Studies in male mice and rats suggest potential nephrotoxicity. Casimersen was administered weekly to male rats by IV injection for 12 weeks (0, 12, 120, or 960 mg/kg) or 22 weeks (0, 300, 960, or 2000 mg/kg) or by subcutaneous injection for 26 weeks (0, 300, 600, or 960 mg/kg). In the 12-week study, microscopic findings in the kidney (cytoplasmic basophilia and microvacuolation) were observed at the highest dose tested. In the 22- and 26-week studies, renal tubular degeneration was observed at all doses. Male rats administered casimersen (0, 250, 500, 1000, or 2000 mg/kg) intravenously for 13 weeks also experienced renal tubular degeneration at all tested doses, as well as microscopic changes accompanied by blood urea nitrogen increase at the highest tested dose. A no-effect dose for adverse effects on the kidneys was not identified in any of these studies. Plasma exposure (AUC) at the lowest dose tested in the 26-week study (300 mg/kg) was approximately two times that in humans at the recommended human dose (RHD) of 30 mg/kg/week, while exposure in the rat studies at the lowest dose was approximately four times that in humans.L32118
Studies involving weekly administration in cynomolgus monkeys found similar tubular basophilia and microvacuolation at doses ?40 mg/kg, which largely resolved by four weeks following the last dose. This study determined a no observed adverse effect level for repeated intravenous administration of 320 mg/kg.A229993
Duchenne muscular dystrophy (DMD) is an X-linked recessive allelic disorder characterized by a lack of functional dystrophin protein, which leads to progressive impairment of ambulatory, pulmonary, and cardiac function and is invariably fatal. A related, albeit a less severe, form of muscular dystrophy known as Becker muscular dystrophy (BMD) is characterized by shortened and partially functional dystrophin protein production. Although corticosteroids effectively slow disease progression in both DMD and BMD patients, they do not address the underlying molecular pathogenesis.A218171, A218176, A229988
The application of antisense oligonucleotides in DMD patients with specific mutations allows for exon skipping to produce truncated BMD-like dystrophin proteins, which restore partial muscle function and slow disease progression.A218171, A218176, A229993, A188574, L32118 Casimersen is a phosphorodiamidate morpholino oligonucleotide (PMO); PMOs are oligonucleotides in which the five-membered ribofuranosyl ring is replaced with a six-membered morpholino ring, and the phosphodiester links between nucleotides are replaced with a phosphorodiamidate linkage.A218186, L32118 In this manner, PMOs are much less susceptible to endo- and exonucleases and exhibit drastically reduced metabolic degradation compared to traditional synthetic oligonucleotides.A218186 Casimersen is the most recent in a line of approved PMOs for treating DMD, including eteplirsen and viltolarsen. However, the specific mutations, and hence the precise exon skipping, targeted by each is different.
Casimersen was granted accelerated FDA approval on February 25, 2021, based on data showing an increase in dystrophin levels in skeletal muscle of patients treated with casimersen; this approval is contingent on further verification in confirmatory trials. Casimersen is currently marketed under the tradename AMONDYS 45™ by Sarepta Therapeutics, Inc.L32118
Fitur visualisasi ini dikembangkan menggunakan pendekatan Graph Theory untuk memetakan hubungan polifarmasi dan molekuler. Entitas (Obat, Target, Gen) direpresentasikan sebagai Simpul (Nodes), sedangkan hubungan biologisnya sebagai Sisi (Edges).
drugbank-id dan name pada skema XML DrugBank.targets/target yang memuat polipeptida sasaran.gene-name dan varian snp-effects.Tata letak grafik menggunakan algoritma Force-Directed Graph (Barnes-Hut). Model fisika ini menerapkan gaya tolak-menolak antar simpul (Gravitasi: -3000) agar tidak tumpang tindih, serta gaya pegas (Spring: 0.04) pada garis penghubung untuk fleksibilitas interaksi.