cyclosporin

Ciclosporin can be classified chemically as a macrolide.
cyclosporin


Ciclosporin can be classified chemically as a macrolide
Indication:
Ciclosporin (cyclosporin), a calcineurin inhibitor, is a potent immunosuppressant which is virtually non-myelotoxic but markedly nephrotoxic. It has an important role in organ and tissue transplantation, for prevention of graft rejection following bone marrow, kidney, liver, pancreas, heart, lung, and heart-lung transplantation, and for prophylaxis and treatment of graft-versus-host disease.
أي إن هذا الدواء هو مثبط مناعة قوي يستخدم في الحالات التي تستوجب ذلك مثل حالات زرع الكلى أو أجزاء الكبد أو نخاع العضم أو زراعة القلب أو الرئة أو بقية الأعضاء لمنع حدوث رفض للعضو الغريب
كما إنه من الممكن استخدامه في حالة Rheumatoid arthritis يستخدم ( Neural or Gengraf only )
كما إنه يستخدم في حالات أخرى مثل Atopic Dermatitis ويستخدم استخداما موضعيا على شكل مرهم
وكذلك في الصدفية Psoriasis. يستخدم ( Neural or Gengraf only ) الشفاء في هذه الحالات قد يأخذ فترة 12-16 إسبوع أو أكثر.
كما يوجد منه قطرات عيون تستخدم في حالة يحدث فيها زيادة في إفراز الدمع keratoconjunctivitis sicca
Increased tear production in patients whose tear production is presumed to be suppressed because of ocular inflammation associated with keratoconjunctivitis sicca
Trade Names:
Sandimmune® ( Novartis, the original formulation )
- Capsules, soft gelatin 25 mg
- Capsules, soft gelatin 50 mg
- Capsules, soft gelatin 100 mg
- Oral solution 100 mg/mL
- IV solution 50 mg/mL


Neoral® ( Navartis, Microemulsion formulation )
- Capsules, soft gelatin, for microemulsion 25 mg
- Capsules, soft gelatin, for microemulsion 50 mg
- Oral solution for microemulsion 100 mg/mL


Gengraf® ( Abbott )
- Capsules 25 mg
- Capsules 100 mg
- Oral solution 100 mg/mL


Restasis®
- Ophthalmic emulsion 0.05%




ملاحظة هامة جدا

Any conversion between brands should be undertaken very carefully and the manufacturer contacted for further information. ……
Because of differences in bioavailability, the brand of oral ciclosporin to be dispensed should be specified by the prescriber
يعني إن لا يجوز تغيير الماركة التي يتخدم منتجها المريض، فلا يجوز تغيير من ساندميون إلى نيورال أو بالعكس، لكن ( وهذه ملاحظة مهمة أخرى ) يجوز للمريض أن يغير الشكل الدوائي من كبسول إلى شراب أو بالعكس من دون أن يغير الجرعة ( حسب النشرة المرفة مع ساندميون )
Gengraf® and Neoral® are interchangable, while Sandimmune® is not.


Mode of Action:
Cyclosporin is thought to bind to the cytosolic protein cyclophilin (immunophilin) of immunocompetent lymphocytes, especially T-lymphocytes. This complex of ciclosporin and cyclophylin inhibits calcineurin, which under normal circumstances is responsible for activating the transcription of interleukin-2. It also inhibits lymphokine production and interleukin release and therefore leads to a reduced function of effector T-cells. It does not affect cytostatic activity.
It also has an effect on mitochondria. Cyclosporin A prevents the mitochondrial PT pore from opening, thus inhibiting cytochrome c release, a potent apoptotic stimulation factor. However, this is not the primary mode of action for clinical use but rather an important effect for research on apoptosis.


Pharmacokinetics
Absorption
Oral
Absorption is incomplete and variable. Bioavailability is less than 10% in liver transplant patients (Sandimmune), up to 89% in renal transplant patients (Sandimmune), and about 30% for the oral solution. T max is 1.5 to 2 h (Gengraf and Neoral) and 3.5 h (Sandimmune). Food decreases the AUC and C max.
ومن هنا نلاحظ إختلاف الجرعة بالنسبة مرضى زرع الكلى ومرضى زرع الكبد، إذ إننا نحتاج إلى جرعة أعلى لمرضى زراعة الكبد كون هذا الدواء يتأثر بالأيض في الكبد، كما يجب أن نأخذ في عين الإعتبار تفاعلاته الدوائية مع الكثير من الأدوية التي تتأثر بالأيض في الكبد.


Distribution
Vd is 3 to 5 L/kg at steady state (IV). Cyclosporine is 90% protein bound (primarily lipoprotein) and is excreted in human milk.
وهذا يجعله يتفاعل مع الكثير من الأدوية والتي تتأثر بالارتباط بالبروتين وكذلك يحذر أو يمنع استخدام للمرأة المرضع أو تجبر على الإمتناع من إرضاع طفلها


Metabolism

cyclosporin
It is extensively metabolized by CYP3A in the liver and to a lesser degree in the GI tract and kidney.


Elimination
Eliminated primarily in the bile; 6% is excreted unchanged in the urine (0.1% as unchanged drug). The t ½ is about 8.4 h (Gengraf and Neoral) and about 19 h (Sandimmune). Blood Cl is about 5 to 7 mL/min/kg (IV).




Side-effects
dose-dependent increase in serum creatinine and urea during first few weeks; less commonly renal structural changes on long-term administration; also hypertrichosis, headache, tremor, hypertension (especially in heart transplant patients), hepatic dysfunction, fatigue, gingival hypertrophy, gastro-intestinal disturbances, burning sensation in hands and feet (usually during first week); occasionally rash (possibly allergic), mild anaemia, hyperkalaemia, hyperuricaemia, gout, hypomagnesaemia, hypercholesterolaemia, hyperglycaemia, weight increase, oedema, pancreatitis, neuropathy, confusion, paraesthesia, convulsions, benign intracranial hypertension (discontinue), dysmenorrhoea or amenorrhoea; myalgia, muscle weakness, cramps, myopathy, gynaecomastia (in patients receiving concomitant spironolactone), colitis and cortical blindness also reported; thrombocytopenia (sometimes with haemolytic uraemic syndrome) also reported; incidence of malignancies and lymphoproliferative disorders similar to that with other immunosuppressive therapy


Dose
بصورة عامة الجرعة عن طريق الوريد تمثل ثلث الجرعة المطلوبة عن طريق الفم، ولا يتم استخدام الحقن الوريدي إلا حينما يكون استخدام الأشكال الفموية غير ممكنا
Organ transplantation, used alone, adult and child over 3 months 10–15 mg/kg by mouth 4–12 hours before transplantation followed by 10–15 mg/kg daily for 1–2 weeks postoperatively then reduced gradually to 2–6 mg/kg daily for maintenance (dose should be adjusted according to blood-ciclosporin concentration and renal function); dose lower if given concomitantly with other immunosuppressant therapy (e.g. corticosteroids); if necessary one-third corresponding oral dose can be given by intravenous infusion over 2–6 hours


Bone-marrow transplantation, prevention and treatment of graft-versus-host disease, adult and child over 3 months 3–5 mg/kg daily by intravenous infusion over 2–6 hours from day before transplantation to 2 weeks postoperatively (or 12.5–15 mg/kg daily by mouth) then 12.5 mg/kg daily by mouth for 3–6 months then tailed off (may take up to a year after transplantation)


Nephrotic syndrome, by mouth, 5 mg/kg daily in 2 divided doses; child 6 mg/kg daily in 2 divided doses; maintenance treatment reduce to lowest effective dose according to proteinuria and serum creatinine measurements; discontinue after 3 months if no improvement in glomerulonephritis or glomerulosclerosis (after 6 months in membranous glomerulonephritis)


monitor kidney function—dose dependent increase in serum creatinine and urea during first few weeks may necessitate dose reduction in transplant patients (exclude rejection if kidney transplant) or discontinuation in non-transplant patients; monitor liver function (dosage adjustment based on bilirubin and liver enzymes may be needed); monitor blood pressure—discontinue if hypertension develops that cannot be controlled by antihypertensives; hyperuricaemia; monitor serum potassium especially in renal dysfunction (risk of hyperkalaemia); monitor serum magnesium; measure blood lipids before treatment and thereafter as appropriate; pregnancy and breast-feeding; porphyria; use with tacrolimus specifically contra-indicated and apart from specialist use in transplant patients preferably avoid other immunosuppressants with the exception of corticosteroids (increased risk of infection and lymphoma)


بالنسبة لتاكروليمس فهو بديل لسايكلوسبورين، وأي تحويل أو تبديل بينهما فيجب أن يتكر المريض علاجه الأول لمدة يومين قبل أن يشرع باستخدام العلاج الجديد


Contra-indication
In uncontrolled hypertension, uncontrolled infections, and malignancy; reduce dose by 25–50% if serum creatinine more than 30% above baseline on more than one measurement; in renal impairment initially 2.5 mg/kg daily; in long-term management, perform renal biopsies at yearly intervals


Drug- Interaction
من خلال الأدوية الكثيرة والتي يتفاعل معها ساكلوسبورين يتبين لنا أهمية متابعة المرضى الذين يستخدمون هذا الدواء، ونشير ادناه إلى أهم الأدوية التي تظهر تفاعلا واضحا
1- increased risk of nephrotoxicity
· ACE Inhibitors
· Aminoglycosides
· Amphotericin (Close monitoring required with concomitant administration of nephrotoxic drugs or cytotoxics
· Angiotensin-II Receptor Antagonists

cyclosporin
· Melphalan
· NSAIDs (Interactions do not generally apply to topical NSAIDs)
· Polymyxins
· Quinolones
· Sulphonamides
· Trimethoprim
· Vancomycin
· Bezafibrate
· tacrolimus


2- increased risk of hyperkalaemia
· Aciclovir (Interactions do not apply to topical aciclovir preparations)
· potassium-sparing diuretics and aldosterone antagonists
· potassium salts (Includes salt substitutes)


3- increased plasma concentration of ciclosporin ( يضاف إليها الأدوية التي تسبب increased risk of nephrotoxicity(
· Allopurinol
· Amiodarone (Amiodarone has a long half-life; there is a potential for drug interactions to occur for several weeks (or even months) after treatment with it has been stopped)
· Atazanavir
· Carvedilol
· Chloroquine (increased risk of toxicity)
· Hydroxychloroquine (increased risk of toxicity)
· Cimetidine
· colchicine (possible increased risk of nephrotoxicity and myotoxicity)