Dapsone, colchicine

1. SEMINAR PRESENTATION
Uses of dapsone, colchicine, and
thalidomide in dermatology
Moderator:-Dr. Puneet Bhargava

2. DAPSONE

3. History
• In past, sulfones were used preferentially as
antimicrobial/chemotherapeutic agents to treat infections
• Currently, dapson is the only remaining sulfone congener used
in human therapeutics.
• Because of its dual mechanism of action—antimicrobial and
anti-inflammatory/immunomodulatory effects—dapsone
alone or in conjunction with other drugs is used worldwide for
preventing and treating pathogen-caused diseases (eg,
leprosy)
• Or chronic inflammatory diseases,(eg, autoimmune bullous
eruptions)

4. History
• Synthesis of dapsone was reported in 1908 by Emil Fromm
• In 1937, soon after the discovery of sulphonamides as
antibiotics, two research groups (one in England and one in
France) were the first to investigate dapsone
• Both groups concurrently published the observed antiinflammatory potency in experimentally induced infections in
mice
• After extensive use of with promin and related sulfones in the
treatment of Hansen’s disease at the U.S. leprosarium in
Carville, Louisiana early in the 1940s by Faget and coworkers
sulfones ultimately developed from simple chemical
compounds into valuable therapeutic agents

5. History
• In 1950, the Portuguese Esteves and Brandao introduced
sulfones (eg, Sulphetrone, Diasone) into dermatology through
their reports of their successful use in treating DH
• Later, Sneddon and Wilkinson in England reported a remission
in subcorneal pustulosis after dapsone administration.
• Since that time, dapsone has been increasingly considered
effective in treating neutrophil-mediated processes and
autoimmune skin diseases, and retains its place in the
therapeutic armamentarium as a unique and essential agent

6. DAPSONE
• Dapsone is an aniline derivative.
• All sulfones share the structure of a sulfur atom linking to two
carbon atoms
• 4-4’-diamino-diphenyl sulfone (DDS)
• Available as 25 & 100-mg tablets
• Inexpensive drug

7. Absorption & Bioavailability
• Lipid soluble, water insoluble compound, penetrates well into
cells & tissues
• Well absorbed from gut (70-80%)
• Peak levels reached in 2-6 hrs
• Protein binding 70-90%
• Can cross placenta & is excreted in breast milk, hemolysis has
been demonstrated in nursing infants of mothers on dapsone

8. Metabolism
• Primarily metabolised by N-acetylation & N-hydroxylation
• Acetylated in liver by N-acetyl transferase to monoacetyl
dapsone (MADDS)
• MADDS undergoes glucuronidation to form water soluble
metabolites and renal excretion
• Acetylation is genetically determined, resulting in significant
variability in acetylation (rapid or slow acetylator)

9. Metabolism
• Also metabolised by dapsone N-hydoxylase, leading to a more
reactive metabolite dapsone hydroxylamine (DDS-NOH)
• Both efficacy and induction of adverse effects, the most
important factor is the generation of DDS-NOH;
• Normally, G-6-PD converts DDS-NOH to reduced metabolites
• In G-6-PD deficiency, hydroxylamine metabolites serve as a
strong oxidant causing RBC membrane damage with resultant
hemolysis

10. Elimination
• Elimination half life is 24-36 hours
• Dapsone remains in circulation for as long as 30 days after
single oral dose due to
- significant enterohepatic circulation &
- strong protein binding of dapsone & its metabolites

11. Mechanism of action
• Antimicrobial activity- bacteriostatic in nature
• Inflammatory disorders- similarities to (NSAIDs)
• Anti-inflammatory effects- ability to inhibit reactive oxygen
species (ROS)
• Decreases H2O2 as effectively as catalase
• Interference with activation or function of the G-protein,
resulting in an inhibition of signal transduction
• A protective effect on a1-protease Inhibitor
• Inhibition of cysteinyl leukotrienes (leukotriene C4)

12. Mechanism of action
• Inhibition of neutrophil & eosinophil myeloperoxidase
• Inhibition of neutrophil adhesion to vascular endothelium
integrins
• Inhibition of chemotaxis
• Inhibition of LTB4 binding
• Inhibition of generation of 5-lipogenase products in
neutrophils & macrophages
• Inhibition of dihydropteroate synthetase (enzyme in reduction
of folic acid)

13. Unique pharmacologic properties of
dapsone
1. Combination of antimicrobial and antiphlogistic effects (eg,
treatment of opportunistic infections in patients with AIIDS,
use of in acne)
2. Safety of long-term treatment (eg, life-long use in leprosy,
long-term ongoing or chronic intermittent approach in
inflammatory dermatoses)
3. Disease-specific antiphlogistic activity (eg, prompt decrease of
pruritus and control of skin lesions in DH)

14. Unique pharmacologic properties of
dapsone
4. Steroid-sparing effect (eg, long-term treatment in
autoimmune blistering diseases and as an adjuvant treatment
in bronchial asthma)
5. UV protection (eg, suppression of UVB-induced erythema by
dapsone and DDS-NOH)
6. Anticonvulsive effect (eg, in animal models)
7. Pharmacoeconomic benefits (eg, low cost of treatment).

15. Indications
•
•
-
FDA-approved indications
Dermatitis herpetiformis
leprosy
Dermatologic indications (consistent efficacy)
Linear IgA dermatosis
Bullous eruptions of SLE
Erythema elevatum diutinum

16. Other dermatologic uses
(variable efficacy)
•
•
•
-
Autoimmune bullous dermatoses:
Bullous pemphigoid
Pemphigus vulgaris/ foliaceous
Cicatricial pemphigoid
Subcorneal pustular dermatosis
Vasculitis:
Cutaneous vasculitis
Urticarial vasculitis
Neutrophilic dermatoses:
Sweet syndrome
Pyoderma gangrenosum
Bechet’s syndrome/ aphthous stomatitis

17. Indications
•
-
Other dermatoses:
Subacute LE
Relapsing polychondritis
Granuloma annulare
Granuloma faciale
Rosacea
Panniculitis
Pustular psoriasis
Nodulocystic acne

18. Dosage of dapsone in chronic
inflammatory dermatoses
• Adults- initiated at 50 to 100 mg/d
• If the treatment goal is not achieved after some weeks, a
higher dosage may be tried (150–300 mg/d); {depends on
tolerability and laboratory monitoring}
• Prophylactic administration of ascorbic acid, folate, iron, and
vitamin E reportedly may prevent, to a small degree, the
hematologic adverse effects associated with dapsone

19. Dosage of dapsone in chronic
inflammatory dermatoses
• Children- commercially available tablets of dapsone must be
crushed and dissolved, for example, in strawberry syrup.
• Some indications in childhood• Infantile acropustulosis or eosinophilic folliculitis, a daily
dosage of 2 mg per kilogram of body weight is recommended

20. Contraindications
• Absolute:
- Prior hypersensitivity to dapsone, including agranulocytosis &
hypersensitivity syndrome
• Relative:
- Allergy to sulphonamides
- Significant cardiopulmonary disease
- Significant liver or renal function impairment
- Pre-existing peripheral neuropathy

21. Adverse effects of dapsone
•
•
-
Pharmacologic:
Hemolytic anemia
methemoglobinemia
Idiosyncratic:
Hematologic: leukopenia, agranulocytosis
Hepatic: hepatitis, cholestatic jaundice, hypoalbuminemia
Cutaneous reactions: morbilliform eruption, hypermelanosis,
phototoxicity, exfoliative erythroderma, TEN
- Gastrointestinal: gastric irritation, anorexia
- Neurological & psychiatric: psychosis, peripheral neuropathy

22. Hemolytic anemia
- Due to N-hydroxy metabolites of dapsone, which are potent
oxidants which lead to hemolysis by:
- Depletion of RBC-reduced glutathione
- Structural changes in RBC
- Splenic sequestration of RBC
• Dose related adverse effect
• More common in G6PD deficient individuals

23. Methemoglobinemia
• Due to N-hydroxy metabolite of dapsone
• Dose-related side effect
• Methemoglobin formed has decreased oxygen-carrying
capacity & causes cyanosis
• In emergency, oral methylene blue (100-300mg daily) can be
used to acutely decrease methemoglobin levels
• Vitamin E(800 IU daily) & cimetidine (400mg TDS) decrease
methemoglobin formation.

24. Dapsone hypersensitivity syndrome
• Severe idiosyncratic adverse event, also known as dapsone
syndrome or sulfone syndrome
• Treated with systemic corticosteroids
• S/S:
- Fever
- Cutaneous eruption, ranging from maculopapular eruption to
TEN
- Hepatitis, with both hepatocellular & cholestatic features
- Peripheral eosinophilia

25. Monitoring guidelines
•
•
-
Baseline:
History & clinical examination
CBC, LFTs, RFTs, urinalysis, G6PD levels
Follow-up:
S/s of methemoglobinemia
Assess peripheral motor neurologic examination
CBC every wk for 4 wks, then every 2 wks for 12 wks & then
every 3-4 months
- Reticulocyte count to assess degree of hemolysis
- LFTs, RFTs, urinalysis every 3-4 months

26. Colchicine

27. Introduction
• Toxic natural product
• Active principle of the plant, Colchicum autumnale (autumn
crocus or meadow saffron), and other plants of Colchiaceae
family
• Isolates from the seeds and tubers of these plants
• Still in use today for the treatment of gout and
familial Mediterranean fever

28. Mechanism of Action
• Anti-mitotic - interrupt mitosis is due to its linkage to dimers
of tubulin, cause cessation of mitosis in metaphase and
interference in cellular mobility.
• Anti-inflammatory - Reduces mobility, adhesiveness, and
chemotaxis of polymorphonuclear cells.
- Interferes with ICAM, selectins, thus inhibiting T-lymphocyte
activation and its adhesion to endothelial cells.
- Impairs cellular secretion of procollagen and increases
collagenase production that promotes a larger collagenolytic
action.

29. Mechanism of Action
• Immunosuppressive action - inhibits cell-mediated immune
responses, by inhibiting Ig secretion, IL-1 production,
histamine release and HLA-DR expression.
• Other pharmacological effects - Decrease of the corporal
temperature, depression of the respiratory center, increased
response to sympathomimetic agents, contraction of blood
vessels, hypertension by central vasomotor stimulation, and
alteration of the neuromuscular function

30. Pharmacology and Pharmacokinetics
• Pale to greenish yellow crystals or powder.
• Oxidizes into a dark color, {different photoisomers }When
exposed to UV radiation, Hence, it must be shielded
• Rapidly absorbed when taken orally; peak plasma levels are
reached 30 - 120 min after ingestion.
• 50% of the drug circulates and links to plasma proteins.
• Metabolized in the liver, and the majority is eliminated
through bile in the feces.
• Also distributed in spleen and kidney.
• Overall, 10-20% of the dose is eliminated unchanged in the
urine.

31. Uses in Dermatology
• Until now, there was no formal indication approved by the
FDA for colchicine use in dermatology; however, several
uncontrolled studies have showed exciting results, mainly in
neutrophilic dermatoses.

32. Uses in Dermatology
• Papulosquamous Dermatoses
• Psoriasis was Ist cutaneous diseases to be treated with
colchicine.
• Wahba and Cohen used oral colchicine in 22 psoriasis patients
and found greater than 50% improvement in 11 patients.
• Results were better in those whose lesions were small
papules and plaques.
• Kaidbey et al. observed usefulness of topical colchicine in
patients with recalcitrant plaque psoriasis.
• Effectively used in psoriatic arthritis.
• Effective in generalized pustular psoriasis and palmoplantar
pustulosis.

33. Uses in Dermatology
• Recurrent aphthous stomatitis - In the dose of 0.6 mg twice
or thrice daily was found to decrease morbidity.
Behcet's syndrome - Effective in treatment of ocular, articular,
oral, and genital lesions.
- It was postulated that by blocking phagocytosis, increase
superoxide scavenging activity of neutrophils
• Sweet's syndrome - Improvement with a daily dose of 1.5 mg
colchicine was found in Sweet's syndrome.

34. .
Uses in Dermatology
• Bullous diseases - Several bullous diseases can be treated
• Dermatitis herpetiformis
- Silvers et al. used dose of 1.2-1.8 mg/day to treat patients
with DH.
- They found it useful as alternate therapy in those who could
not take sulfonamides.
• Linear IgA diseaseAram found very useful in patients who failed to respond to
dapsone.
• The good response to colchicine in this disease may be based
on the fact that there are many neutrophils.

35. Uses in Dermatology
• Epidermolysis bullosa acquisita (EBA)
- Megahed and Scharrffetter-Kochanek described successful
treatment of EBA with colchicine.
• Chronic bullous dermatosis of childhood (CBDC)
• Very useful in G6PD deficiency.
• In all the immunobullous dermatoses dapsone is the better
choice and colchicine is an alternative where the patient
cannot take dapsone due to G6PD deficiency or some other
reason or dapsone is not effective in a particular patient.

36. Uses in Dermatology
• Leucocytoclastic vasculitis (LCV) and Urticarial vasculitis
- Several case reports have described the beneficial effects in
this condition with involvement of the skin, with or without
joint manifestations, and also in urticarial vasculitis.
- Effective in urticarial vasculitis A/W hypocomplementemia.
- It reduces neutrophilic chemotaxis and motility in both these
conditions.
• Scleroderma
- Action on production, regulation of collagen, adhesion
molecules, and matrix digester enzymes justifies its use in this
disease.

37. Uses in Dermatology
• Amyloidosis
- Cutaneous lesions develop in upto 40% of patients
- This drug prevents amyloid deposition and slows disease
progression in amyloidosis associated with familial
Mediterranean fever.
• It blocks the release of lysosomal enzymes within
degenerated epidermal cells thereby preventing conversion of
the cells tonofilaments into amyloid.

38. Uses in Dermatology
• Miscellaneous
Colchicine was found to be effective in
• ENL,
Pyoderma gangrenosum,
• Severe cystic acne,
Calcinosis cutis,
• Keloids,
Condyloma acuminata,
• Fibromatosis,
Relapsing polychondritis,
• Primary anetoderma,
Subcorneal pustular dermatosis,
• Erythema nodosum,
Scleredema,
• Actinic keratosis,
Sarcoid.

39. Adverse Effects
• Usually well tolerated.
• GI- diarrhea, nausea, vomiting, and abdominal pain{due to
increase in gut motility by neural mechanisms as well as by
inhibition of mitosis in its rapid turnover mucosa}.
• Symptoms decrease on reducing the dose.
• Iv administration avoids the occurrence of these side effects.
• Long-term therapy may induce- steatorrhea, malabsorption
with reduced absorption of vitamin B 12 , fat, sodium,
potassium, nitrogen, xylose, and other actively transported
sugars.

40. • BM suppression - agranulocytosis, thrombocytopenia, and
aplastic anemia occurs after prolonged treatment.
• leukopenia occurs with accidental or intentional overdose and
prompt administration of G-CSF must be considered in such
cases.
• Myopathy and neuropathy occur particularly in patients with
renal impairment.
• Colchicine induces autophagic vacuolar changes in muscle
• Presents as proximal muscle weakness, with rise in CPK,
abnormal proximal muscle fibrillations, and axonal
neuropathy.

41. •
•
•
•
Recovers on withdrawal of drug.
Neuropathy resolution is more prolonged.
Azoospermia is a reported side effect.
Dermatological adverse effects include urticaria, TEN, and
precipitation of porphyria cutanea tarda.
• Alopecia occurs 2-3 weeks after the onset of therapy and
involves face, axilla, and pubic area.

42. Colchicine Overdose
• Published cases of death occurring after colchicine doses as
little as 6 or 7.
• Overdosage can lead to cholera-like syndrome with
dehydration, hypokalemia, hyponatremia, metabolic acidosis,
renal failure, and ultimately shock.
• RDS, DIC, and BM suppression occur.
• Patients may develop convulsions, delirium, muscle weakness,
neuropathy, and muscle paralysis.

43. Colchicine Overdose
• After prolonged therapy, leukopenia, aplastic anemia,
myopathy and alopecia can occur.
• Intoxication - multi-organ involvement and poor prognosis
• Therapy is basically supportive and symptomatic because of
the rapid distribution and binding to the affected tissues.
• Use of anticolchicine antibodies is a novel approach still in an
experimental stage.

44. Drug Interactions
• Coadministration CYP3A4 inhibitors may inhibit its
metabolism resulting in toxicity such as by macrolide
antibiotics.
• It may increase the serum concentration of cyclosporine, and
verapamil, and vice versa.
• It may cause malabsorption of vitamin B 12 leading to
megaloblastic anemia.
• Coadministration with simvastatin may induce acute
myopathy.

45. Monitoring Guidelines
• CBC, platelet count, serum multiphasic analysis (i.e. RFT, LFT),
and urinalysis be performed at least every 3 months.
• Monthly laboratory monitoring for the first few months of
therapy is a reasonable protocol.
• Should not be used during pregnancy (risk of teratogenicity)

46. Conclusion
• Colchicine has many useful actions in dermatological
disorders and is well tolerated.
• Not a first-line medication for any of the conditions
mentioned, we are more likely to use it early in patients with
leukocytoclastic vasculitis, Sweet's syndrome, and aphthous
ulcers.
• Inexpensive and safe in moderate doses than most
immunosuppressive agents

47. Thalidomide

48. Introduction
• First synthesized in West Germany in 1954 and was
introduced to the German market as Contergan in 1956 as an
over-the-counter medication
• In the U.K. it was known as Distaval.
• It was thought to be one of the safest sedatives ever
produced as it was effective in small doses, was not addictive,
and did not have acute side-effects such as motor impairment

49. • Accidental overdosing or deliberate suicide attempts at doses
as high as 14 g did not result in adverse effects.
• Its use started to become widespread in the home and
hospital, and it became popular among pregnant women to
reduce morning sickness
• By 1960 it became clear that long-term thalidomide use was
associated with polyneuritis.
• Further, rare congenital abnormalities such as phocomelia

50. • In mid-1961, thalidomide was withdrawn from the world
market due to the increasing numbers of infants born with
deformities
• In 1965, it was given to patients with leprosy in Israel for use
as a sedative to relieve ‘lepra suffering’.
• Researchers noticed an unexpected clinical improvement in
the signs and symptoms of ENL.

51. • In 1998, thalidomide was approved by the U.S. Food and Drug
Administration (FDA) for ENL and multiple myloma is classified
as an orphan drug.
• Orphan drug status has led to its use in many currently
unapproved dermatological conditions that are refractory to
other medications

52. Mechanism of action
• Several modes of action through its sedative,
immunomodulatory and other properties
• Sedative-Activation of the sleep centre in the forebrain
• Immunomodulatory-Inhibition of phagocytosis by neutrophils
• Inhibition of chemotaxis of monocytes and leucocytes
• Prevention of lymphocyte proliferation in response to
mitogenic and antigenic stimuli by changing the lymphocytic
response from T-helper 1 to 2

53. • Decrease in the CD4 ⁄CD8 ratio by reducing the number of
CD4+ cells and increasing the CD8+ cells
• Decrease the HIV binding to CD4+ cells by blocking the
expression of CD26 on the T lymphocytes
• Suppression of the production of IgM antibodies
• Inhibition of TNF-α, IL-8, IL-12
• Enhancement of IL-2, IL-4, IL-5, interferon-c
• Downregulation of expression of class II MHC antigens and
cellular adhesion molecules
• Increase in the expression of CD40L
• Decrease of B lymphocytes in the spleen

54. • Other• Antagonism of acetylcholine, histamine, prostaglandins E2
and F2, and serotonin
• Stabilization of lysosomal membranes
• Inhibition of basic fibroblast growth factor-induced
angiogenesis
• Reduction of cellular proliferation, myelin phagocytosis and
subperineural oedema.
• Decrease in the production of hydroxyl and superoxide
radicals at sites of inflammation
• Decrease in the capacity to release elastase and lactoferrin by
lipopolysaccharide or lipoteichoic acid-stimulated
granulocytes

55. Therapeutic use
•
-
Strong supporting literature (RCT or multiple series)ENL
Actinic prurigo
Adult Langerhans cell histiocytosis (histiocytosis X)
Aphthous stomatitis
Aphthous ulceration associated with HIV
Behcet’s syndrome
Cutaneous sarcoidosis
Erythema multiforme

56. -
Graft-versus-host disease
Jessner–Kanof lymphocytic infiltration of the skin
Kaposi sarcoma
Lichen planus
Lupus erythematosus
Melanoma
Prurigo nodularis
Uraemic pruritus

57. •
-
Less supporting literature (single series or case reports)Chronic erythematous oedema
Cutaneous benign lymphoid hyperplasia
Cutaneous Rosai–Dorfman disease
Cutaneous vasculitis
Generalized eruptive histiocytosis
Immune complex vasculitis
Palmoplantar pustulosis
Pemphigoid
Perforating folliculitis

58. -
Polymorphic light eruption
Porphyria cutanea tarda
Postherpetic neuralgia
Pyoderma gangrenosum
Refractory vulval ulcerations associated with Crohn disease
Schnitzler syndrome
Scleromyxoedema
Weber–Christian disease

59. Adverse effects
•
•
-
SeriousTeratogenicity
Common
Sedation
Constipation
Rash
Peripheral neuropathy
Thromboembolism
Dizziness

60. •
-
UncommonAmenorrhoea
Neutropenia
Dry mouth and skin
Headache
Increased appetite
Male sexual dysfunction
Tachycardia
Oedema
Bradycardia
Pruritus
Hypotension
Mood changes
Nausea
Weight gain

61. Drug interactions
• It enhances activity of alcohol, barbiturates, chlorpromazine
and reserpine.
• It raises serum levels of acetaminophen and increases its
toxicity.
• It antagonizes acetylcholine, histamine, prostaglandins and
serotonin in vitro.
• Other drugs that cause sedation, neuropathy, or decrease the
efficacy of oral contraceptives should be used carefully if
thalidomide is added to the patient’s regimen.

62. Monitoring guidelines
• British guidelines for the use of thalidomide include informed
consent being obtained in every case and routine dispensing
of information leaflets.
• Women of childbearing potential should have a negative
pregnancy test 2 weeks prior to starting treatment, along with
appropriate contraceptive advice
• Baseline nerve conduction studies (NCS) are recommended to
monitor for the subclinical development of peripheral
neuropathy

63. • To prevent teratogenic exposure, the manufacturer of
thalidomide has created a comprehensive programme to
control prescribing, dispensing and use of the drug, known as
the System for Thalidomide Education and Prescribing Safety
(S.T.E.P.S.),
• Which is now running in the U.K. Its main goal is to prevent
fetal exposure to thalidomide
• If they are interested in participating, they must agree to:
(i) Give comprehensive patient counselling on the risks and
benefits of thalidomide;

64. (ii) Give appropriate contraception counselling and pregnancy
testing;
(iii) Have patients complete informed consent forms and submit
them to the Slone Epidemiologic Unit;
(iv) Complete and submit the prescriber section of the patientmonitoring survey;
(v) Prescribe no greater than 28 days of therapy without refills;
(vi) Tell patients to return unused thalidomide to the pharmacy.
• Pharmacies must also register in the S.T.E.P.S. programme to
dispense thalidomide

65. Conclusions
• Effective medication for ENL as well as several other
dermatological diseases refractory to conventional therapies.
• Adverse effects of teratogenicity and peripheral neuropathy
have to be considered before starting thalidomide.
• In appropriately selected patients, thalidomide can be an
extremely efficacious medication

66. References
• Dermatol Clin 28 (2010) 599–610
doi:10.1016/j.det.2010.03.014 Department of Dermatology,
University Hospital Carl Gustav Carus, Technical University of
Dresden, Fetscherstr. 74, D-01307 Dresden, Germany
• Konda C, Rao AG. Colchicine in dermatology. Indian J Dermatol
Venereol Leprol 2010;76:201-5
• 2005 British Association of Dermatologists • British Journal of
Dermatology 2005 153, pp254–273

67. THANKS