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Amrubicin was launched in Japan as an injectable preparation for the treatment of non-small and small-cell lung cancers. Amrubicin, a completely synthetic anthracycline derivative, mediates its growth inhibitory action via topoisomerase II inhibition. It is activated in vivo by the formation of its 13-OH metabolite, amrubicinol, via reaction with carbonyl reductase. In contrast to doxorubicin and daunorubicin whose metabolites are inactive in the blood, amrubicinol is 10-100 fold more cytotoxic than amrubicin. In phase II clinical trials, amrubicin showed antitumor activity against non-small-cell lung cancers (response rate exceeding 20%) and against untreated extensive stage small-cell-lung cancers (response rate 78.8%). Amrubicin demonstrated a smaller distribution-volume, a shorter half-life in mice and also less chronic cardiotoxicity in preclinical studies compared to doxorubicin. Amrubicin was generally well tolerated with major adverse events being anaemia, leucopenia, thrombocytopenia and neutropenia.

Anti-digoxin polyclonal antibody (antidote) (15-17)

Country of Origin : UK Class : Polyclonal antibody

Originator : Protherics Type : Anti digoxin immune Fab

First Introduction : US Molecular Weight : 46 kDa

Introduced by : Savage Laboratories Expression system : Immunized sheep

Trade Name : DigiFab Manufacturer : Protherics

CAS Registry No : 339086-83-8

Digoxin is widely prescribed for the treatment of cardiac conditions such as atrial arrhythmias and congestive heart failure. Because of its narrow therapeutic range, digoxin-related toxicity resulting from acute or chronic overdose is common. Digoxin toxicity can be rapidly and safely reversed by intravenous administration of anti-digoxin immune fragments (Fab) such as DigiFab which act by binding digoxin with high affinity (10 9 -10 10 L/mol), favoring movement of digoxin out of tissue and thus promoting elimination. DigiFab is obtained from the blood of healthy sheep immunized with a digoxin derivative, digoxin-dicarboxymethoxylamine. The final product is prepared by isolating the immunoglobulin fraction of the serum, digesting it with papain and isolating the digoxin-specific Fab fragments by affinity chromatography. Digibind® from Glaxo-SmithKline has been available in the US since 1986 but produced by immunization with digoxin. Comparison of the pharmacokinetics and in vivo bioaffinity of DigiFab™ versus Digibind® showed that both drugs are equally effective in binding and neutralizing serum free digoxin (40mg of Fab binds 0.5 mg of digoxin approximately). In this clinical study involving 15 DigiFab™-treated patients, 93% had complete resolution of the induced digoxin toxicity within 20 hours. No patients developed a measurable immune response (human antiovine antibodies) to DigiFab™. The elimination half life of DigiFab™ is 15 hours.

Aripiprazole (neuroleptic) (18-22)

Country of Origin : Japan Trade Name : Ability

Originator: Otsuka CAS Registry No: 129722-12-9

First Introduction : USA Molecular Weight: 448.40 Introduced by : Bristol-Myers Squibb

Aripiprazole was launched for the treatment of psychoses including schizophrenia and offers a novel mechanism of action as a partial D2 receptor agonist. Aripiprazole can be synthesized in three steps beginning by the condensation of 7-hydroxy-1,2,3,4-tetrahydroquinolin-2-one with 1,4-dibromobutane followed by reaction with 1-(2,3-dichlorophenyl)piperazine. Aripiprazole is a significant D2 agonist/antagonist, 5-HT2 antagonist and 5-HTia agonist combined with minimal affinity for ai-adrenergic, H1 and M1 receptors. It has a low D4:D2 selectivity ratio and a D2:5-HT2 affinity ratio that exceeds 15; resulting in different pharmacological characteristics compared to other atypical antipsychotics agents such as clozapine. In animal models, aripiprazole inhibits apomorphine-induced stereotypy without causing catalepsy and ptosis. Moreover, in contrast to classical antipsychotics that produce disabling movement disorders, aripiprazole does not cause an upregulation of D2 receptors or an increase in immediate early gene expression of e.g. the c-fos mRNA in the striatum. In patients with acute relapse of schizophrenia, treatment with aripiprazole provided significant improvement in both positive and negative syndrome scale (PANSS) total score in both short- and long-term evaluations. These results were comparable to those observed with haloperidol or risperidone; however, the early response rate was greater with aripiprazole. Aripiprazole was well tolerated with mild to moderate adverse events such as nausea, dizziness, somnolence and weight gain. The rates of extrapyramidal symptoms were lower than with haloperidol, prolactin levels increase has been uncommon and no significant Q-Tc interval prolongation was observed compared with placebo. Finally, studies suggested a minimal impact of aripiprazole administration on total cholesterol levels and on fasting blood sugar in contrast to other antipsychotics. Aripiprazole has a bioavailability of 87%, a tmax of 3-5 h and a half-life time of 48-68 h. Aripiprazole has been found to have linear kinetics and is mainly metabolized via the cytochrome systems CYP2D6 and CYP3A4. It has little effect on the blood levels of other medications; interaction with both lithium and divalproex sodium found minimal impact. Aripiprazole has also been studied in other psychiatric disorders, including bipolar disorders and has shown great efficacy.

Balofloxacin (antibacterial) (23-28)

Country of Origin : Japan

Originator : Chugai Pharmaceutical

First Introduction : South Korea

Introduced by : Choongwae Pharma Corporation

Trade Name : Q-Roxin

CAS Registry No : 127294-70-6

Molecular Weight : 389.43 h3c

Balofloxacin, a novel orally-active fluoroquinolone antibiotic, was introduced in South Korea for the treatment of urinary tract infections (UTI). It can be synthetized by reaction of 3-(methy!amino)piperidine with the classical 4-quinolone-3-carboxylic acid template. In vitro antibacterial activity of balofloxacin against gram-positive bacteria (Staphylococcus aureus including methicillin-resistant S. aureus, Staphylococcus epidermis, Streptococcus pneumonia, Streptococcus pyrogenes) was almost equal to that of Sparfloxacin or tosufloxacin, in contrast its activity against gram-negative bacteria was 2 times or more lower. In clinical trials, balofloxacin was well tolerated and showed comparable efficacy to ofloxacin in patients with UTIs. After oral administration, balofloxacin was well absorbed, and was primarily eliminated unchanged in the urine with an elimination half-life of approximately 8 h. In animal studies, balofloxacin did not exhibit any phototoxicity.

Biapenem (antibacterial) (29-31)

Country of Origin : US

Originator: Wyeth

First Introduction : Japan

Introduced by : Meiji Seika

Trade Name : Omegacin CAS Registry No.: 120410-24-4

Molecular Weight: 350.42

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