Miglustat, an N-alkylated imino sugar, is a synthetic analogue of D-glucose. Miglustat is an inhibitor of the enzyme glucosylceramide synthase, which is a glucosyl transferase enzyme responsible for catalyzing the formation of glucosylceramide (glucocerebroside). Glucosylceramide is a substrate for the endogenous glucocerebrosidase, an enzyme that is deficient in Gaucher's disease. The accumulation of glucosylceramide due to the absence of glucocerebrosidase results in the storage of this material in the lysosomes of tissue macrophages, leading to widespread pathology due to infiltration of lipid-engorged macrophages in the viscera, lymph nodes, and bone marrow. This results in secondary hematologic consequences including sever anemia and thrombocytopenia, in addition to the characteristic progressive hepatosplenomegaly, as well as skeletal complications including osteonecrosis and osteopenia with secondary pathological fractures. Miglustat functions as a competitive and reversible inhibitor of the enzyme glucosylceramide synthase, the initial enzyme in a series of reactions which results in the synthesis of most glycosphingolipids. The goal of treatment with miglustat is to reduce the rate of glycosphingolipid biosynthesis so that the amount of glycosphingolipid substrate is reduced to a level which allows the residual activity of the deficient glucocerebrosidase enzyme to be more effective (substrate reduction therapy), reducing the accumulation of glucocerebroside in macrophages. In vitro and in vivo studies have shown that miglustat can reduce the synthesis of glucosylceramide-based glycosphingolipids. In clinical trials, miglustat improved liver and spleen volume, as well as hemoglobin concentration and platelet count. Inhibition of glycosphingolipid synthesis has also shown to reduce intracellular lipid storage, improve fluid-phase endosomal uptake and normalize lipid transport in peripheral blood B lymphocytes of NP-C patients, which results in a decrease in the potentially neurotoxic accumulation of gnagliosides GM2 and GM3, lactosylceramide and glucosylceramide, possibly preventing further neuronal damage. Other studies have also suggested that miglustat may indirectly modulate intracellular calcium homeostasis through its effects on glucosylceramide levels, and evidence has shown that an initiating factor in the pathogenesis of NP-C may be impaired calcium homeostasis related to sphingosine storage. Therefore, the effect that miglustat exerts on intracellular calcium levels may influence an important underlying pathogenic mechanism of NP-C. Miglustat is used for the treatment of adult patients with mild to moderate type 1 (nonneuropathic) Gaucher's disease for whom enzyme replacement therapy is not a therapeutic option (e.g. due to constraints such as allergy, hypersensitivity, or poor venous access). Now approved in some countries for the treatment of progressive neurological symptoms in adult and pediatric patients with Niemann-Pick disease type C (NP-C). Miglustat is marketed under the trade name Zavesca.

Olmesartan medoxomil, a prodrug, is hydrolyzed to olmesartan during absorption from the gastrointestinal tract. Olmesartan is a selective AT1 subtype angiotensin II receptor antagonist. Olmesartan blocks the vasoconstrictor effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor in vascular smooth muscle. Oral olmesartan medoxomil 10-40 mg once daily is recommended for the treatment of adult patients with hypertension, this dosage has consistently helped achieve a double-digit reduction both in systolic and diastolic blood pressure, a reduction which is maintained for one year. Extensive clinical evidence from several large well designed trials and the clinical practice setting has confirmed the antihypertensive efficacy and good tolerability profile of oral olmesartan medoxomil, as monotherapy in patients with hypertension. Olmesartan medoxomil has shown no clinically important pharmacokinetic interactions with digoxin, warfarin or antacid (aluminium magnesium hydroxide). Adverse events were infrequent in clinical studies of olmesartan medoxomil and were similar to those attributed to placebo.

Eletriptan (eletriptan hydrobromide, trade name Relpax) is a selective 5-hydroxytryptamine (5-HT1B/1D) serotonin receptor agonist (triptan) indicated for the acute treatment of migraine with or without aura in adults. Eletriptan binds with high affinity to 5-HT1B, 5-HT1D and 5-HT1F receptors, and has modest affinity for 5-HT1A, 5-HT1E, 5-HT2B and 5-HT7 receptors. The therapeutic activity of eletriptan for the treatment of migraine headache is thought to be due to the agonist effects at the 5-HT1B/1D receptors on intracranial blood vessels (including the arterio-venous anastomoses) and sensory nerves of the trigeminal system which result in cranial vessel constriction and inhibition of pro-inflammatory neuropeptide release. Eletriptan (Relpax) has been approved for use in the acute treatment of migraine in 51 countries and has been introduced in 17 countries including Mexico, Italy, France and Japan.

Dutasteride is a synthetic 4-azasteroid compound that is a selective inhibitor of both the type 1 and type 2 isoforms of steroid 5 alpha-reductase (5AR), intracellular enzymes that convert testosterone to 5 alpha-dihydrotestosterone (DHT). Type I 5a-reductase is predominant in the sebaceous glands of most regions of skin, including scalp, and liver. Type I 5a-reductase is responsible for approximately one-third of circulating DHT. The Type II 5a-reductase isozyme is primarily found in prostate, seminal vesicles, epididymides, and hair follicles as well as liver, and is responsible for two-thirds of circulating DHT. Dutasteride inhibits the conversion of testosterone to 5 alpha-dihydrotestosterone (DHT), which is the androgen primarily responsible for the initial development and subsequent enlargement of the prostate gland. Testosterone is converted to DHT by the enzyme 5 alpha-reductase, which exists as 2 isoforms, type 1 and type 2. Dutasteride is a competitive and specific inhibitor of both type 1 and type 2 5 alpha-reductase isoenzymes, with which it forms a stable enzyme complex. Dissociation from this complex has been evaluated under in vitro and in vivo conditions and is extremely slow. Used for the treatment of symptomatic benign prostatic hyperplasia (BPH) in men with an enlarged prostate gland to improve symptoms, and reduce the risk of acute urinary retention and the need for surgery. Marketed under the brand name Avodart.

Imatinib (GLEEVEC®) is a tyrosine kinase inhibitor and antineoplastic agent that inhibits the BCR-ABL tyrosine kinase, the constitutive abnormal tyrosine kinase created by the Philadelphia chromosome abnormality in chronic myeloid leukaemia (CML). It inhibits proliferation and induces apoptosis in BCR-ABL positive cell lines as well as fresh leukemic cells from Philadelphia chromosome positive CML. Imatinib (GLEEVEC®) inhibits colony formation in assays using ex vivo peripheral blood and bone marrow samples from CML patients. It is also an inhibitor of the receptor tyrosine kinases for platelet-derived growth factor (PDGF) and stem cell factor (SCF), c-kit, and inhibits PDGF- and SCF-mediated cellular events. In vitro, imatinib (GLEEVEC®) inhibits proliferation and induces apoptosis in gastrointestinal stromal tumor (GIST) cells, which express an activating c-kit mutation.

Caspofungin is an echinocandin antifungal drug, which is approved and is sold under the brand worldwide name cancidas. Caspofungin inhibits the synthesis of beta (1,3)-D-glucan, an essential component of the cell wall of susceptible Aspergillus species and Candida species. Beta (1,3)-D-glucan is not present in mammalian cells. Cancidas is indicated for the treatment of candidemia and the following candida infections: intra-abdominal abscesses, peritonitis, and pleural space infections in adult and pediatric patients. Also is indicated for the treatment of esophageal candidiasis in adult and pediatric patients and for the treatment of invasive aspergillosis in adult and pediatric patients, but has not been studied as initial therapy for invasive aspergillosis.

Galantamine (RAZADYNE®, galantamine hydrobromide) is a benzazepine derived from norbelladine. It is found in Galanthus and other Amaryllidaceae. It is a reversible, competitive acetylcholinesterase inhibitor that is used for the treatment of mild to moderate dementia of the Alzheimer’s type. Although the etiology of cognitive impairment in Alzheimer’s disease is not fully understood, it has been reported that acetylcholine-producing neurons degenerate in the brains of patients with Alzheimer’s disease. The degree of this cholinergic loss has been correlated with degree of cognitive impairment and density of amyloid plaques (a neuropathological hallmark of Alzheimer’s disease). While the precise mechanism of galantamine’s (RAZADYNE®, galantamine hydrobromide) action is unknown, it is postulated to exert its therapeutic effect by enhancing cholinergic function. This is accomplished by increasing the concentration of acetylcholine through reversible inhibition of its hydrolysis by acetylcholinesterase. If this mechanism is correct, galantamine’s (RAZADYNE®, galantamine hydrobromide) effect may lessen as the disease process advances and fewer cholinergic neurons remain functionally intact. There is no evidence that galantamine (RAZADYNE®, galantamine hydrobromide) alters the course of the underlying dementing process.

Pimecrolimus, an ascomycin macrolactam derivative, is an inhibitor of T-cell and mast-cell activation, developed and launched by Novartis for the potential treatment of psoriasis and allergic, irritant and atopic dermatitis. The topical formulation had been launched in the US by February 2002 for mild-to-moderate atopic dermatitis in patients aged two years and older. Pimecrolimus is an immunomodulating agent. The mechanism of action of pimecrolimus in atopic dermatitis is not known. While the following have been observed, the clinical significance of these observations in atopic dermatitis is not known. It has been demonstrated that pimecrolimus binds with high affinity to macrophilin-12 (FKBP-12) and inhibits the calcium dependent phosphatase, calcineurin. Therefore, it inhibits T cell activation by blocking the transcription of early cytokines. In particular, pimecrolimus inhibits at nanomolar concentrations Interleukin-2 and interferon gamma (Th1-type) and Interleukin-4 and Interleukin-10 (Th2-type) cytokine synthesis in human T-cells. In addition, pimecrolimus prevents the release of inflammatory cytokines and mediators from mast cells in vitro after stimulation by antigen/IgE. Following the administration of a single oral radiolabeled dose of pimecrolimus numerous circulating O-demethylation metabolites were seen. Studies with human liver microsomes indicate that pimecrolimus is metabolized in vitro by the CYP3A sub-family of metabolizing enzymes. No evidence of skin mediated drug metabolism was identified in vivo using the minipig or in vitro using stripped human skin.

Fondaparinux is a synthetic and specific inhibitor of activated Factor X (Xa). By selectively binding to antithrombin III (ATIII), fondaparinux sodium potentiates (about 300 times) the innate neutralization of Factor Xa by ATIII. Neutralization of Factor Xa interrupts the blood coagulation cascade and thus inhibits thrombin formation and thrombus development. Fondaparinux is indicated for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE): in patients undergoing hip fracture surgery, including extended prophylaxis; in patients undergoing hip replacement surgery; in patients undergoing knee replacement surgery; in patients undergoing abdominal surgery who are at risk for thromboembolic complications. The most serious adverse reactions reported with Fondaparinux are bleeding complications and thrombocytopenia. Agents that may enhance the risk of hemorrhage should be discontinued prior to initiation of therapy with Fondaparinux unless these agents are essential.

Almotriptan is a triptan drug for the treatment of migraine headaches. Almotriptan is marketed under the trade name Axert. Almotriptan is used for treating acute migraine headaches with or without aura (eg, dark spots, flashing lights, wavy lines). Almotriptan binds with high affinity to 5-HT1D, 5-HT1B, and 5-HT1F receptors. Almotriptan has weak affinity for 5-HT1A and 5-HT7 receptors, but has no significant affinity or pharmacological activity at 5-HT2, 5-HT3, 5-HT4, 5-HT6; alpha or beta adrenergic; adenosine (A1, A2); angiotensin (AT1, AT2); dopamine (D1, D2); endothelin (ETA, ETB); or tachykinin (NK1, NK2, NK3) binding sites.