Sivelestat is an acyi enzyme inhibitor of neutrophil elastase, developed as an injectable formulation for the treatment of acute lung injury associated with systemic inflammatory response syndrome. A neutrophil predominant inflammation associated with excessive release of human neutrophil elastase (HNE) from azurophilic granules is capable of damaging both the lung parenchymal cells and the extracellular matrix allowing an alveolar capillary barrier disruption. Sivelestat is a sulfonanilide-containing pivaloyloxy benzene derivative prepared in a three step synthesis. This agent acts as a reversible and selective inhibitor of HNE with an IC5o value of 0.044 |iM. Sivelestat has exhibited potent protective effects against various causes of lung injuries in animal models. In an acid-induced acute lung injury model in conscious hamster, administration of sivelestat for 48 h following HCI instillation, dose-dependently reduced mortality and significantly improved the protein levels in bronchoalveolar lavage fluids and pulmonary artery pressure. In a similar study, the agent inhibited the endotoxin-induced acute lung dysfunctions (marked elevation of pulmonary vascular permeability, leukocyte migration, hemorrhage and parenchymal injury) in different animal species. Moreover, in a cardiopulmonary bypass model in dog, sivelestat ameliorated the respiratory index and interstitial-intra-alveolar edema. Sivelestat has a relatively poor bioavailability, due to an extensive first-pass metabolism and is easily hydrolyzed in vitro to an inactive metabolite. In two animal species, the half-life time was approximately 5-7 min. Clinical trials have shown that treatment with the agent improves respiratory function and facilitates early removal of patients from mechanical ventilation. However, in the last clinical study, conducted by Eli Lilly in patients with acute lung injury, no difference in mortality and safety was seen between sivelestat and placebo.

Temoporphin (antineoplastic/photosensitizing) (142-145)

cancers. This porphyrin derivative can be synthesized from pyrrole and 3-hydroxybenzaldehyde. The pharmacological activity is initiated, 4 days after intravenous injection, by laser-light photoactivation of temoporphin, that has selectively accumulated in cancer tissues. The resulting generation of highly reactive oxygen species leads to malignant cells death thereby inducing tumor necrosis up to a depth of 15 mm. An advantage of temoporphin over other photosensitizing agents is its extreme sensitivity to wavelengths of light that penetrate tissues, resulting in lower light/dose and irradiation time. PDT with intravenous temoporphin has produced relatively high complete and partial response rates in head and neck cancers, with higher response rates generally observed with higher light dose. Temoporphin is well-tolerated and does not preclude surgery/radiotherapy as a later option. Adverse effects were photosensitivity and pain at the injection site.

Country of Origin : UK Originator: Quanta Nova

First Introduction : UK Introduced by: Quanta Nova Trade Name: Foscan CAS Registry No. : 122341-38-2 Molecular Weight: 680.75

Temoporphin, a second generation photosensitizer, was launched last year in UK for the photodynamic therapy (PDT) of advanced head and neck

Temoporphin, a second generation photosensitizer, was launched last year in UK for the photodynamic therapy (PDT) of advanced head and neck


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

Tiotropium bromide is a long-acting inhaled muscarinic antagonist, developed for the once-daily treatment of chronic obstructive pulmonary disease. Tiotropium bromide can be prepared in three steps. The Grignard condensation of 2-thienyl magnesium bromide with oxalic acid dimethyl ester, followed by a transesterification with scopine provided the ester which was quaternized with methyl bromide. Tiotropium bromide binds to human recombinant muscarinic receptors Mr, M2- and M3-subtypes with high and similar affinity, comparable to those obtained with ipratropium. Tiotropium bromide is characterized by its novel property of kinetic selectivity : while ipratropium rapidly dissociated from each of the receptor subtypes, tiotropium dissociated rapidly from M2 receptors (ti/2=3.6 h) but slowly from Mi (ti/2=14.6 h) and M3 (ti/2=34.7 h) receptors. Inhibition of cholinergic bronchospasm by tiotropium bromide was demonstrated in anesthetized guinea pigs, rabbits and dogs. In healthy volunteers, inhalation of tiotropium bromide resulted in an absolute bioavailability of 19.5%, a tmax value of 5 min. and the terminal half-life value of 5-6 days. There was no evidence of drug accumulation after repeated administration. The extent of biotransformation was small with a urinary excretion of 74% of unchanged substance after i.v. administration. Long term studies in patients with stable COPD have demonstrated that tiotropium bromide gave an effective bronchodilation that was maintained over 24h, significantly improved lung function as measured by FEV1 (+11-12%) and showed progressive reduction in dyspnea. It also reduced exacerbations of COPD patients and improved quality of life. Tiotropium bromide produced greater and more sustained bronchodilation than ipratropium bromide. Tiotropium has been shown to cause superior bronchodilatation and symptomatic improvements when compared to twice daily salmeterol in COPD. Tiotropium bromide was well tolerated and caused few adverse effects. The most common side effect reported was the mechanism-related effect of dry mouth.

lide (bronchodilator)

  • 146-150)
  • Germany

Boehringer Ingelheim : Netherlands / Philippines Boehringer Ingelheim / Pfizer Spiriva : 136310-93-5 : 472.42

Treprostinil sodium (antihypertensive) (151-154)

Country of Origin : USA Originator: Pharmacia/

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