Molecular Weight : 379.42
Frovatriptan succinate was launched as an oral treatment for acute migraine attacks with or without aura in adults. It is the eighth member of the "triptan" class. Frovatriptan is a conformationally-restricted analog of the 5-HTi-receptor agonist 5-carboxytryptamine which can be prepared in six steps. The key intermediate (R)-6-cyano-3-N-methylamino-1,2,3,4-tetrahydrocarbazole is obtained by Fischer reaction of 4-cyanophenylhydrazine with the appropriate ketone followed by resolution using L-pyroglutamic acid. This drug acts as a dual 5-HTid /ib receptor partial agonist and has high and selective affinity for 5-HTib and 5-HTiD receptors in cranial vessels. It has no significant activity at 5-HT2, 5-HT3, 5-HT4, a-adrenergic, histaminergic or GABAa receptors. Frovatriptan is also a moderately potent full agonist at 5-HT7 receptors, which have a dilatory action and are expressed in the human coronary artery. In vitro studies appear to indicate frovatriptan's functional selectivity for cerebral circulation as shown by the concentrations needed to induce threshold contractile activity and maximum response in basilar arteries as compared with coronary arteries. Frovatriptan is mainly metabolized by CYP1A2 and most of its metabolites are excreted renally. Co-administration of frovatriptan with the monoamine oxidase-A inhibitor moclobemide or with the potent CYP1A2 inhibitor fluvoxamine did not affect its pharmacokinetics parameters. Although frovatriptan has a poor bioavailability (2430%), it has a very long half-life compared to other triptans (25 h) and has an onset of action and efficacy similar to those of naratriptan. The most striking features of this drug are the low headache recurrence rate, which is one of the lowest among the triptans and which may be attributed to its long half-life, and excellent tolerance profile. No significant effect on the cardiovascular system was seen after administration of a single oral dose of 14 fold the therapeutic dose of frovatriptan.
Fulvestrant (anticancer) (70-73)
Country of Origin : UK
Originator: Astra Zeneca
First Introduction: US
Introduced by : Astra Zeneca
Trade Name : Faslodex CAS Registry No. : 129453-61 -8 Molecular Weight : 606.79
Fulvestrant was launched in the US as a novel once monthly injectable steroidal estrogen antagonist for the treatment of hormone receptor positive metastatic breast cancer in postmenopausal women with disease progression following estrogen therapy. This 7a-alkylsulphinyl derivative of estradiol can be prepared in 10 steps from 6,7-didehydro-19-nortestosterone by successive conjugate addition of the organocuprate derived from O-protected 9-bromononan-1-ol followed by aromatization of the resulting enone, then activation of the protected primary alcohol, substitution with 4,4,5,5,5-pentafluoropentanthiol and oxidation to the sulfoxide. Fulvestrant is the first "pure" estrogen antagonist from a novel class known as selective estrogen receptor down regulators (SERDs). It binds to the estrogen receptor (ER), with affinity close to that of estradiol and 100 fold greater than that of tamoxifen (a partial estrogen antagonist), preventing estrogen-stimulated gene activation, thereby interfering with the estrogen-related processes essential for cell-cycle completion. Fulvestrant also appears to downregulate the ER by 80-90% often to non detectable level both in vitro and in vivo. In comparison to tamoxifen, fulvestrant is devoid of systemic estrogenic activity, it displays no uterotrophic activity and is able to block the uterine stimulation of estradiol or tamoxifen. Furthermore, fulvestrant completely blocks the cell growth in tamoxifen-resistant breast cancer cell-lines and prevents growth of tamoxifen resistant tumor in mice. In clinical trials, it was also shown that fulvestrant is comparable to anastrozole (a third generation aromatase inhibitor) both in efficacy and tolerability in postmenopausal women with tamoxifen-resistant advanced breast cancers.
Gefitinib (antineoplastic) (74-77)
Molecular Weight : 446.91
Gefitinib was introduced in Japan as a daily oral monotherapy for the treatment of inoperable or recurrent non-small cell lung cancers (NSCLC). This anilinoquinazoline derivative can be synthesized in 6 steps starting from 6,7-dimethoxyquinazolin-4(3H)-one by successive monodemethylation/acetylation of the 6-hydroxy-group followed by chlorination and reaction with 3-chloro-4-fluoroaniline, finally deacetylation and alkylation with 3-(4-morpholinyl)propylbromide complete the synthesis. Gefitinib reversibly inhibits the activity of the epidermal growth factor receptor tyrosine kinase (EGRF TK). This inhibits autophosphorylation of EGRF and blocks the cascade of intracellular events which have been implicated in the proliferation, survival and metastasis of cancer cells. Gefitinib diplays good selectivity for the EGRF TK relative to other growth factors in human umbilical endothelial cells. It is similarly selective relative to other kinases, for example c-erB2. Data from two large phase II studies in patients with pretreated NSCLC have shown that gefitinib induces a response rate approaching 20% in patients receiving the agent as a
Introduced by : Astra Zeneca Trade Name : Iressa
Country of Origin : UK
CAS Registry No. : 184475-35-2
Originator : Astra Zeneca
First Introduction : Japan
second line therapy and approximately 10% in those pretreated with more lines of chemotherapy. Gefitinib has good bioavailability and is metabolized in the liver via the cytochrome P450 3A4 enzyme system with a mean elimination half life of 28 h. Gefitinib has been generally well tolerated in cancer patients with predominant side effects being acne-like skin-rash, diarrhea, nausea, vomiting and mild to moderate myelosuppression.
Ibritumomab tiuxetan (anticancer) (78- 81)
Country of Origin : US
First Introduction : US
Introduced by: Syncor
Trade Name : Zevalin
CAS Registry No : 206181-63-7
Class : Monoclonal antibody Type : murine anti (human CD20)
radioimmunoconjugate Molecular Weight : 148 kDa Expression system : CHO cells Manufacturer : Syncor
Radioimmunotherapy (RIT) is a new treatment modality for B-cell non-Hodgkin's lymphoma (NHL). The goal of RIT is to deliver ionizing radiation selectively to tumors while minimizing radiation absorbed in normal tissues. Y-lbritumomab tiuxetan is the first commercially available radiolabeled antibody for cancer therapy and more specifically for the treatment of relapsed or refractory low-grade, follicular, or transformed B-cell NHL including patients with rituximab-refractory follicular NHL. Ibritumomab is a murine immunoglobulin G1 kappa isotype monoclonal antibody produced in Chinese hamster ovary cells. It targets CD20, a B-lymphocyte antigen. The purified antibody is subsequently reacted with the isothiocyanatobenzyl derivative of DTPA to form ibritumomab tiuxetan. Tiuxetan forms a stable covalent urea type bond with the antibody and can chelate a radionuclide via its five carboxyl groups: either indium-111 for imaging (medium energy gamma emitter) oryttrium-90 for radiotherapy (pure high-energy beta-emitter, mean=0.94 MeV). Rituximab (Rituxan®, MabThera) is an unlabeled chimeric antibody also directed against CD20. The Zevalin™ therapeutic regimen starts with the imaging protocol: infusion of 250 mg/m2 rituximab to clear peripheral B-cells and improve targeting of radioisotope to tumor cells, followed by 5 mCi 111ln-Zevalin™ for whole body imaging to enabie determination of favorable biodistribution of radiolabeled antibody. The therapeutic dose (0.3-0.4 mCi/kg) of 90Y-Zevalin™ is delivered on days 7-9 following another predosing of 250 mg/m2 rituximab. The pure beta-emitting Y can be given with few radiation precautions. It has a long path length (Xgo=5 mm) allowing the delivery of a cytotoxic radiation dose to tumor cells more distant to the antibody-bound cell. Its short half-life (64 h) approximates the biological half-life of the radiolabeled antibody (47 h) which may minimize radiotoxicity to nontarget organs. The non tumor distribution is primarily to the bone. In a phase III clinical trial of 143 patients with relapsed or refractory low-grade, follicular, or CD20-positive transformed B-cell NHL, Zevalin™ combined with Rituxan® showed an overall response rate (ORR) of 80%, compared to Rituxan® alone which gave an ORR of 56%. Also, 30% of Zevalin™-treated patients achieved complete responses compared to 16% of Rituxan® patients.
Country of Origin Originator : First Introduction : Introduced by :
Ono Pharmaceutical Japan
Trade Name : Onoact CAS Registry No. : 133242-30-3 Molecular Weight : 509.60
Landiolol was launched last year as iv infusion for the treatment of tachyarrhythmia during surgery. This structurally related derivative of esmolol can be synthesized in 3 linear steps from 3-(4-hydroxyphenyl)propionic acid by successive esterification followed by alkylation of the phenol function with (2S)-glycidyltosylate and opening of the resulting epoxide by the appropriate amine. Landiolol is an ultra short acting pi-adrenergic blocker more cardioselective (p1/p2 = 255) than esmolol (pi/ p2 = 32). It showed 6-8 times greater efficiency compared to esmolol in reducing isoproterenol-induced increase in heart rate and ventricular contraction in anesthetized dogs. In clinical trials, landiolol was effective against a variety of arrhythmias with efficacy seen in patients with atrial fibrillation, proxysmal supraventricular tachycardia, ventricular tachycardia and premature complexes. Landiolol produced a dose-related pharmacokinetic behavior, has a rapid onset of action (10 min.) and is rapidly hydrolyzed to inactive acidic metabolites by esterases after iv administration. This results In an ultra-short half-life (approx. 3 min.) and p-blocade, allowing rapid termination of the drug effect by termination of infusion if side effects occur. Hypertension was the most frequent adverse event and resolved in less than 30 min. after drug withdrawal.
Country of Origin : Originator: First Introduction : Introduced by: Trade Name : CAS Registry No. Molecular Weight:
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