cyclosporine seminar

7/29/2019 Cyclosporine seminar

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o 1970, isolated as narrow antifungal

from Tolypocladium inflatum Gams

o 1976, found to be a potent immunosuppressive

o 1983, FDA approval for transplant rejection.

o 1997, FDA approval for Rx of psoriasis

o Approved for atopic dermatitis in other

countries.


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o Sandimmune (cyclosporine, USP)

o

Gengraf (cyclosporine, USPModified)o Neoral (cyclosporine, USPMicroemulsion)


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o 1. Action on the calcineurin / NFATpathway

o 2. Action on JNK and p38 signalingpathways

o 3. Action by Induction of TGF-b


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Action on calcineurin / NFAT pathway


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o JNK and p38 act in stress responses,

(inflammation and apoptosis),

o Activated when T cell responses are triggered

through both TCR and CD28 co-stimulatoryreceptor

o Are sensitive to CsA (Su et al., 1994;Matsuda

et al., 1980) .o JNK and p38 with ERK leads to activation of

transcription factors including AP-1 (Karin,

1995)


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o CsA induces synthesis of TGF-b in vitro and invivo (Li et al., 1991; Khanna et al., 1994; Wolf etal.,1995; Shihab et al., 1996)

o TGF-b is known to stimulate cells to increase theirextracellular matrix ECM composition

o Decreases production of ECM-degradingproteases,

o Thereby inducing a profibrogenic state(Massague,1990) .

o TGF-b produced by CsA administration directly

promotes cancer progression (Hojo et al., 1999) .


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o US FDA approved

Psoriasis

Severe Psoriasis Recalcitrant, treatment resistant Psoriasis

Disabling Psoriasis

o Approved in other countries

Psoriasis

Atopic dermatitis


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Disease CsA dose Duration of

Rx

Response Time to relapse

after discontinued

Other

drugs

Comm

ents

Psoriasis 12-16 wks,

12 mos

maximum

Excellent Average 111 days; however,

30% had no relapse 6 mos

after CsA discontinued

A. Intermittent

short-term

therapy

2.5-5 mg/kg/day for 12-16 wks,

course repeated when relapse occurs

B. Rescue

therapy

5 mg/kg/day for 12-16 wks for

flaring of disease

C. Long term

therapy


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Disease CsA

dose

Duratio

n of

treatme

nt


after discontinued

Other

drugs

Comments

Psoriaticarthritis

3-4mg/kg/da

y, max 5

mg/kg/da

y

6-12 mos Very good MTX15

mg/wk,

occasio

nally

50% reduction in jointcomplaints required 24

wks of CsA monotherapy,

CsA-MTX combination

therapy given to patients

with partial MTX response

Atopic

dermatitis

2.5-3

mg/kg/da

y, max 5

mg/kg/da

y

12-16

wks, 12

mos max

Excellent 2 wks (50%), 6

wks (80%)

Used for short treatment of

severe, AD that cannot be

controlled with topical

therapy. Approved for this

in Europe and UK

Pyoderma

gangrenosu

m

5

mg/kg/da

y

>6 mos Excellent Methylprednisolo

ne (0.5-1

mg/kg/day, or

pulse treatment 1

g/day for 1-5

days) usually

given concurrently


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Disease CsA dose Duration of

treatment


after

discontinued

Other

drugs

Comments

Dyshidrotic

eczema

2.5-3

mg/kg/day

6 wks, up to

16 wks

Equivalent 77% of patients

continued to have a 54%

improvement at 1 y

CsA equivalent to

BDP cream

Behet

disease

5 mg/kg/day >6 mos Very good Prednisone, occasionally Used for refractory

eye disease, topical

steroid

resistantmucocutaneous

disease, and arthritis.

Poor prevention of

neurologic

involvement

Chronic

urticaria

4 mg/kg/day 12-16 wks Very good 33% at 3-6 mos, relapse

less severe

Cetirizine 10 mg/day,

occasionally concurrently

Used as a steroid

sparing agent or in

cases refractory to

corticosteroids


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Disease CsA dose Duration

of

treatment


after

discontinued

Other

drugs

Comments

Pityriasis

rubrapilaris

3-5

mg/kg/day,maintenance

dose 2

mg/kg/day

>8 mos Mixed Used in erythrodermic

classic adult anderythrodermic juvenile

PRP

Dermato -

myositis

1-1.8

mg/kg/day,

>200

mg/day

Very good Prednisone 40 mg/day Used in cases not responsive

to prednisone combined with

MTX or azathioprine.

Effective for lung and

esophageal involvement

Pemphigus

vulgaris

1-3

mg/kg/day

8 mos

11.8 mos

Good, but

better

treatment

options

available

43% free of relapse

after combination

therapy with

cyclosporine and

prednisone 5 y after

discontinuation of

therapy

Prednisone,

usually given

concurrently

Used as a

steroid

sparing agent


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Disease CsA

dose

Duration

of

treatment


after

discontinued

Other drugs Comments

Epidermolysis

bullosaacquisita

4-5

mg/kg/day

1-24 mos Good, but better

treatment optionsavailable

Prednisone,

usually givenconcurrently

Used as

steroidsparing agent

Photodermatoses

A. Chronicactinic

dermatitis

4-4.5mg/kg/day

Good

B.

Polymorphic

light

eruption

3-4

mg/kg/day

May be given 1 wk

before sun exposure,

and discontinued

upon return

Good

C. Solar

urticaria

4.5

mg/kg/day

Short courses during

summer months

Flares once cyclosporine

discontinued


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Disease CsA

dose

Duration

of

treatment


after discontinued

Other

drugs

Comments

Lichenplanopilaris

3-5mg/kg

/day

3-5 mos Good Symptom free,stable disease at 12

mos

postcyclosporine

CsA may beeffective in the

initial phases

before severe

follicular damage

occurs

Prurigo

nodularis

3.5-4

mg/kg

/day

6-9 mos Good

Lichenplanus

3-4.5mg/kg

/day

2-3 mos Good Prednisone,occasionally

topical

steroids

Used for disseminated ,erosive LP, and LP

resistant to systemic

corticosteroids and

retinoids. Topical CsA

may be effective in

treatment of oral LP


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o Pemphigoido Linear IgA bullous dermatosiso Lupus erythematosuso Granuloma annulareo Sarcoidosiso Kimuras ds.o Morpheao Papular erythroderma of ofujio Purpura pigmentosa chronicao Reiters syndromeo Scleromyxedemao Sezarys syndromeo Mycosis fungoides


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o Department of Dermatology, Health

Waikato, New Zealand.

o Abstract

o A patient developed toxic epidermalnecrolysis while on carbamazepine, 80% ofher skin surface being involved. She alsodeveloped a pancytopenia with aneutropenia of 0.77 x 10(9)/l (normal range2-7.5 x 10(9)/l), but was treated withcyclosporin and granulocyte colonystimulating factor and made a full recovery.

o Int J Dermatol. 1989 Sep;28(7):441-4.


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Drug-induced toxic epidermal necrolysistreated with cyclosporin.

Renfro L, Grant-Kels JM, Daman LA.

Division of Dermatology, University ofConnecticut Health Center, Farmington.

Abstract A 35-year-old woman developed toxic

epidermal necrolysis secondary tophenytoin. Because the life-threatening

eruption was resistant to prednisone andhigh-dose methylprednisolone therapy,cyclosporine therapy was initiated. Within24-48 hours, the eruption stabilized and thepatient improved.
http://www.ncbi.nlm.nih.gov/pubmed?term=Renfro%20L[Author]&cauthor=true&cauthor_uid=2777442http://www.ncbi.nlm.nih.gov/pubmed?term=Grant-Kels%20JM[Author]&cauthor=true&cauthor_uid=2777442http://www.ncbi.nlm.nih.gov/pubmed?term=Daman%20LA[Author]&cauthor=true&cauthor_uid=2777442http://www.ncbi.nlm.nih.gov/pubmed?term=Daman%20LA[Author]&cauthor=true&cauthor_uid=2777442http://www.ncbi.nlm.nih.gov/pubmed?term=Grant-Kels%20JM[Author]&cauthor=true&cauthor_uid=2777442http://www.ncbi.nlm.nih.gov/pubmed?term=Grant-Kels%20JM[Author]&cauthor=true&cauthor_uid=2777442http://www.ncbi.nlm.nih.gov/pubmed?term=Grant-Kels%20JM[Author]&cauthor=true&cauthor_uid=2777442http://www.ncbi.nlm.nih.gov/pubmed?term=Grant-Kels%20JM[Author]&cauthor=true&cauthor_uid=2777442http://www.ncbi.nlm.nih.gov/pubmed?term=Grant-Kels%20JM[Author]&cauthor=true&cauthor_uid=2777442http://www.ncbi.nlm.nih.gov/pubmed?term=Renfro%20L[Author]&cauthor=true&cauthor_uid=2777442


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o ABSOLUTE Uncontrolled

hypertension,

Significant renal

impairment, Serious infections, Previous

history of malignancy,excluding BCC

High cumulativedose of previouspsoralen and ultravioletA light phototherapy

Cutaneous T-cell

lymphoma

oRELATIVE


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o Drugs that inhibit or stimulatecytochrome P450

o Nephrotoxic drugs should be avoidedo A full drug history should be taken at

every visit


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o Calcium channel blockersDiltiazem, nicardipine,verapamil, and mibefradil

o Antifungals

Ketoconazole >itraconazole >Fluconazole, andvoriconazole

o Antibiotics

Erythromycin,clarithromycin, andjosamycin, Doxycycline,Gentamicin andtobramycin, Ticarcillin,

Ciprofloxacino Oral contrace tives

o Amiodaroneo Cimetidine

o Protease inhibitorso Warfarin

o Grapefruit juiceo SSRIs (sertraline)

By other mechanismo Methylprednisolone

o Allopurinolo Thiazide diuretics

o Furosemide


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o Anticonvulsants(carbamazepine,phenobarbitone,

phenytoin, andvalproate)

o Rifampicin

o Rifabutino Isoniazid

o Griseofulvin

o Probucol

o Ticlopidine

o Nafcillin

o Octreotideo Orlistat

o Bexarotene


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Drug Type Comments

Nephrotoxic agents

NSAIDs

Vancomycin

Ganciclovir

Aminoglycosides

Monitor renal function

NSAIDs may have increased nephrotoxicity

with hepatic impairment

Potassium-sparing diuretics Hyperkalemia has been reported

Antacids Magnesium and aluminum antacids may inhibit

absorption of CNIs

If necessary, should be taken 2 hours after CNI

dose

HMG-CoA reductase inhibitors

(statins)

Increased risk of rhabdomyolysis, bone marrow

suppression


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o Are leading cause of its limited use in

dermatology.

o Depend on dose and duration of therapy

o Reversible on discontinuation,

o Structural renal abnormalities may be

persistent.

o Mitochondrial dysfunction (ion channelregulation)

o Inhibition of immunophilins may play a role


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Event Comments

CutaneousHypertrichosis, epidermal cysts,keratosis pilaris, acne, folliculitis,

and sebaceous hyperplasia.

Cyclosporine modulates protein kinase Cexpression and translocation in hairepithelial cells and promotes

proliferation of these cells

Gingival hyperplasia Caused by fibrous hyperplasia and has beenreported in up to 30% of patients

on cyclosporine, with a higher incidence

reported in children

Infections Rare and seldom severe,treatment of the infection or

withdrawal of the drug led to resolution

Other side effects Slight NC, NCr anemiaFatigue, lethargy, and flu-like symptomsare commonjoint pain and muscle aches in 10% to40%
http://www.dermnetnz.org/common/image.php?path=/treatments/img/csa-gums.jpg


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o Patients should be instructed to attend theirdentist at 6-month intervals

o National malignancy screening programsshould be adhered to

o Where possible Vaccination should takeplace before initiation of treatment


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Investigation Details

Full history Previous infections: TB, hepatitis B/C;

history of hypertension, kidney disease,

liver disease, or malignancy; full

medication history, which should be

repeated at every subsequent visit

Blood pressure Baseline (2 separate measurements,

should be


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Investigation Details

Tuberculin test Baseline

Glomerular filtration rate After 1 y of continuous therapy

Screening Programs Cervical, breast, and colon cancer

screening as per national guidelines

Vaccinations Annual pneumococcal and influenzavaccinations


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Low risk Mod Risk High risk

0-6 m 150-250 ng/ml 175-325 ng/ml 200-350 ng/ml

6-12 m 100-200 ng/ml 125-225 ng/ml 150-250 ng/ml

> 12 m 50-150 ng/ml 75-175 ng/ml 100-200 ng/ml

S Hariharan. Am J Kidney Dis. 2006. 47(S2):S22-S36.

Trough or C0 level (samples are collectedimmediately before next scheduled dose)


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Cyclosporin: C2 Level (two-hour sample)

< 6 months: 1000-1500 ng/ml

> 6 months: 800-900 ng/ml

Little evidence from prospective studies tosupport theoretical benefits of C2 monitoring.Potential dose reductions in stable patients may

reduce costs, but no short-term clinical benefit isseen.*

*Knight, S R. et al. Transplantation 2007 Jun; 83(12):1525-1535


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o Crosses placental, category C drug inpregnancy

o Pregnancy registries show no increase inrisk of teratogenicity,

o Although there were trends towards lowbirth weight and prematurity

o Excreted in breast milk


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o Use in psoriasis changed entire field of psoriasis

researcho From that of a hyperproliferative, keratinocyte-

driven disorder to that of an immune-drivendisease,

o Provided a way for biologic revolution in

psoriasis.

o Useful in treatment of significant

flares of cutaneous diseaseespeciallypsoriasis and atopic dermatitis

o Bridging agent during induction of other

maintenance agents.


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o Combination or rotational therapy can be

used to minimize cumulative dosage andlong-term side effects.

o Treatment for more than 1 year should beavoided where possible.

o Side effects are dose andduration dependent, reversible ondiscontinuation

o It is a drug that should be an integral

part of our therapeutic armamentariumo Provided that guidelines are closely

followed.


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