Talaporfin Sodium Anticancer [9195

Country of Origin:

Japan

CO2Na

Nippon Petrochem. Japan

Nippon Petrochem./ Light Sciences Corp./Meiji Seika Kaisha

Laserphyrin

CO2Na

Originator: First

Nippon Petrochem. Japan

Introduction: Introduced by:

Nippon Petrochem./ Light Sciences Corp./Meiji Seika Kaisha

Trade Name: CAS

Laserphyrin

110230-98-3

Registry No: Molecular Weight:

799.69

In collaboration with Light Sciences Corp. and Meiji Seika Kaisha, Nippon Petrochemicals has developed and launched the injectable photosensitizer talaporfin sodium in Japan for the photodynamic therapy (PDT) of cancer. The initial approval is for the treatment of early stage lung cancer, but Light Sciences Corp. and its subsidiaries are also developing talaporfin sodium for other hyperproliferative diseases, such as, liver metastases arising from colorectal cancer, wet age-related macular degeneration, and atherosclerosis. Talaporfin sodium is typically supplied as a lyophilized green powder, and it is synthesized via a carbodiimide-mediated coupling of chlorin e6 (obtained from precursors that were extracted from natural sources) with L-aspartic acid. Since chlorin e6 contains three carboxylic acid groups, the coupling reaction produces a mixture of aspartic acid conjugates. The desired site of conjugation is the acetic acid side chain of C-20, and the other regioisomers are removed by chromatographic purification. Compared to other photosensitizers, talaporfin sodium is associated with minimal cutaneous photosensitivity, is activated at long wavelengths permitting deeper tissue penetration, and requires a shorter interval between intravenous administration and photoactivation. It has a serum half-life of nine hours and is excreted unmetabolized, predominantly by the biliary system. In the clinical study of patients with early lung cancer, a complete response was obtained in approximately 86% of the lesions (administration at 40mg/m2 followed by laser irradiation at 100J/cm2, 4-6 hours later). In addition to laser activation, a clinical study involving a variety of refractory solid tumors demonstrated that intratumoral delivery of light-emitting diodes was effective; a 33% overall response rate was observed with no cutaneous phototoxicity. Regardless of the mode of activation, the outcome is the same; the activated photosen-sitizer reacts with endogenous oxygen to generate singlet oxygen that ultimately leads to apoptosis and vascular ischemia of the targeted tissue. The most significant adverse effect associated with talaporfin sodium was generalized cutaneous pho-tosensitivity, and erythema and oedema were common as well. Individual cases of nausea, vomiting, diarrhea, heartburn, headache, and pruritus were also reported.

Ximelagatran, a prodrug of melagatran with improved oral bioavailability, is a direct thrombin inhibitor that was launched for the prevention of venous thrombo-embolic events (VTE) in elective hip or knee replacement surgery in Germany with several European countries following with approval for the same indication. A mutual recognition European filing was subsequently submitted for the prevention of stroke and other thromboembolic complications associated with atrial fibrillation (AF). While studies indicate that ximelagatran is as effective as traditional therapies for preventing strokes and recurring blood clots, the U.S. Food and Drug Administration has currently declined approval due to potential hepatotox-icity. Elevation of alanine aminotransferase (three times the upper limit of normal) has been observed in the first four months of therapy, but levels regress to normal upon discontinuation of the drug. Despite the questions surrounding the toxico-logical consequences of this elevated liver enzyme, ximelagatran remains an attractive alternative to the current antithrombotic therapies that utilize either the low molecular weight heparin (LMWH) or warfarin. Since LMWH is administered subcutaneously once or twice daily, the oral agent ximelagatran is preferable for patient compliance. In addition to the convenience of oral therapy, ximelagatran does not require the frequent laboratory monitoring and dosage adjustment that is necessary with warfarin treatment. A clinical study comparing the efficacy of a fixed dose (36mg b.i.d.) of ximelagatran with adjusted dose warfarin for stroke prevention in patients with nonvalvular atrial fibrillation concluded that ximelagatran is not inferior to warfarin, and major bleeding occurred at rates similar to warfarin. The synthesis route to ximelagatran involves the coupling of the three major components, cyclohexylglycine, azetidine-2-carboxylic acid, and protected

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