SEMINAR PRESENTATION

Uses of dapsone, colchicine, and thalidomide

in dermatology

Moderator:-Dr. Puneet Bhargava

DAPSONE

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)

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 anti-inflammatory 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

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

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

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

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)

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

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

• 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)

Mechanism of action

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)

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)

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).

Indications

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

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

Indications

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

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

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

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

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

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

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.

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

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

Colchicine

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

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.

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

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.

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.

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.

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.

.

• 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 disease-

Aram 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.

Uses in Dermatology

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.

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.

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.

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.

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.

• 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.

• 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.

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.

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.

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.

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)

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

Thalidomide

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

• 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

• 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.

• 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

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

• 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

• 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

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

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

• 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

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

Adverse effects

• Serious-- Teratogenicity• Common- Sedation- Constipation- Rash- Peripheral neuropathy- Thromboembolism- Dizziness

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

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.

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

• 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;

(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 patient-monitoring 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

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

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

THANKS