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Overview |
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Definition |
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Erythema is defined as redness of the skin, resulting from congestion of the
capillaries. There are many causes and manifestations of erythema; some examples
include photosensitivity, erythema multiforme and erythema nodosum. Erythema
multiforme is a an acute inflammatory eruption of the skin and/or mucosal
membranes. Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)
have been historically considered severe forms of erythema multiforme, although
some people view them as separate but related conditions. Erythema nodosum (also
called subacute migratory panniculitis) is a nodular erythematous eruption that
is typically limited to the extremities. The following sections address
background and treatment information about erythema multiforme and erythema
nodosum; the complementary and alternative therapies section also covers
approach for adjunctive treatment of erythema in general, particularly
photosensitivity. |
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Etiology |
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Erythema multiforme
- Idiopathic—50% of cases
- Infectious—primarily herpes simplex virus
(HSV) and mycoplasma pneumonia, but numerous others (e.g., Epstein-Barr virus,
hepatitis B, influenza A, Salmonella,
Streptococcus pyogenes, Trichomonas vaginalis)
- Drugs—including sulfonamides,
anticonvulsants, penicillin, poliomyelitis vaccine, 5-fluorouracil
- Radiation therapy
- Malignancies
- Serum sickness
- Erythema infectiosum (fifth disease)—human
parvovirus B19
- Chemicals
Erythema nodosum
- Idiopathic—50% of cases
- Tuberculosis
- Streptococcal infection
- Sarcoidosis
- Systemic lupus erythematosus (SLE)
- Ulcerative colitis
- Pregnancy
- Drugs—especially oral contraceptives,
sulfonamides, bromides
- HSV
- Leprosy (usually after initiation of antimicrobial
therapy)
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Risk Factors |
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Erythema multiforme
- Previous history
- Males at greater risk than females
- Sun exposure
Erythema nodosum
- Familial
- Females at greater risk than
males
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Signs and Symptoms |
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Erythema multiforme
- Prodromal symptoms—malaise, fever, sore
throat, cough, and itching or burning at impending site
- Sudden onset
- Target lesions and papules—central erythema
surrounded by normal skin, which is surrounded by erythematous ring; central
portion dusky red, 1 to 3 cm circumference, may become cyanotic, purpuric, or
vesicular; heal without scarring; hyperpigmentation or hypopigmentation
common
- Knees, elbows, palms, soles; oral lesions appear in 25% of cases;
trunk in severe cases
- Lesions recur in crops
- Erythema infectiosum—facial "slapped cheek"
rash; reticulated rash (upper extremities) lasting about 2 weeks
- SJS—upper respiratory infection; flat
atypical targets on trunk; mucosal involvement (oral blisters, conjunctivitis,
nares, anorectal junction, vulvovaginal region); hacking cough; fever
- TEN—initial SJS-type symptoms progress to
generalized detachment of the epidermis; sepsis, fluid loss;
death
Erythema nodosum
- Prodromal symptoms—fatigue, malaise, upper
respiratory infection; low-grade fever, flu-like symptoms
- Tender nodules—2 to 6 cm in diameter; resolve
without scarring or joint damage
- Lesions change from red, hard, and painful to fluctuant and bluish,
fading to yellowish or brown
- Arthralgias
- Arthritis
- Typically in crops, may be solitary
- Shins, forearms, thighs, trunk
- Leprosy—severe and systemic
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Differential
Diagnosis |
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Erythema multiforme
- Kawasaki disease
- Behcet's syndrome
- Urticaria
- HSV
- Stomatitis
Erythema nodosum
- Nodular nonsuppurative panniculitis (Weber-Christian
disease)
- Thrombophlebitis
- Erysipelas
- Cellulitis
- Arteriosclerosis obliterans
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Diagnosis |
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Physical Examination |
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Clinical appearance helps to identify the type of erythema. Physical
examination may identify underlying disease. A thorough history can reveal
agents. |
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Laboratory Tests |
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Erythema multiforme
- Skin biopsy—may reveal HSV-specific DNA
- Immunoglobulin (IgM) antibody to B19—fifth
disease
- Immunofluorescence—SJS
- Test for
lymphopenia—TEN
Erythema nodosum
- Elevated erythrocyte sedimentation rate
- Mild leukocytosis
- For differential diagnosis: throat culture, stool culture, tuberculin
skin test
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Pathology/Pathophysiology |
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Erythema multiforme
- Circulating immune complexes and mononuclear and T lymphocyte-rich
cell infiltrates around upper dermal blood vessels
- Increased expression of intracellular adhesion molecule 1
(ICAM-1)
- TEN—keratinocyte necrosis
Erythema nodosum
- Lymphohistiocytic infiltrate
- Granulomatous inflammation
- Fibrosis in the septa of subcutaneous
fat
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Imaging |
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X ray—bilateral hilar adenopathy with erythema
nodosum, related to a particular disease or may be nonspecific reaction
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Other Diagnostic
Procedures |
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Treatment Options |
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Treatment Strategy |
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Underlying disease is treated and causative drugs stopped. Measures to
control symptoms are instigated. While mild cases need not be treated, bed rest
and medication are used for moderate or severe cases. |
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Drug Therapies |
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Erythema multiforme
- Prednisone—high dose for 1 to 3 weeks until
controlled, then taper quickly; prevents recurrence; use is controversial
- Acyclovir (400 mg bid for 6 months)—continual
use prevents HSV-related lesions
- Valacyclovir (500 mg/day) or famciclovir (250 mg
bid)—newer antiviral agents
- Azathioprine (100 to 150 mg/day)—anecdotal
reports of efficacy; however, recurs upon discontinuation
- Thalidomide (100 mg/day, then titrate to effective
level)—for refractory cases; severely teratogenic
- Levamisole hydrochloride (150 mg/day for 3
days)—for oral lesions
- Antihistamines—control pruritus
- Burrow's compresses—for cutaneous
blisters
- Analgesics—preferably not NSAIDs
- Topical steroids—for papules and
plaques
- Antibiotics—for secondary infection, avoiding
drugs associated with erythema
- Human intravenous immunoglobulin—promising
experimental treatment for SJS and TEN
Erythema nodosum
- Intralesional triamcinolone acetonide (2.5 to 5
mg/mL)—for symptom relief
- Corticosteroids—reduces symptoms; masks
underlying disease; recurs on discontinuation
- Antibiotics—for underlying infections
- Thalidomide (200 mg bid for 2 to 3 days, then
reduce)—for leprosy; severely teratogenic
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Complementary and Alternative
Therapies |
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Treatment of any type of erythema is dependent upon the underlying cause.
Certain CAM therapies may:
- Reduce inflammation
- Support the immune system
- Help prevent secondary infections
Antioxidant compounds, for example, have demonstrated protective effects for
the skin against ultraviolet-induced damage in clinical trials. Therefore, the
question raised is whether antioxidants may confer protection to the skin from
other sources of damage. In addition, because sun exposure is one of the risk
factors for erythema multiforme, photoprotective antioxidants may,
theoretically, confer some protection against this disease
process. |
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Nutrition |
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According to scientific studies, dietary supplementation or topical
administration of antioxidants provides some protection against damage to the
skin, such as that which ultraviolet radiation may cause. The mechanism of
action is not entirely understood but antioxidants are scavengers of ROS
(reactive oxygen species). ROS and oxygen-derived free radicals cause damage to
the skin by depleting it of important protective antioxidants. These reactive
substances also interact with lipids, proteins, and other biomolecules and, in
the process, make the skin tissue more susceptible to damage (Dreher et al.
1998).
The studies described in the following subsections suggest that
supplementation with antioxidants may provide at least modest photoprotective
benefit when used prior to exposure. It is not clear from the data whether
topical or oral antioxidants confer protection to the skin from other types of
damage leading to erythema multiforme, erythema nodosum, or other forms of
erythema; such protection, though, seems plausible. Supplements with antioxidant
properties that have been investigated include:
- Carotenoids
- Vitamin C
- Vitamin E
- Melatonin
- Zinc
Caution should be exercised when considering supplementation with megadoses
of vitamins. Although they may provide photoprotection, the impact of long term
supplementation is unknown. In addition, the results are not yet conclusive and
more research is needed.
Carotenoids
Carotenoids are highly effective natural scavengers of ROS. Several small
studies have investigated whether carotenoids help to protect against
UV-light-induced erythema and have reported positive results. In one study, for
example, twenty healthy subjects, ages 20 to 57, were randomly assigned to two
groups:
- Group one received 25 mg of carotenoids (primarily beta-carotene)
daily for 12 weeks
- Group two received the same oral carotenoid supplementation together
with 500 IU alpha-tocopherol (vitamin E)
Subjects were categorized by skin type:
- Type I (fair, white skin; red or blonde hair; green or blue eyes;
extremely sensitive to sun exposure; absence of tanning)
- Type II (white skin, blonde or light brown hair, blue eyes; sensitive
to sun exposure; and minimal tanning).
In both groups, participants' unprotected skin response prior to
supplementation was used as the control. Both groups experienced greater
protection against erythema formation during supplementation, as indicated by
higher MED (minimal erythema dose) levels than baseline values. Group two showed
less erythema formation than group one, indicating a possible additional
protection from vitamin E, although this difference was not statistically
significant (Stahl et al. 2000).
Vitamins C and E
A few small studies suggest that vitamins C and E, taken in combination, may
have photoprotective properties. In one double-blind, placebo-controlled study,
for example, 10 subjects took the following for eight days:
- Ascorbic acid 2 g
- d-alpha-tocopherol 1,000 IU
MEDs were assessed before and after the trial. In the vitamin group, MED
level increased in eight subjects following eight days compared to no change in
the placebo group (Eberlein-König et al. 1998).
These synergistic effects were further examined in a prospective, randomized,
placebo-controlled study of 40 healthy volunteers. Results showed that oral
supplementation with megadoses of vitamins C and E (3 grams and almost 3,000 IU
respectively), in combination, achieved greater photoprotective effects than
supplementation with either vitamin alone (Fuchs and Kern 1998). As stated
earlier, though, caution must be exercised when using megadoses of vitamins
because of lack of knowledge regarding long term safety.
Melatonin
A small scale study suggests that topical melatonin may confer added
photoprotection when combined with both vitamin C and vitamin E in topical form
(Dreher et al. 1998). In this study by Dreher et al (1998), significant
differences were also seen when vitamin E was combined with either melatonin or
vitamin C. Even melatonin alone achieved significant dose-dependent effects
compared to placebo. Vitamin C or vitamin E alone, however, demonstrated only
modest to no effect.
Given the size of the melatonin, vitamin C and vitamin E studies to date,
more research is required before drawing conclusions about efficacy or even
safety of these substances for skin protection from the sun or other damaging
processes.
If there are benefits to topical antioxidants in protecting against sun
damage to the skin, it seems that these free radical scavengers should be used
prophylactically rather than as treatment. Six volunteers applied topical
vitamin C, vitamin E, melatonin, or placebo cream alone or in combination
following UV-light irradiation. (An unexposed and untreated skin area served as
a negative control for each subject.) Significant reductions in erythema
response were not observed with single antioxidants or combinations, nor with
single or multiple applications. The authors concluded that the benefits of
topical antioxidants in erythema suppression appear to be limited to
preparations applied prior to, not following, UV exposure. The authors suggest
that oxidative skin damage is a rapid event and that antioxidants can help
prevent such damage only when present in UV-exposed skin prior to and during
exposure (Dreher et al. 1999).
Zinc Sulfate
A review article describes seven known cases of necrolytic acral erythema
(NAE; a condition akin to TEN as described earlier) and adds an eighth case.
Dosages of oral zinc sulfate (60 to 440 mg/day), administered alone or in
combination with interferon, were reported to be effective for five of the eight
patients (Sinclair and Reynolds 1997).
Flavonoids
In theory, flavonoids confer a benefit for erythematous skin conditions such
as erythema multiforme and erythema nodosum because they act as
anti-inflammatories and strengthen connective tissue. Examples include (Murray
1996):
- Quercetin 200 to 400 mg tid 20 minutes prior to meals
- Rutin 50 to 250 mg bid to tid
- Hesperidin 250 mg bid to tid
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Herbs |
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Green Tea
Antioxidant properties in green tea may provide protection against
UV-light-induced erythema. Epigallocatechin-3-gallate (EGCG), the major
polyphenolic constituent of green tea (Camellia sinensis), has
demonstrated photoprotection in previous animal models. In a human study,
volunteers were subjected to UVB radiation equal to a 4 MED dose, delivered to
buttock skin with or without topical EGCG applied 30 minutes before exposure.
Skin punch biopsies were obtained from the treated areas and nontreated control
areas. EGCG significantly (Katiyar et al. 1999):
- Inhibited erythema formation
- Reduced myeloperoxidase and cyclooxygenase
- Protected against leukocyte infiltration
- Diminished prostaglandin metabolite formation
- Reduced cellular oxidative damage
Other Herbs
Although not studied scientifically, herbs used traditionally to promote
dermal healing, stimulate lymphatic circulation, and possibly help treat the
underlying cause include the following examples:
- Burdock root (Arctium lappa) can be used topically for skin
inflammation and wound healing (Blumenthal et al. 2000)
- Goldenseal (Hydrastis canadensis)—for
an infectious etiology
- Lemon balm (Melissa officinalis) cream or wash can be applied
to HSV lesions (which may cause erythema multiforme –
see section entitled Etiology) (Blumenthal et al. 2000).
- Licorice root (Glycyrrhiza glabra)—in
the case of a virus; contraindicated with hypertension (Blumenthal et al.
2000)
- Meadowsweet (Filipendula ulmaria)—for
pain, particularly arthralgias (as may be seen with erythema nodosum)
(Blumenthal et al. 2000)
- Milk thistle (Silybum marianum)—for a
chemical etiology (Blumenthal et al. 2000)
- Slippery elm (Ulmus fulva) may be combined with goldenseal root
and applied topically for treatment of an open wound (Blumenthal et al.
2000)
- Yarrow (Achillea millefolium) can be used topically for skin
inflammation and wound healing (Blumenthal et al.
2000)
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Homeopathy |
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Independent studies published by two groups of researchers have demonstrated
positive photoprotective effects of homeopathic treatment with Apis in
albino guinea pigs subjected to radiation. Although neither of these studies was
methodologically rigorous, both reported positive results (Vickers 1999).
Additional remedies commonly used in clinical practice for skin conditions
include:
- Chininum sulphuricum
- Rhus toxicodendron -- used in the case of blisters and vesicles
accompanied by intense itching that worsens at night and improves with the
application of heat; the appropriate patient is generally restless and unable to
get comfortable at night
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Massage |
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Should be avoided in the case of acute erythematous skin
conditions |
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Patient Monitoring |
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Erythema multiforme
- Burn unit—preferred when 20% of body affected
- Monitor fluid and electrolyte abnormalities, protein loss, organ
damage
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Other
Considerations |
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Prevention |
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- Treat underlying disease
- Avoid known triggers
- Acyclovir—with
HSV
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Complications/Sequelae |
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- SJS—may lead to blindness
- TEN—may lead to death (see Prognosis
section below)
- Erythema nodosum—pulmonary hilar
adenopathy
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Prognosis |
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Erythema multiforme
- Episodes generally resolve in 4 to 6 weeks
SJS and TEN
- SJS—generally resolves in 1 month without
complication; 10% mortality with extensive disease
- TEN—34% to 40% overall mortality; 25% to 100%
with full-thickness epidermal loss
- Prompt withdrawal of causative drug decreases mortality
Erythema nodosum
- Recurs for months; may persist for 2
years
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Pregnancy |
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- Thalidomide—severely teratogenic
- Precipitating factor with erythema nodosum
- Erythema infectiosum—can lead to fetal
infection, causing fetal anemia, heart failure, fetal hydrops,
death
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References |
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Beers MH, Berkow R, eds. The Merck Manual of Diagnosis and Therapy.
17th ed. Whitehouse Station, NJ: Merck Research Laboratories; 1999.
Blumenthal M, Goldberg A, Brinckmann J, eds. Herbal Medicine: Expanded
Commission E Monographs. Newton, Mass: Integrative Medicine Communications;
2000:230-239, 253-263, 419-423.
Dambro MR. Griffith's 5 Minute Clinical Consult. Baltimore, Md:
Lippincott Williams & Wilkins, Inc.; 1999.
Dreher F, Denig N, Gabard B, Schwindt DA, Maibach HI. Effect of topical
antioxidants on UV-induced erythema formation when administered after exposure.
Dermatology. 1999;198(1):52-55.
Dreher F, Gabard B, Schwindt DA, Maibach HI. Topical melatonin in combination
with vitamins E and C protects skin from ultraviolet-induced erythema: a human
study in vivo. Br J Dermatol. 1998;139(2):332-339.
Eberlein-König B, Placzek M, Przybilla B. Protective effect against sunburn
of combined systemic ascorbic acid (vitamin C) and d-alpha-tocopherol. J Am
Acad Dermatol. 1998;38(1):45-48.
Fauci AS, Braunwald E, Isselbacher KJ, et al., eds. Harrison's Principles
of Internal Medicine. 14th ed. New York, NY: McGraw-Hill; 1998.
Fuchs J, Kern H. Modulation of UV-light-induced skin inflammation by
D-alpha-tocopherol and L-ascorbic acid: a clinical study using solar simulated
radiation. Free Radic Biol Med. 1998;25(9):1006-1012.
Garcia-Doval I, LeCleach L, Bocquet H, Otero XL, Roujeau JC. Toxic epidermal
necrolysis and Stevens-Johnson syndrome: does early withdrawal of causative
drugs decrease the risk of death? Arch Dermatol. 2000;136(3):323-327.
Garcia-Porrua C, Gonzalez-Gay MA, Vazquez-Caruncho M, et al. Erythema
nodosum: etiologic and predictive factors in a defined population. Arthritis
Rheum. 2000;43(3):584-592.
Habif TP. Clinical Dermatology. 3rd ed. St. Louis, Mo: Mosby-Year
Book; 1996.
Halliday GM, Yuen KS, Bestak R, Barnetson RS. Sunscreens and vitamin E
provide some protection to the skin immune system from solar-simulated UV
radiation. Australas J Dermatol. 1998;39(2):71-75.
Katiyar SK, Matsui MS, Elmets CA, Mukhtar H. Polyphenolic antioxidant
(-)-epigallocatechin-3-gallate from green tea reduces UVB-induced inflammatory
responses and infiltration of leukocytes in human skin. Photochem
Photobiol. 1999;69(2):148-153.
Khanna VJ, Shieh S, Benjamin J, et al. Necrolytic acral erythema associated
with hepatitis C: effective treatment with interferon alfa and zinc. Arch
Dermatol. 2000;136(6):755-757.
Lee J, Jiang S, Levine N, Watson RR. Carotenoid supplementation reduces
erythema in human skin after simulated solar radiation exposure. Proc Soc Exp
Biol Med. 2000;223(2):170-174.
Lo SK, Yip D, Leslie M, Harper P. 5-flourouracil-induced erythema multiforme.
Int J Clin Pract. 1999;53(3):219-221.
Mandell GL, Bennett JE, Dolin R, eds. Principles and Practices of
Infectious Diseases. 5th ed. Philadelphia, Pa: Churchill Livingstone, Inc.;
2000.
Martinez AE, Atherton DJ. High-dose systemic corticosteroids can arrest
recurrences of severe mucocutaneous erythema multiforme. Pediatr
Dermatol. 2000;17(2):87-90.
Murray M. Encyclopedia of Nutritional Supplements. Rocklin, Calif:
Prima Publishing; 1996:320-335.
Rakel RE, ed. Conn's Current Therapy. 51st ed. Philadelphia, Pa: W.B.
Saunders; 1999.
Sinclair SA, Reynolds NJ. Necrolytic migratory erythema and zinc deficiency.
Br J Dermatol. 1997;136(5):783-785.
Stahl W, Heinrich U, Jungmann H, Sies H, Tronnier H. Carotenoids and
carotenoids plus vitamin E protect against ultraviolet light-induced erythema in
humans. Am J Clin Nutr. 2000;71(3):795-798.
Stern RS. Improving the outcome of patients with toxic epidermal necrolysis
and Stevens-Johnson syndrome. Arch Dermatol. 2000;136(3):410-411.
Vickers AJ. Independent replication of pre-clinical research in homoeopathy:
a systematic review. Forsch Komplementarmed.
1999;6(6):311-320. |
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Copyright © 2000 Integrative Medicine
Communications This publication contains
information relating to general principles
of medical care that should not in any event be construed as specific
instructions for individual patients. The publisher does not accept any
responsibility for the accuracy of the information or the consequences arising
from the application, use, or misuse of any of the information contained herein,
including any injury and/or damage to any person or property as a matter of
product liability, negligence, or otherwise. No warranty, expressed or implied,
is made in regard to the contents of this material. No claims or endorsements
are made for any drugs or compounds currently marketed or in investigative use.
The reader is advised to check product information (including package inserts)
for changes and new information regarding dosage, precautions, warnings,
interactions, and contraindications before administering any drug, herb, or
supplement discussed herein. | |