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HISTORY OF CYCLOSPORIN
1970- J.F BOREL Discovered from a soil fungus TOLEPOCLADIUM INFLATUM
GAMS
1976 - immunosuppresive properties were identified 1978 -first organ transplant is succesful using cyclosporine
CYCLOSPORINE
Structure:C-62,H-111,N-11,O-12. Cyclic polypeptide consisting of 11 amino acids
Reduces the effect of the transcription factor in T cells nuclear factor of activated T cells (NF-AT) in regulating transcription of a number of cytokine genes, the most significant being interleukin (IL)-2
Inhibits histamine release from mast cells and down regulates various cellular adhesion molecules, adding to the prominent anti-inflammatory activity
Mechanism Of Action
Pharmacokinetics
Absorption & Bio-availabity
a. Thermodynamically stable, self-emulsifying, little effected by physiological state of GI tract. b. Faster and more consistent rate of absorption ,(Tmax) =1.5 to 2
hours.
C . peak concentration-2-4hrs & half life -5-18hrs c. Advantageous profile with regard to efficacy and tolerability. d. Clinically proved to produce a more rapid response and higher remission rate than conventional cyclosporine. e. A high fat meal , decreases the AUC by 13% and Cmax by 33%.
Metabolism
Extensively metabolized by the cytochrome P-450 3A enzyme system in the liver, and to a lesser degree in the G I tract, and the kidney.
Severe active, rheumatoid arthritis where the disease has not adequately responded to methotrexate
Adult, non-immuno compromised patients with severe (i.e. extensive and/or disabling), Recalcitrant Plaque Psoriasis who have failed to respond to at least one systemic therapy
Indications
Psoriasis Dishydrotic dermatitis
Atopic dermatitis
Chronic urticaria Pyoderma gangrenosum SLE
Vitiligo
Scleroderma Sezary syndrome Mycosis fungoides Pemphigus pemphigoid EB Aquisita
PRP
Prurigo nodularis Behcets disease Alopecia areata
Lichen planus
Dermatomyositis Hailey Hailey Disease
Hidradenitis suppurativa
Sarcoidosis
Contraindications
Absolute: Impaired renal function Insufficient controlled BP Severe infectious diseases Malignancy PUVA therapy Relative: Previous potential carcinogenic therapies Significant hepatic diseases Hyperuricaemia Hyperkalaemia Simultaneous nephrotoxic drugs
Drug administration
DOSE 2.5-5mg/kg/day Low dose approach High dose approach
2.5 mg/kg/day 2 divided doses Increments -0.5- 1 mg/kg/day- Every 2wks
Duration of treatment
Cyclosporine in psoriasis
Intermittent short course therapy 2.5mg/kg -5 mg/kg Rescue therapy 5mg/kg Long term therapy 3.5mg/kg Combination therapy with top cs,anthralin, reduced vitD3derivatives,MTX, MFM, Biologicals, fumaric acid esters Rotational therapy retenoids,MTX,biologicals Sequential therapy - 12 -16wks - 12-16 wks -upto 1yr - dose can be
Rescue therapy
Long-term therapy
Combination therapy
Rotational therapy
2.5-5 mg/kg/day for 12-16 wks, course repeated when relapse occurs. Duration: 12-16 weeks of CsA therapy
Corticosteroids, anthralin, or vit D3 analogues for an improved response. MTX, fumaric acid esters, and mycophenolate Mofetil in severe cases
SEQUENTIALTHERAPY
PHASE - 1 CSA AT MAXIMUM DOSE 5mg/kg (3-4 months) PHASE - 2 Maintain CSA AT 4mg/kg/day Introduce acitretin taper off CSA PHASE - 3A MAINTAIN WITH ACETRETIN or Topical PHASE -3B MAINTAIN WITH ACETRETIN +UVB OR ACETRETIN + PUVA
When dosed at 3 mg/kg/d, cyclosporine leads to a PASI 75 response in 50% to 70% ofpatients and a PASI 90 response in 30% to 50% of patients. (Nast et al 2007).
Adverse Events
Renal Dysfunction Headache Hypertension Hypertriglyceridemia Hirsutism/Hypertrichosis Paresthesia /Hyperesthesia Influenza like symptoms: nausea/ vomitting Diarrhea Abdominal discomfort Lethargy Musculoskeletal or joint pain
Continuous monitoring
Serum creatinine and blood urea nitrogen Blood pressure CBC, uric acid, potassium, lipids, and magnesium
CCB: Amplodipine , Nicardipin , Felodipin . ACE Inhibitors: Benzapril Hydrochloride, ARBs: Candesartan, Eprosartan, Irbsartan,
Captopril, Enapril Maleate, Fosinopril Sodium, Lisinopril, Ramipril, Trandopril. Telmisartan, Valsartan, Losartan, Olmesartan.
Over Dosage
Seek emergency medical attention if you think you have used too much of this medicine.
Overdose can cause nausea, vomiting, pain in your upper stomach, loss of appetite, jaundice (yellowing of the skin or eyes), and urinating less than usual or not at all.
Forced emesis and gastric lavage is done until 2 hours after administration of Psorid. There may be nephrotoxicity. transient and reversible hepatotoxicity and
ADVANTAGES OF CsA Are: (1) safety in pregnancy (2) absence of tachyphylaxis (3) absence of rebound phenomenon
CONCLUSIONS
CSA can be recommended for short term rescue treatment of psoriasis & AD in appropriate patients CSA may be used for therapy of pyoderma gangrenosum & refractory chronic urticaria CSAin low dose with CS is effective in dermatomyositis CSA should be included in the list of systemic drugs for severe childhood psoriasis along with MTX & RETENOIDS Intermittent short course regemen is established as the ideal in clinical practice Duration of therapy should be < 2yrs & preferably 1yr Yearly estimation of GFR is advocated in pts taking CSA for >1yr
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