchlor-
`tetracycline in which the incidence approaches 20
`per cent,5 photosensitization reactions are not com-
`mon with tetracyclines.5'8'26 Careful history cou-
`pled with clinical follow-up should avoid or
`promptly identify these side effects.
`Nausea, vomiting, diarrhea and superinfection
`with bacteria and yeasts are all uncommon com-
`plications in otherwise healthy persons27 and the
`debilitated patient who would be more susceptible
`to these problems is not likely to be a candidate
`for long-term tetracycline therapy for acne.
`The incidence of intercurrent infections resist-
`ant to treatment appears to be no higher in acne
`patients treated with antibiotics for long periods
`than it is in comparable patients not so treated.8'46
`Finally, since degraded tetracyclines may pro-
`duce severe interference with renal tubular func-
`tion, only "in date" drug which has not been sub-
`jected to extremes of heat and humidity should be
`used.14'50
`Thus the tetracyclines have at present a secure
`place in the management of carefully selected pa-
`tients with recalcitrant pustulocystic acne, but
`their use must be carefully supervised, and al-
`though at times it may seem convenient, refillable
`prescriptions should obviously not be dispensed.
`Progestin-estrogen therapy
`The androgen-stimulated increase in sebaceous
`gland activity occurring at puberty which provides
`the necessary but not sufficient basis for the devel-
`opment of acne vulgaris may be antagonized ef-
`fectively by sufficient levels of estrogen. The pre-
`cise mechanism of this activity is not established,
`but it is thought to be due to inhibition of ovarian
`androgen.43 To exert this effect, doses well in
`excess of normal physiologic replacement amounts
`are required-at least 0.06 mg of ethynyl estradiol
`daily.3' However, the pronounced menstrual ab-
`normalities and menometrorrhagia resulting from
`employment of such doses has made estrogen alone
`an unsatisfactory therapeutic agent in many pa-
`tients who might otherwise have benefited from
`such therapy. Because of feminization, estrogen
`therapy is, of course, not applicable to male pa-
`tients.
`
`32 JANUARY 1967 * 106 * 1
`
`The more recent development of a large series
`of progestin-estrogen combinations for contracep-
`tive use has provided a group of compounds which
`have both the sebum suppressive effect desired for
`control of acne and good control of menstrual
`cycling.42'43 There are a wide variety of such
`agents-one recent publication35 lists over 70-
`but evidence indicates that their favorable effect
`in acne is due almost entirely if not entirely to the
`sebum-suppressive effect of the estrogenic moi-
`ety.43 Quantitative sebum determinations demon-
`strate that clinical improvement and decrease in
`sebum levels are well correlated and that cyclic
`progestin-estrogen therapy for approximately two
`to five months is required to produce sebum sup-
`pression and clinical improvement in most women
`with acne,43 the majority responding within the
`first three cycles.28
`Such therapy should not be undertaken without
`adequate examination before it is begun, and care-
`ful observation during therapy is necessary.
`An adequate pretherapy examination should
`include, at a minimum'7,85,48
`(1) History to rule out previous thromboem-
`bolic phenomena, thrombophlebitis, cerebrovascu-
`lar accident, or estrogen dependent neoplasms;
`(2) Physical examination including bimanual
`pelvic examination and speculum examination of
`cervix and vaginal vault to rule out malignant dis-
`ease and fibroid tumors of the uterus (in young
`women with a virginal introitus, rectal examination
`is ordinarily preferred); breast examination to rule
`out carcinoma of the breast and, in the light of
`recent evidence,48 routine ophthalmologic exam-
`ination;
`(3) Laboratory examination to include routine
`blood cell count, urinalysis, cytologic examination
`of cervical exudate, and a liver function test.
`If results from these studies are within normal
`limits, selected women with recalcitrant pustulo-
`cystic acne unresponsive to the measures pre-
`viously discussed may be considered for cyclic
`progestin-estrogen therapy of the older combined
`type or the more recent sequential type. Although
`there may be a flare of the acne during the first
`one or two cycles, control can ordinarily be ex-
`pected within three to four cycles, occasionally
`five.28,31,42'43 If no improvement is noted by the
`end of the fifth cycle, it is unlikely to occur with
`continued use of the compound although in-
`creased dose levels may achieve control.
`
`Exh. 1064
`
`

`
`These agents are not without side effects, which
`should be carefully watched for. They include:
`* Nausea and vomiting. These are the most
`frequently encountered side effects and often dis-
`appear with time. They may be minimized by tak-
`ing the drug at bedtime.17,28,',42,43
`* Breakthrough bleeding. The incidence of this
`side effect may be diminished by regularity of tab-
`let intake17 and usually can be controlled by in-
`creasing the dosage.85
`* Weight gain. This may be secondary to fluid
`retention and it may spontaneously remit or require
`diuretic therapy.17,31,35
`* Mastalgia and breast engorgement. This usu-
`ally improves with change to a preparation with
`less estrogen.17
`* Dizziness, headache, abdominal pain, pelvic
`pain, fatigue and nervousness have all been occa-
`sionally noted but are difficult to evaluate.17'85
`* Chioasma. This occasionally becomes enough
`of a cosmetic problem to require discontinuation
`of the drug.17,28,4
`* Increased bromsulfalein retention. This has
`been occasionally noted but to date has not been
`shown to be clinically significant and may dis-
`appear despite continued therapy.'7
`* Thrombophlebitis. Although this has been
`the focal point of much interest, most observers
`seem to feel that there is no causal relationship
`between the use of progestin-estrogen combina-
`tions and thrombophlebitis.17'35
`* Neuro-ophthalmological complications. A re-
`cent survey by Walsh and coworkers48 suggested
`the possibility of the association of progestin-estro-
`gen therapy and the occurrence of a variety of
`problems, including pseudotumor cerebri, stroke
`syndromes, intraocular vascular lesions and severe
`headaches of the migraine type. The investigators
`emphasized the preliminary nature of their find-
`ings and concluded that no firn relationship be-
`tween the observed pathologic changes and the
`use of the progestational drugs was established,
`but that further study is warranted. In the interim
`it would appear prudent to be aware of the possi-
`bility and to withhold therapy from patients who
`develop during therapy or who give a previous his-
`tory of cerebrovascular disease, partial or com-
`plete visual loss, proptosis, diplopia, migraine,
`papilledema, retinal vascular lesions or thrombo-
`embolic phenomena.
`* Irregular menses, amenorrhea and infertility
`
`of varying and in some instances prolonged (12 to
`18 months) duration have recently been reported
`following withdrawal of therapy with progestin-
`estrogen combinations.52 This may be of particular
`importance to a young woman who has not yet
`had her family.
`Despite this long list of side effects the actual
`incidence of difficulty has been remarkably low,
`considering the vast number of women using these
`contraception.17'28'35 However,
`compounds for
`acne does not carry the risk that pregnancy may
`in selected situations, and therefore patients must
`be chosen carefully and this group of drugs re-
`served for patients with recalcitrant acne.
`
`REFERENCES
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`vulgaris, Brit. Med. J., 5352:294-96, 3 August 1963.
`2. Andrews, G. C., Domonkos, A. N., and Post, C. F.:
`Treatment of acne vulgaris, J.A.M.A., 146:1107, 1951.
`3. Baer, R. L., and Witten, V. H.: Editorial Comment
`in Year Book of Dermatology, 1960-1961, Yearbook
`Medical Pub., Chicago, 1961, p. 67.
`4. Brandt, R., and Beyer, A.: Controlled study of sulfa-
`dimethoxine (Madribon) in infected acne, Ohio Med. J.,
`56:1649-52, December 1960.
`5. Cahn, M. M., Levy, E. J., and McMillen, J. A.:
`Nature and incidence of photosensitivity reaction to de-
`methyl chlortetracycline, Arch. Derm., 84:485-89, Sep-
`tember 1961.
`6. Clendenning, W. E.: Complications of tetracycline
`therapy, Arch. Derm., 91:628-32, 1965.
`7. Cohlan, S. Q., Bevelander, G., and Tiamsic, T.:
`Growth inhibition of prematures receiving tetracycline,
`Am. J. Dis. Child., 105:453-61, May 1963.
`8. Combes, B., Shibata, H., Adams, R., Mitchell, B. D.,
`Alteration in sulfbromophthalein
`and Trammell, V.:
`sodium removal mechanisms from blood during normal
`pregnancy, J. Clin. Invest., 42:1431-42, September 1963.
`9. Cornbleet, Theodore: Long-term therapy of acne
`with tetracycline, Arch. Derm., 83:414-16, March 1961.
`10. Cornbleet, Theodore: Comparison of demethyl-
`chlortetracycline and tetracycline in acne, Arch. Derm.,
`89:204-06, 1964.
`11. Cronk, G. A., Naumann, D. E., Heitzman, E. J.,
`Marty, F. N., McDermott, K. J., and Vercillo, A. A.:
`Tetracycline hydrochloride in treatment of acne vulgaris,
`Arch. Derm., 73:228-35, March 1956.
`12. Crounse, Robert G.: The response of acne to pla-
`cebos and antibiotics, J.A.M.A., 193:906-10, September
`1965.
`13. Editorial: Anaphylactic reaction to tetracycline,
`J.A.M.A., 192:992, 1965.
`14. Editorial: Effects of tetracycline and degradation
`products, J.A.M.A., 194:143, 1963.
`15. Fellner, M. J., and Baer, R. L.: Anaphylactic re-
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