Country of origin Originator
First introduction Introduced by
Trade name CAS registry no Molecular weight
Spain Recordati Espana UK
Altana/ Aventis/ Teijin Alvesco 126544-47-6 540.69
Ciclesonide, a new inhaled corticosteroid (ICS), is indicated for the prophylactic treatment of persistent asthma. ICS treatment is a widely accepted standard of care for maintenance therapy of chronic asthma, and the currently available agents include fluticasone propionate, budesonide, triamcinolone acetonide, flunisolide, and beclomethasone dipropionate. These agents exert their potent anti-inflammatory effects via modulation of the glucocorticoid receptor (GR). Although ICS drugs are generally safe and well tolerated compared with oral corticosteroids, many have measurable systemic exposures, and concerns over potential side effects resulting from it severely limit the dose at which they can be administered for long-term therapy. Systemic adverse effects associated with corticosteroids include HPA axis suppression, osteoporosis, abnormal glucose metabolism, cataracts, and glaucoma, some of which could potentially occur with the long-term use of high dose ICS. The key differentiators for ciclesonide relative to other ICS drugs are its longer duration of action and lower systemic exposure. Ciclesonide is an isobutyryl ester prodrug. It is cleaved by the endogenous esterases in the lung to des-isobutyryl ciclesonide (des-CIC), which is a potent GR agonist. The binding affinity of des-CIC for human GR (K = 0.31 nM) is similar to other ICS such as budesonide (K = 0.44 nM) and fluticasone propionate (K = 0.24 nM), while ciclesonide itself has about 100-fold lower affinity (K = 37 nM). In lung tissue, des-CIC undergoes reversible lipid conjugation to form oleate and palmitate ester conjugates, which act as a slow-release pool for the drug and increase the pulmonary residence time. This, in turn, contributes to the enhanced local effects and the long duration of action. Des-CIC has a pulmonary bioavailability of about 50%, whereas the oral bioavailability of both ciclesonide and des-CIC are <1%. Des-CIC has a high-clearance rate of 396 L/h, a volume of distribution of 1190 L, and a mean elimination half-life of 3.5 h. Any systemically available ciclesonide and Des-CIC undergo extensive first-pass liver metabolism, whereby they are rapidly hydoxylated by CYP3A4 to produce inactive metabolites. In addition, both ciclesonide and des-CIC have high protein binding (99%), which also contribute to low-systemic exposure of the free drug. The dosing regimen of ciclesonide is 80-320 mg once daily, and it is delivered in solution form via a hydro-fluoroalkane metered-dose inhaler. In multiple 12-week clinical studies in asthma patients, 80-320 mg once daily ciclesonide was at least as effective as 400 mg once daily budesonide or 88 mg twice daily fluticasone at increasing forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) from baseline. Inhaled ciclesonide was generally well tolerated in these clinical studies. Ciclesonide did not suppress biochemical markers of adrenal function in 52-week studies; however, the long-term (>52 weeks) systemic effects remain unknown. Ciclesonide is chemically produced via a semi-synthesis starting from 16-a-hydroxyprednisolone by first converting to a triisobutyryl ester intermediate with isobutyric anhydride, and subsequent reaction of the triester with cyclohexane carboxaldehyde and hydrochloric acid in dioxane. The latter step produces the cyclic ketal as a mixture of diastereomers, which is subjected to HPLC and fractional crystallization to produce ciclesonide.
Clofarabine is a new member of the purine nucleoside antimetabolite class of drugs, and it was launched last year as an intravenous infusion for treating pediatric patients (1-21 years old) with relapsed or refractory acute lymphoblastic leukemia (ALL) after at least two prior regimens. Adenosine-related antimetabolites, such as cladribine and fludarabine have proven successful in treating low-grade lymphomas, chronic lymphocytic leukemia, and hairy-cell leukemia. Although structurally similar to cladribine and fludarabine, a key differentiator for clofarabine is the presence of a fluorine in the C-2' position, which renders it less susceptible to phosphor-olytic cleavage of the glycosydic bond and inactivation by purine nucleoside phosphorylases. In addition, the C-2' fluoro group improves the acid stability relative to its predecessors. As seen with other purine nucleoside analogs, the mechanism of action of clofarabine involves intracellular phosphorylation to active triphosphate by 2'-deoxycytidine kinase, and subsequent inhibition of RNA reductase and DNA polymerase a. Clofarabine is cytotoxic to rapidly proliferating and quiescent cancer cell types in vitro. It exhibits superior cytotoxicity (IC50 = 5nM) than cladribine and fludarabine (IC50 = 16 and 460 nM, respectively) in K-562 cells.
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