GRISEOFULVIN: A NEWLOOK AT ANOLD DRUG
Oscar E. Araujo, Franklin P. Flowers, and Mark M. King
ABSTRACT: Griseofulvin is the oral antifungal agent of choice for the
treatment of dermatophytoses, This article reviewsthe history,
pharmacokinetics, adversereactions,and traditional therapeutic
applications of griseofulvin. In addition, reports since 1960of the use
of the drug in the treatmentof Raynaud'sphenomenon, progressive
systemicsclerosis, lichenplanus, mycosisfungoides, herpes roster,
eosinophilic fasciitis, and molluscumcontagiosumare discussed,
notingthe varyingdegreeof therapeutic success.
DlCP Ann Pharmacother 1990;24:851-4.
GRISEOFULVIN HASBEENONTHE MARKETfor several decades
having as its primary indicated use the treatment of der-
matophyte infections. However, in the course of the last 20
years the drug has been reported to be useful in the therapy
of a number of non-fungal disease states. The history ofthis
versatile medication, its pharmacokinetic properties, and
its application in conventional and non-conventional treat-
ment regimens is reviewed.
History
In 1939, Oxford et al. published a manuscript reporting
an interesting metabolic product of a strain of Penicillium
received from Professor Biourge of the University of Lou-
vaine. The name proposed for this new compound was
"griseofulvin," since the parent mold was termed Pen-
icilliumgriseofulvum.' Since its original discovery, grise-
ofulvin has been derived from other organisms such as P.
janczewskii, P. patulum, and P. raistriki?
For the next 20 years, little else was discovered about the
new compound until Gentles found that griseofulvin was
useful in the treatment of ringworm in guinea pigs.' Fol-
lowing this revelation, a flurry of experiments was con-
ducted on the new compound to determine its effectiveness
in the treatment of dermatophytoses, fungal infections that
until the advent of griseofulvin were very difficult to treat.
The first experiments of the use of griseofulvin in humans
were conducted in 1958 in Germany, Great Britain, and the
United States."
Since the 1960s, reports of the use of griseofulvin in
OSCAR E. ARAUJO, Ph.D., is a Professor, DepartmentofPhannacy Practice,College
of Phannacy; FRANKLIN P. FLOWERS, M.D., is an AssociateProfessorof Medi-
cine, Division of Dermatology, Departmentof Medicine, College of Medicine, Univer-
sity of florida, Gainesville, A..; and MARK M. KING, Phann.D., is a Community
Pharmacist,Bartow,A... Reprints: Oscar E. Araujo,Ph.D., Box1-486,JHMHC, Gain-
esville, A.. 32610.
This article is approved for continuing education credit.
DICP, The Annals of Pharmacotherapy • 1990September, Volume 24 • 851
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many non-fungal disease states have been published. It has
been noted by various researchers and clinicians to be use-
ful in the treatment of other disease states such as lichen
planus, leprosy, scleroderma, and Raynaud's disease."
These reports of effectiveness are often in the form of case
reports from the clinical setting rather than a result of con-
trolled trials.
Meclumism ofAction
Even at high concentrations, griseofulvin is fungistatic
and not fungicidal. 4 It was first believed that the mecha-
nism of action of griseofulvin was the disruption of the syn-
thesis of chitin, a compound in fungal cell walls." The
actual mechanism of action is still unknown, however, sev-
eral theories have been proposed. One theory holds that the
mechanism of action of griseofulvin lies in its ability to dis-
rupt the mitotic spindle structure, thus arresting the fungal
cell growth in the M-phase of its life cycle. Another pro-
posed mechanism suggests that griseofulvin may lead to
the production of defective DNA, resulting in an inability
of the fungal cells to replicate. 4,5
The reason an oral dose of griseofulvin is effective against
a fungal infection lying in the skin is that the drug tends to
be deposited in keratin precursor cells. 5 Griseofulvin also
shows a preference for infected cells instead of healthy
ones." In addition to its antifungal actions, griseofulvin
also displays certain antiinflammatory and minor vasodila-
tory effects. 5
Pharmacokinetics
ABSORPTION
The absorption of griseofulvin following oral dosing is
variable. The white, bitter compound is virtually insoluble
in water, diluted acid, or alkali. In vivo, the drug is mostly
absorbed from the duodenum, although it can also be ab-
sorbed from the jejunum and ileum. 4-6
The absorption of griseofulvin is enhanced by the reduc-
tion of the particle size, thereby increasing the surface area
of the compound." Currently, there are two formulations
of griseofulvin on the market utilizing different particle
sizes, and these ultramicrosize formulations are more rap-
idly, completely, and uniformly absorbed than the micro-
size formulations due to the polyethylene glycol added. 5.7
However, despite the claims of manufacturers that ultra-
microsize griseofulvin 250 mg is equivalent to 500 mg of
the microsize preparations, there have been studies show-
ing that the plasma concentrations of the microsize forms
may be greater over a period of time than those obtained
from the ultramicrosize griseofulvin. 4,7 The peak serum
concentrations usually achieved following oral administra-
tion of 500 mg of microsize or 250 mg of ultramicrosize
griseofulvin are 0.4-2.0 IJ.g/mL and occur four to eight
hours after administration. 2-5
Other means of increasing the absorption of griseofulvin
include the use of a high-fat diet, or preparation of an oil-in-
water emulsion of the microsize drug. 4,7
DISTRIBUTION
Upon oral administration, griseofulvin becomes concen-
trated in the body's skin, hair, nails, liver, fat, and skeletal
muscles. 2-6 As mentioned earlier, the drug has a predis-
position for deposition into keratin precursor cells, leading
to an unfavorable environment for fungal growth. Since the
drug also displays an affinity for diseased skin, it is be-
lieved that griseofulvin disrupts the fungal cells already
present by the disruption of the cell's mitotic spindle struc-
ture. 3,5
Griseofulvin appears in the skin approximately four hours
after an oral dose at a concentration of 1 IJ.g/g of skin. Eight
hours after administration, it is present at a concentration of
approximately 3 IJ.g/g. 5
An interesting property of griseofulvin is that more of the
drug can be found in the outer layers of the skin than one
would suspect from an orally administered preparation.
The reason for this property is believed to be that some of
the drug is transported to the outer layers via the sweat
glands.v"
ELIMINATION
The elimination half-life of griseofulvin is variable (9-
24 hours) even within the same patient. 3,6 After an oral
dose, 50 percent of the compound is excreted in the urine
and 36 percent in the feces within five days.4,6 The major
metabolites of griseofulvin are 6-desmethyl-griseofulvin
and its glucuronide conjugate. 6
Adverse Reactions
The most common adverse effects that occur during gri-
seofulvin therapy are headaches, nausea, vomiting, anorex-
ia, abdominal cramps, flatulence, and diarrhea. Usually,
the headache is transient and resolves upon continued use
of the drug. 4,5 By taking the medicine with meals, one not
only increases the absorption of griseofulvin, but also de-
creases the gastrointestinal discomforts associated with the
compound."
One of the more disturbing adverse effects of the drug is
the photosensitivity reaction it can induce, which may even
lead to a precipitation or exacerbation of lupus erythemato-
SUS. 4 ,5,8
Hypersensitivity reactions to griseofulvin include urti-
caria, erythema multiforme, and serum sickness." A case
of fatal toxic epidermal necrolysis following the use of gri-
seofulvin has been reported, and is only the second docu-
mented case recorded in the literature." Since griseofulvin
is derived from species of Penicillium, there is a remote
chance of a cross-sensitivity reaction with penicillin.
Central nervous system reactions include dizziness, fa-
tigue, and insomnia. On rare occasions, elevations ofpor-
phyrin have been reported with griseofulvin therapy.5
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Therapeutic Indications
DERMATOPHYTOSES
Since Gentles first reported the effectiveness of griseo-
fulvin in eradicating ringworm infections, the drug has
been used in the treatment of a number of fungal infections
of the hair and skin, especially tinea corporis, tinea pedis,
tinea capitis, tinea barbae, tinea cruris, and tinea unguium. 2-5
Susceptible organisms include species of Trichophyton,
Microsporum, or Epidermophyton.r':" The response to
therapy with griseofulvin depends on the amount of kerati-
nization present in the infected skin surface along with the
time necessary for the natural desquamation process to
occur.5,10
Because of the site involved, treatment of fungal infec-
tions of the toenails requires many months.v'? Hay et al.
demonstrated positive results in the treatment of onychomy-
coses caused by Trychophyton rubrum by using a topical
solution of 28% tioconazole applied twice daily, as adjunc-
tive therapy to oral griseofulvin 500 mg bid. They reported
that when the combination of drugs was used as therapy, the
chance of complete remission and more rapid improvement
was greater than when griseofulvin was used with a base
placebo. However, they also noted that despite this combina-
tion treatment, 30 percent of the patients being treated with
griseofulvin failed to gain complete remission even after a
year of therapy. In all cases the patients were followed for one
year. Statistically significant differences (p<0.005) were
detected, where 69 percent of nails achieved clinical remis-
sion when treated with griseofulvin plus tioconazole com-
pared with 41 percent receiving oral drug plus base only."
In another study, Tanz et al. compared the effectiveness of
ketoconazole 3.3-6.6 mg/kg/d versus griseofulvin 10-20
mg/kg/d for a 12-week treatment of tinea capitis caused by T.
tonsurans. Using a randomized, double-blind study design,
they attempted to ascertain if there was a significant dif-
ference in the remission rates of 48 patients with tinea capitis.
Of the 22 patients receiving ketoconazole, 16 (73 percent)
were considered successfully treated, and 25 of 26 patients
(96 percent) receiving griseofulvin were cured. The re-
searchers concluded that while the results of their study
showed differences that were not statistically significant,
(p<0.10) griseofulvin should remain the drug of choice."
RAYNAUD~PHENOMENON
In 1973, Sabri et al. conducted a double-blind, crossover
clinical trial to determine the effects of griseofulvin treat-
ment in patients with Raynaud's phenomenon. Twenty-four
patients were assigned to one of two groups, based on the
severity of pain associated with their disease state. Four-
teen patients assigned to Group A had the most severe pain
and randomly received either two 500-mg tablets bid of gri-
seofulvin (British Pharmacopeia) or a placebo. For the ten
patients in Group B, 500 mg of the same formulation of gri-
seofulvin or the placebo was given in the morning and
again at night. Each patient was on hislher initially assigned
therapy for four weeks, followed by a one-week wash-out
period. At the conclusion of the wash-out period, the
patients were assigned to their alternative four-week treat-
ment regimen (either drug or placebo). 13
Different treatment regimens were evaluated as a prefer-
ence by the patient as to clinical success at the end of the
study. Ten of the patients in Group A preferred the treat-
1990 September, Volume 24

ments with griseofulvin and four expressed no preference.
In Group B, five of the ten patients expressed a preference
for the griseofulvin treatment, three patients for the place-
bo, and two expressed no preference. Physician assessment
showed no significant differences between griseofulvin and
pl~cebo. The authors suggest that griseofulvin may help
relieve the symptoms of Raynaud's phenomenon by in-
creasing the blood flow in small arteries and that the effect
appears to be dose-related. 13
PROGRESSrvESYSTEMUCSCLEROS~
The effectiveness of griseofulvin in the treatment of pro-
gressive systemic sclerosis (PSS) has been observed. Ferri
et al. treated 33 patients with a fine-particle griseofulvin
preparation in doses of 375-500 rng/d for 18-84 (mean 33)
months. Patients were followed at 12-month intervals and
evaluated at the end of the treatment. Both the observers
and the patients noted a definite improvement in the con-
dition of the skin. Increased skin elasticity, hair growth,
and better joint mobility were observed in 85 percent of the
patients. As noted by the authors, this study was open-
ended and did not allow a definite assessment of griseoful-
vin's true effectiveness in the treatment ofPSS. 14 However,
the drug seems to counteract skin thickening and improve
skin elasticity as indicated by chest expansion. No mecha-
nism of action was proposed.
LICHEN PLANUS
An accidental observation led to the use of griseofulvin
in the treatment of lichen planus when a patient being
treated for a concomitant tinea corporis infection showed
clinical improvement of his lichen planus. These observa-
tions led Sehgal et al. to conduct a double-blind study of 44
patients who received a treatment regimen of either griseo-
fulvin fine particles 500 mg or placebo for an eight-week
period. At the end of the trial, patients were assessed clini-
cally and histologically for improvement. 15
Complete clinical improvement, defined as a decrease in
pruritus, a decrease in scaling, and a flattening of lesions
followed by postinflammatory pigmentation, was observed
in 81.8 percent of the patients receiving griseofulvin versus
none in the placebo group. A partial clinical improvement
was noted in 18.2 percent of the drug-treatment group as
opposed to 22.7 percent partial improvement in the placebo
group. Histological improvement was noted only in the gri-
seofulvin patients, where the histopathology of lichen planus
could no longer be observed. The authors theorized that the
drug may have interfered with nucleic acid metabolism vital
to the keratinization process to produce these dramatic re-
sults."
Levy et al. have published a study of 26 patients with
lichen planus who were treated with two griseofulvin fine
particle 125-mg tablets bid for three weeks to six months.
At two-week intervals, the patients were assessed for sub-
jective (decreased pruritus) and objective (appearance of
lesions) improvement. After the treatment period, the
patients were followed for an additional six months to two
years. An overall resolution of the lesions was noted in
80-90 percent of all patients with initial improvement
observed in two weeks."
Not all of the reports using griseofulvin for the treatment
of lichen planus are positive. Bagan et al. observed a wors-
ening of the lesions of lichen planus in five patients in a
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Griseofulvin
seven-patient study and no improvement of the disease in
the r~maining two patients. The patients were given griseo-
fulvin 500 mg for 2Yz months. It is conceivable that the
negative clinical results were related to the fact that therapy
was carried out for only ten weeks."
MYCOS~ FUNGOIDES
Griseofulvin also has been shown to have a possible role
in the treatment of mycosis fungoides. Shelley reported on
a patient with well-delineated, bilateral, erythematous,
scaling atrophic plaques in the axillae and bathing suit area.
The patient was diagnosed as having mycosis fungoides
and treated with nitrogen mustard for a period of ten days.
A papulosquamous area developed in the patient's groin
and the nitrogen mustard was discontinued. The new le-
sions were diagnosed as tinea cruris, and griseofulvin ther-
apy was initiated at a dose of 500 mg bid."
After a month of treatment, the plaques of mycosis
fungo ides had resolved and griseofulvin dosing was con-
tinued for three years. When the drug was discontinued, the
plaques reappeared. Griseofulvin therapy was reinstituted,
and the plaques again subsided after one month. It was sug-
gested that the griseofulvin may inhibit chronic infections
leading to antigen release, which may be responsible for the
plaques of mycosis fungoides." Similar results were re-
ported a few months later by Thomsen." Although the
data for this novel treatment is sparse it should be kept in
mind for patients recalcitrant to traditional treatment.
HERPES roSTER
Griseofulvin has also been used for herpes zoster. Jou-
bert treated four patients experiencing severe pain from the
disease. After treatment with griseofulvin, dramatic im-
provement was observed in all patients. 20 Castelli et al. con-
ducted a placebo-controlled trial of 57 patients with con-
firm.ed herpes zoster. They were randomly assigned to
receive one of four treatments: methisoprinol (inosine pran-
obex) I g qid, griseofulvin 125 mg qid, griseofulvin and
methisoprinol concomitantly at the above doses, or a placebo
qid. Griseofulvin alone afforded no improvement of the con-
dition and the methisoprinol-griseofulvin combination
provided significantly more pain relief than either treatment
alone." The mechanism for this potentiation is not clear,
but the effect of griseofulvin on the immune system may
interact positively with the immunomodulating action of
methisoprinol.
EOSINOPHILIC FASCDTIS
Giordano et al. reported the case of a 25-year-old man suf-
fering from eosinophilic fasciitis who was treated with grise-
ofulvin for eight months. Significant clinical improvement
occurred, where previous treatment with corticosteroids and
azathioprine had failed. Eosinophils, gammaglobulins, and
the erythrocyte sedimentation rate decreased after only one
hour of treatment. The authors suggested that griseofulvin
may prove to be an effective alternative to corticosteroid
therapy in eosinophilic fasciitis.P
MOLLUSCUM CONTAGIOSUM
Treatment of molluscum contagiosum with griseofulvin
was reported by Singh and Kanwar in a study of five pa-
• 1990 September, Volume 24 • 853
tients who had extensive viral infections. The patients were
given griseofulvin 500 mg/d for four to six weeks. Each
patient saw a complete disappearance of the lesions within
this time. The researchers reported complete resolution of
the lesions, and no recurrences of their condition were
noted in eight months of follow-up. 23
Summary
Since its discovery 50 years ago, griseofulvin has been
used in the treatment of various skin conditions. Although
many nonfungal diseases have shown some response to gri-
seofulvin therapy, the major impact of the compound still
lies in its ability to effectively treat susceptible species of
dermatophytes (tineas). It must also be stated that most of
the studies have limited data to support the use of griseoful-
vin routinely to treat these nonfungal diseases. Nonethe-
less, the drug should be kept in mind as a potential treatment
alternative for the several conditions discussed.s>
References
I. OXFORD AE, RAlSTRICK H, SIMONART P. Griseofulvin, C. 7H I70.CI, a
metabolic product of Pennicillium Griseo-fulvum Dierckx. Biochem J
1939;33:240-8.
2. ANDERSON DW. Griseofulvin: biology and clinical usefulness. Ann
Allergy 1965;23:103-10.
3. GENTLES Jc. Experimental ringworm in guinea pigs: oral treatment with
griseofulvin. Nature 1958;182:476-7.
4. BECKER LE.Griseofulvin. DermatolClin 1984;2:115-20.
5. MCEVOY GK, ed. Drug information 88. Bethesda, MD: American
Society of Hospital Pharmacists, 1988:76-8.
6. UN C-C,MAGAT J, CHANG R, MCGLOTTEN J, SYMCHOWICZ S. Absorp-
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macol Exp Ther 1973;187:415-22.
7. STRAUGHN AB,MEYER MC,RAGHOW G, ROTENBERG K. Bioavailabil-
ity of microsize and ultramicrosize griseofulvin products in man. J
Pharmacokinet Biopharm 1980;8:347-62.
8. BLANK H. Commentary: treatment of dermatomycoses with griseoful-
vin. Arch DermatoI1982;118:834-6.
9. MION G. VERDON R, LEGULLUCHE Y. CARSIN H. GARCIE A,
GUlLBAUD 1. Fataltoxicepidermalnecrolysisafter griseofulvin(letter).
Lancet 1989;2:1331.
10. HAY RJ,CLAYTON YM, GRIFFITHS WAD, OOWD PM.A comparativedou-
ble blind study of ketoconazole and griseofulvin in dermatophytosis.
BrJ DermatoI1985;112:691-6.
II. HAY RJ, CLAYTON YM, MOORE MK. A comparison of tioconazole 28%
nail solution versus base as an adjunct to oral griseofulvin in patients
with onychomycosis. Clin Exp DermatoI1987;12: 175-7.
12. 1J\NZ RR,HEBERT AA.ESTERLY NB.Treatingtinea capitis: should keto-
conazole replace griseofulvin? J Pediatr1988;1/2:987-91.
13. SABRI S, ROBERTS VC, HIGGINS RF, COTTON LT, WILLIAMS Dl, WIL-
SON Le. A double-blind clinical trial of griseofulvin in patients with
Raynaud's phenomenon. PostgradMed J 1973;49:641-3.
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15. SEHGAL VN, BIKHCHANDANI R, KORANNE RV, NAYAR M, SAXENA
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22-7.
16. LEVY A, STEMPLER D. YUZUK S. SCHEWACH-MILLET M, RONEN M.
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EXTRACTO
La griseofulvina sigue siendo el agente antift1ngico oral de elecci6n
para eI tratamiento de dermat6fitosis. Este articulo revisa la
historia, farmacocinetica, reacciones adversas, y aplicaciones
terapeuticas tradicionales de la griseofulvina asf como su empleo
con resultados variables en el tratamiento del fen6meno de
Raynaud, esclerosis sistemica progresiva, liquen plano, micosis
fungoides, herpes zoster, fascitis eosinofflica, y molluscum
contagiosum.
CARMEN CAO
RESUME
La griseofulvine est toujours un agent antifongique de choix pour Ie
traitement des dermatophytoses. Cet article revise l'historique, la
pharmacocinetique, les reactions adverses et les applications
therapeutiques traditionnelles de la griseofulvine. De plus on y
discute des rapports existants depuis 1960 sur son utilisation dans Ie
traitement du phenomene de Raynaud, de la sclerose systemique
progressive, du lichen plan, de la mucosite fongoide, de l'herpes
zoster, de la fascitite eosinophilique et du molluscum contagiosum
en y denotant Ie degre variable de succes therapeutique.
CHANTAL GUEVREMONT
1990 September, Volume 24