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Nitisinone was originally developed as a pesticide and then launched as an adjunct to dietary restriction of tyrosine and phenylalanine for the treatment of hereditary tyrosinaemia type I. In this inborn error of metabolism, fatal liver disease results either from liver failure during infancy or early childhood or from development of hepatocellular carcinoma during childhood or adolescence. This is caused by accumulation of toxic metabolites due to deficiency of fumarylacetoacetase, the last enzyme of the tyrosine catabolic pathway. Nitisinone, which acts as an inhibitor of the 4-hydroxyphenylpyruvate dioxygenase, prevents the formation of toxic metabolites such as succinylacetoacetate in the liver. Administration of a single dose of nitisinone in mice showed a rapid, significant and persistent inhibition of 4-hydroxyphenylpyruvate dioxygenase. In a murine model of tyrosinaemia type I, administration of nitisinone abolished acute liver failure. Additional dietary tyrosine restriction in the same model on long term follow-up (> 2 years) showed complete correction of liver function tests and succinylacetone levels, and cancer-free survival improvements when compared to historical controls. In healthy volunteers, nitisinone was well tolerated, peak plasma concentrations were rapidly attained following a single dose of 1 mg/kg and the half-life time was approximately 54 h. Following the administration of nitisinone (1 mg/kg), the concentrations of tyrosine in plasma increased, were still 8 times those of background at 14 days after dosing, but had returned to background levels within 2 months of the second dose. Elevated tyrosine levels are a potential risk of corneal opacities. No treatment related corneal lesions were seen after administration of high dose of nitisinone in mice. In children diagnosed when they were less than 2 months old, when nitisinone treatment was combined with a restricted diet, the four-year survival rate was 88%, compared to 29% from historical data of children treated with restricted diet alone. So, there is some clear evidence that nitisinone treatment associated with restricted diet can reduce the risk of early hepatocellular carcinoma when started before two years of age. On the contrary, in patients with late start of nitisinone treatment there is a considerable risk of liver malignancy. Even if 10% of patients have not clinically responded to nitisinone, studies have shown that oral nitisinone treatment plus dietary restriction has greatly improved the survival of patients and reduced the need of liver transplantation during early childhood.

Norelgestromin (contraceptive) (102-104)

Molecular Weight : 327.47

Ortho Evra® is the first birth control transdermal patch and contains a combination of norelgestromin and ethinylestradiol. The patch can be applied to the buttocks, lower abdomen, upper torso or arms; changed weekly for 3 weeks, followed by a patch-free week. Norelgestromin is the active metabolite produced following oral administration of norgestimate, the progestin component of the contraceptive, Ortho-Cyclen®. The half-life value of norelgestromin was approximately 28 h. Following application, norelgestromin rapidly appeared in the serum, reached a plateau by approximately 48h and was maintained at an approximate steady state throughout the wear period. Hepatic metabolites of norelgestromin included norgestrel and various hydroxylated and

Country of Origin : USA Originator: Johnson & Johnson

First Introduction : USA Introduced by: Ortho-McNeil Trade Name ; Ortho Evra CAS Registry No : 53016-31-2

conjugated metabolites that were eliminated by renal and fecal pathways. Ortho Evra produced ovarian suppression and cycle control. It was significantly more effective in suppressing follicular development than the leading oral contraceptive Triphasll® (ethinyl estradiol/levornorgestrel); was as effective in preventing pregnancies and had similar tolerability profile. The patch offers 99% efficacy when used appropriately, as shown by three clinical trials. However, a statistically significantly greater proportion of pregnancies occurred among women weighing 90 kg or more. Ortho Evra® was well tolerated, with 2.6% of women discontinuing treatment due to mild to moderate reactions at the site of application. Thus, the patch combined the efficacy of oral contraceptives with the convenience of just once-weekly dosing.

Olmesartan Medoxomil (antihypertensive) (105-107)

Olmesartan medoxomil was launched last year in the US as benicar®, an orally administered treatment for hypertension. This ester prodrug of olmesartan can be synthesized in 8 steps from diaminomaleonitrile by successive reactions with trialkylorthopropanoate to access 2-propyl-imidazole-4,5-dicarbonitrile, conversion of the two nitrile functions to the corresponding ethyl esters, followed by methylmagnesium bromide addition to give the corresponding 4-(1-hydroxyalkyl)lmidazole derivative. The latter is alkylated with the trityl-protected biphenyl tetrazole derivative. Finally detritylation and alkaline hydrolysis leads to olmesartan, that Is esterified to its corresponding prodrug. Olmesartan, is a new selective and competitive nonpeptide angiotensin II type 1 receptor antagonist and potently inhibits the Ang.ll-induced pressor responses. The drug competitively inhibited binding of [125I]-AII to ATi receptors in bovine adrenal cortical membranes, but had no effect on binding to AT2 receptors in bovine cerebellar membranes. In comparative clinical studies in patients with essential hypertension, olmesartan reduced sitting cuff diastolic blood pressure significantly more than losartan, valdesartan and ibesartan, while reductions in systolic blood pressure were similar for all treatments. Olmesartan medoxomil was also shown to reduce blood pressure significantly more effectively than losartan and the ACE inhibitor captopril and as effectively as the p-bloker atenolol. Olmesartan medoxomil is rapidly and completely bioactivated by ester hydrolysis to its active metabolite, olmesartan, during absorption from the gastrointestinal tract. Olmesartan has an absolute bioavailability of approximatively 26%, a mean elimination half-life of 14 h in patients with hypertension and is not further metabolized. Olmesartan medoxomil is well tolerated, has a side-effect profile similar to that of placebo and unlike ACE inhibitors, the incidence of dry cough is rare.

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Country of Origin : Japan Originator : Sankyo

First Introduction : US

Introduced by : Sankyo and Forest Trade Name : Benicar CAS Registry No : 144689-63-4 Molecular Weight: 558.22

Parecoxib sodiu

Country of Origin Originator: First Introduction Introduced by: Trade Name: CAS Registry No Molecular Weight

Parecoxib sodium is an injectable COX-2 Inhibitor, launched as an anti-inflammatory agent and for the management of acute pain. Parecoxib is an amide prodrug of Pharmacia's valdecoxib also launched last year. It can be administered by either i.m. or i.v. routes, in contrast to other currently available COX-2 inhibitors which are poorly water-soluble. Parecoxib sodium can be prepared from valdecoxib by acylation of the sulfonamide with propionic anhydride. Parecoxib sodium exhibited potent acute and chronic antiinflammatory activity in rats, as demonstrated in the carrageenan air pouch model, where 98% of inhibition was achieved with the dose of 0.3mg/kg, and in the adjuvant arthritis model (ED5o = 0.08mg/kg). Moreover, in the carrageenan footpad edema model, parecoxib sodium showed excellent efficacy (ED50 = 5mg/kg) and a rapid onset of action comparable with the most potent analgesic ketorolac. In this model, it produced a complete blockade of the carrageenan-induced hyperalgesia within 1 h after i.v. administration. Pharmacokinetic studies indicated that parecoxib sodium completely and rapidly converted in valdecoxib with bioequivalence found between parenterally administered parecoxib sodium and orally administered valdecoxib. The maximum plasma concentrations of valdecoxib were 25-30% greater after i.v. than i.m. administration of parecoxib and tmax was respectively 0.5 h after i.v. and 1.5 h after i.m. administration. Parecoxib sodium had greater gastrointestinal tolerance than ketorolac and had no significant effect on platelet aggregation. Parecoxib sodium was as effective as ketorolac or even superior to morphine and placebo in the treatment of severe pain (such as that observed following gynaecologic or orthopaedic surgery). Mean times to rescue medication were longer with parecoxib compared to morphine. Parecoxib sodium works 12-14 min after i.v. administration and a dose of 40 mg provides good or excellent relief of pain in approximately 90% of patients. Thus, parecoxib sodium is a non-narcotic, specific COX-2 inhibitor, which provides potent analgesic ability and fulfils some important requirements for the pain management in the post-operative period such as i.v. formulation, rapidity of action, and short half-life. Furthermore, although valdecoxib is a substrate for CYP3A4 as other drugs used in the perioperative period, it does not interfere either with the metabolism of the sedative/tranquilizer, midazolam, or with the intravenous anesthetic propofol.

Pharmacia (Searle) : UK Pharmacia Dynastat : 197502-82-2 : 392.41

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Pazufloxacin (antibacterial)

Country of Origin : Japan

Originator: Toyama

First Introduction : Japan

Introduced by : Toyama and Mitsubishi

(formely Welfide) Trade Name : Pasil, Pazucross CAS Registry No : 127045-41-4 Molecular Weight: 318.30

Pazufloxaciri is a novel quinolone marketed for the treatment of bacterial infections in Japan. This tricyclic fluoro-quinolone can be synthesized in 11 steps from commercially available 2,3,4,5-tetrafluorobenzoic acid. The cyclopropyl substituent is first introduced in 6 steps including 4-F-substitution with ferf-butylcyanoacetate, decarboxylation, aa alkylation with 1,2-dibromoethane, partial nitrile hydrolysis and Hoffmann-rearrangement. The pyridoxazine ring is then introduced in 5 steps including p-ketoester formation and pryridoxazine annulation. Pazufloxacin displays a broad spectrum activity against Grampositive and Gram-negative bacteria, although it is less active that ciprofloxacin against pneumococci and is not active against ciprofloxacln-resistant isolates. In patients with gonococcal urethritis a high prevalence of fluoroquinolone-resistant N. gonorrhoeae isolates with the Ser-91-to-Phe mutation in GyrA was observed. However, good clinical responses have been seen in clinical trials of patients with urinary tract infections and to a lesser extent with respiratory tract infections. Pazufloxacin is mainly excreted in urine with a short half-life (2-2.5 h). It has a phototoxicity equal to that of ciprofloxacin and its adverse effect profile resembles that of other quinolones.

Pimecrolimus (immunosuppressant) (122-129)

Country of Origin : USA ci^

Originator: Novartis

First Introduction : USA

Introduced by: Novartis

Trade Name : Elidel

CAS Registry No : 137071-32-0

Molecular Weight: 810.46

Pimecrolimus is an ascomycin macrolactam derivative, developed as a topical formulation (1% cream) for the treatment of mild to moderate atopic dermatitis for patients aged two years and over in whom the use of conventional therapies is inadvisable. Pimecrolimus is an inflammatory cytokine inhibitor that works by selectively targeting T-cells in the skin. It inhibits in vitro the production and release of pro-Inflammatory cytokines after antigen-specific or non-specific stimulation in T cells and mast cells. Pimecrolimus binds specifically to cytosolic receptor macrophilin-12 at nanomolar concentrations leading to inhibition of the Ca +/calmodulin-dependent phosphatase, calcineurin. Pimecrolimus is a chlorine derivative of the known FK-520, from which it can be synthesized. In a pig model of dinitrofluorobenzene-induced allergic contact dermatitis, pimecrolimus was shown to inhibit erythema and induration, had equivalent efficacy compared to clobetasol-17-propionate, but did not cause atrophogenic effects. In a mouse model of allergic contact dermatitis, pimecrolimus given orally was as potent as tacrolimus and more effective than cyclosporin. The agent also decreased the intensity of cutaneous manifestations in an atopic dermatitis model involving hypomagnesemic hairless mice. Both in adults and in pediatric patients with atopic dermatitis, treatment with pimecrolimus has demonstrated greater efficiency than conventional treatment in reducing the incidence of disease flares, as well as the use of second-line corticosteroids. Moreover, in a 26 week study, in pediatric patients (2-17 years), from 65% of subjects showing improvement, 85% were cleared of

the disease. Oral pimecrolimus administration resulted in an elimination half-life of about 30 to 40 h. It is not metabolized or degraded during skin permeation after topical administration. However, following oral administration, it is metabolized via the liver CYP3A4 pathway and excreted mainly in the feces. Pimecrolimus is well tolerated; no systemic accumulation is seen and the most commonly reported side effect is reaction at the site of application. Moreover, pimecrolimus did not cause skin atrophy in contrast to corticosteroids. At this time, as a replacement therapy for topical corticosteroids, the only competing agent for pimecrolimus is topical tacrolimus (ointment). Preliminary studies demonstrated comparable efficacy and safety between these two agents.

Prulifloxacin (antibacterial) (130-134)

Trade Name: Sword CAS Registry No.: 123447-62-1 Molecular Weight: 461.50

Prulifloxacin was the third fluoroquinone to be launched last year. It was introduced in Japan as an oral treatment for urinary tract infections (UTIs), respiratory tract infections (RTIs) and bacterial pneumoniae. It can be synthesized in 10 steps from commercially available 3,4-difluoroaniline. Key steps involve the cyclization of 6,7-difluoro-4-hydroxy-2-thioquinoline-3-carboxylic acid ethyl ester with 1,1-dibromomethane to give the corresponding thiazeto-[3,2a]quinoline. Aromatic nucleophilic substitution of the 7-fluoro atom with piperazine followed by hydrolysis of the ethyl ester and finally alkylation of the piperazinyl moiety with 4-(bromomethyl)-5-methyl-1,3-dioxol-2-one complete the synthesis. Prulifloxacin is a lipophilic prodrug, which is rapidly hydrolyzed to the corresponding N-dealkylated piperazine, NM 394, by paraoxonase type enzymes in blood and liver following intestinal absorption. The DNA gyrase inhibitor NM 394 accounts for all antimicrobial activity: it shows a similar or greater activity against gram-positive bacteria compared to ciprofloxacin, and a greater activity in the case of gram-negative bacteria. In clinical studies, prulifloxacin has shown good efficacy against UTIs and RTIs. The drug is mainly excreted in the urine and in the feces as unchanged NM 394, which has a plasma half-life of approximately 8 h. Phototoxicity in animal models is less severe than with other quinolones. Prulifloxacin is well tolerated with an adverse effect profile similar to that of other fluoroquinolones.

Sivelestat (antiinflammatory) (135-141)

Originator : Nippon Shinyaku

First Introduction : Japan

Country of Origin : Japan

Introduced by : Nippon Shinyaku and Meiji Seika

Originator : Nippon Shinyaku

First Introduction : Japan

Introduced by : Nippon Shinyaku and Meiji Seika

Country of Origin : Japan

Originator: Ono Pharmaceutical

First Introduction: Japan

Introduced by : Ono Pharmaceutical

Trade Name: Elaspol

CAS Registry No : 201677-61-4

Molecular Weight: 528.53

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