Glatiramer acetate (Copaxone®) is a synthetic copolymer composed of a random mixture of four amino acids that modifies the immune response that results in the CNS inflammation, demyelination and axonal loss characteristic of relapsing-remitting multiple sclerosis (RRMS).

Tenofovir disoproxil fumarate (tenofovir DF) is an orally administered ester prodrug of tenofovir, a nucleotide reverse transcriptase inhibitor that shows potent in vitro activity against both hepatitis B virus (HBV) and HIV-1. As a component of antiretroviral combination therapy regimens, tenofovir DF is well established in the treatment of adults with HIV-1 infection. Tenofovir DF, administered once daily, is also used in the treatment of adults with chronic hepatitis B (CHB) [the main focus of this profile]. In CHB, the efficacy of tenofovir DF against HBV has been evaluated in two large randomized, phase III clinical studies in hepatitis B e antigen (HBeAg)-negative or HBeAg-positive adults, with compensated liver function. The trials (planned duration 8 years) were double-blind for the first 48 weeks; thereafter, patients received open-label tenofovir DF. Results at 48 and 96 weeks are available. In these studies, at week 48, a significantly greater proportion of recipients of tenofovir DF 300 mg once daily than oral adefovir dipivoxil 10 mg once daily achieved a complete response (primary endpoint). A complete response was defined as a reduction from baseline in plasma HBV DNA level to <400 copies/mL and histological improvement (reduction of 2 or more points in Knodell necroinflammatory score without worsening of fibrosis). The efficacy of tenofovir DF in the treatment of CHB was also demonstrated over a 96-week treatment period in both studies. Tenofovir DF was generally well tolerated by adults with CHB in the two phase III trials.

Sorafenib is an orally active multikinase inhibitor with anti-tumour activity. It was recently approved in the US and the EU for the treatment of patients with hepatocellular carcinoma. Oral sorafenib 400 mg twice daily significantly improved survival in patients with advanced hepatocellular carcinoma in the randomized, double-blind, multicentre, phase III SHARP trial (n = 602); the median duration of survival was 10.7 months with sorafenib and 7.9 months with placebo. In addition, the median time to progression was significantly longer in patients receiving sorafenib than in those receiving placebo (5.5 vs 2.8 months). Combination therapy with oral sorafenib 400 mg twice daily and intravenous doxorubicin has potential in the treatment of patients with advanced hepatocellular carcinoma, according to the results of a randomized, double-blind, phase II study (n = 96). Although the addition of sorafenib to doxorubicin did not significantly delay the time to progression, the median durations of overall survival and progression-free survival were significantly longer with sorafenib plus doxorubicin than with doxorubicin alone. Monotherapy with oral sorafenib 400 mg twice daily was generally well tolerated in patients with advanced hepatocellular carcinoma, with a manageable adverse event profile.

A Temsirolimus, an ester of sirolimus (rapamycin), selectively inhibits the kinase mammalian target of rapamycin and consequently blocks the translation of cell cycle regulatory proteins and prevents the over expression of angiogenic growth factors.Patients with advanced renal cell carcinoma and a poor prognosis who received a once-weekly intravenous infusion of temsirolimus 25 mg experienced significant survival benefits compared with patients receiving standard interferon-alpha (IFN alpha) therapy (3-18 MU subcutaneously three times weekly) in a large phase III clinical study. Median overall survival was 10.9 versus 7.3 months, progression-free survival was 5.5 versus 3.1 months.Objective response rates were 8.6% in temsirolimus recipients versus 4.8% in IFN alpha recipients.Temsirolimus monotherapy recipients experienced significantly fewer grade 3 or 4 adverse events and had numerically fewer withdrawals for adverse events than patients receiving IFN alpha.

Ramelteon (Rozerem (TM)) is the first melatonin receptor agonist to be approved for the treatment of insomnia, it is not classified as a controlled substance. In patients with chronic insomnia, objectively assessed latency to persistent sleep (LPS) at week I was improved with oral ramelteon 8 mg administered 30 minutes before bedtime, compared with placebo, and this effect was maintained throughout the duration of 5-week and 6-month clinical studies. Subjectively assessed sleep latency (sSL) improved in some, but not all, studies. When a statistically significant improvement in sSL Occurred at week 1, the effect was maintained throughout the duration of the 5-week studies, but not at all timepoints throughout a 6-month study. Improvements in objectively assessed total sleep time (TST) and sleep efficiency (SE) were only reported during the first week of treatment. Improvements in other objective or subjective measures of sleep were not consistent. Ramelteon was generally well tolerated, did not impair next-day cognitive or motor performance and was not associated with withdrawal symptoms, rebound insomnia or abuse potential. Thus, ramelteon provides a well tolerated option for the treatment of patients with insomnia characterized by difficulty in sleep onset.Pharmacological PropertiesRamelteon is a highly selective melatonin MT1 and MT2 receptor agonist, with no appreciable affinity for the GABA receptor complex or receptors that bind neuropeptides, cytokines, opioids, dopamine or serotonin. Ramelteon enhanced re-entrainment of circadian rhythms to a new light-dark cycle in volunteers, according to measurements of endogenous melatonin secretion offset time. In patients with chronic insomnia, ramelteon was not associated with acute or next-day effects on cognitive or psychomotor function compared with placebo when assessed using standard tests, and had no effect on middle-of-the-night balance/body sway. Doses of ramelteon up to 20-fold greater than that recommended for the treatment of insomnia showed no potential for abuse in adults with a history of sedative abuse.Ramelteon is rapidly absorbed, with a time to peak serum concentration of 0.75 hours. The total absorption of ramelteon is >= 84%; however, the absolute bioavailability is <2% due to extensive first-pass metabolism. Metabolism is via cytochrome P450 (CYP) isozymes, primarily CYP1A2. Fluvoxamine (a CYP1A2 inhibitor) should not be coadministered with ramelteon, and caution should be exercised with some other drug combinations. Eighty-four percent of the drug is excreted in the urine and approximate to 4% in the faeces; <0.1% is excreted as unchanged drug. The elimination half-life of ramelteon is approximate to 1.4 hours.Therapeutic EfficacyIn patients with chronic insomnia, oral ramelteon 8 mg administered 30 minutes before bedtime improved LPS in the first week and throughout the duration of 5-week and 6-month randomized. double-blind studies. The difference between ramelteon 8 mg/night and placebo for LPS throughout the course of the 5-week study was 11-16 minutes. Ramelteon 8 mg/night improved sSL in some, but not all, studies. When a statistically significant improvement in sSL occurred at week 1, the effect persisted throughout the duration of the 5-week studies, but not at every timepoint throughout the 6-month study. TST, when monitored by polysomnography, was significantly greater with ramelteon 8 mg/night than with placebo only during the first week of the studies in patients with chronic insomnia. The changes in subjectively assessed TST were not consistent. Objectively measured SE was significantly higher in recipients of ramelteon 8 mg/night than with placebo only during the first week. There were no significant differences between ramelteon and placebo for other objective or subjective sleep parameters, including sleep quality, awake time and number of awakenings after sleep onset, and difficulty/ease of falling back to sleep.TolerabilityIn a first-night model of transient insomnia in volunteers, LPS was significantly shorter and TST was significantly longer with ramelteon 8 mg than placebo. Ramelteon was generally well tolerated, with the majority of adverse events being of mild or moderate severity. According to data from a pooled analysis of phase I-III trials, the most common treatment-emergent adverse events in recipients of ramelteon 8 mg/night or placebo were headache (both 7%), somnolence (5% vs 3%), dizziness (5% vs 3%) and fatigue (4% vs 2%). Discontinuation due to an adverse event occurred in 6% of ramelteon recipients and 2% of placebo recipients. Increases in prolactin levels were reported in a 6-month trial and abnormalities in cortisol levels were reported in ramelteon recipients in an open-label 1-year trial in patients with chronic insomnia.Ramelteon was not associated with withdrawal effects or rebound insomnia.

Agalsidase beta (Fabrazyme) is a recombinant human alpha-galactosidase A enzyme approved for intravenous use in the treatment of Fabry disease. Fabry disease is a progressive, multisystemic, potentially life threatening disorder caused by a deficiency of alpha-galactosidase A. This deficiency results in accumulation of glycosphingolipids, particularly globotriaosylceramide (GL-3), in the lysosomes of various tissues. This accumulation is the underlying driver of disease progression. Agalsidase beta provides an exogenous source of alpha-galactosidase A.Intravenous agalsidase beta is effective and well tolerated in patients with Fabry disease. In a phase III trial, agalsidase beta was shown to clear GL-3 from various target cells and, in a subsequent extension of this trial, prevent GL-3 reaccumulation. In a post-approval trial, agalsidase beta was shown to provide significant clinical benefit by reducing the risk of a major clinical event. Thus, agalsidase beta represents an important advance in the treatment of Fabry disease, and agalsidase beta therapy should be strongly considered in patients with Fabry disease who are suitable candidates.

Voriconazole (VFEND (R)), a synthetic second-generation, broad-spectrum triazole derivative of fluconazole, inhibits the cytochrome P450 (CYP)-dependent enzyme 14-alpha-sterol demethylase, thereby disrupting the cell membrane and halting fungal growth. In the US, intravenous and/or oral voriconazole is recommended in adults for the treatment of invasive aspergillosis, candidaemia in non-neutropenic patients, disseminated infections caused by Candida spp., oesophageal candidiasis, and in patients with scedosporiosis and fusariosis who are refractory to or intolerant of other antifungal therapy. In Europe, intravenous and/or oral voriconazole is recommended in adults and paediatric patients of at least 2 years of age for the treatment of invasive aspergillosis, candidaemia in non-neutropenic patients, fluconazole-resistant serious invasive Candida spp. infections, scedosporiosis and fusariosis.In large randomised trials, voriconazole was an effective and generally well tolerated primary treatment for candidiasis and invasive aspergillosis in adults and adolescents. More limited data also support the use of voriconazole for the treatment of invasive fungal infections in children, in those with rare fungal infections, such as Fusarium spp. or Scedosporium spp., and in those refractory to or intolerant of other standard antifungal therapies. The availability of both parenteral and oral formulations and the almost complete absorption of the drug after oral administration provide for ease of use and potential cost savings, and ensure that therapeutic plasma concentrations are maintained when switching from intravenous to oral therapy. On the other hand, the numerous drug interactions associated with voriconazole may limit its usefulness in some patients. Further clinical experience will help to more fully determine the position of voriconazole in relation to other licensed antifungal agents. In the meantime, voriconazole is a valuable emerging option for the treatment of invasive aspergillosis and rare fungal infections, including Fusarium spp. and Scedosporium spp. infections, and provides an alternative option for the treatment of candidiasis, particularly where the causative organism is inherently resistant to other licensed antifungal agents.

Agalsidase beta (Fabrazyme®) is a recombinant human α-galactosidase A enzyme approved for intravenous use in the treatment of Fabry disease. Fabry disease is a progressive, multisystemic, potentially life threatening disorder caused by a deficiency of α-galactosidase A. This deficiency results in accumulation of glycosphingolipids, particularly globotriaosylceramide (GL-3), in the lysosomes of various tissues. This accumulation is the underlying driver of disease progression. Agalsidase beta provides an exogenous source of α-galactosidase A.

Agalsidase beta (Fabrazyme®) is a recombinant human α-galactosidase A enzyme approved for intravenous use in the treatment of Fabry disease. Fabry disease is a progressive, multisystemic, potentially life-threatening disorder caused by a deficiency of α-galactosidase A. This deficiency results in accumulation of glycosphin-golipids, particularly globotriaosylceramide (GL-3), in the lysosomes of various tissues. This accumulation is the underlying driver of disease progression. Agalsidase beta provides an exogenous source of α-galactosidase A.

Reteplase (Retavase®) is a plasminogen activator, mimicking endogenous tissue plasminogen activator (t-PA), a serine protease, converting plasminogen to plasmin and thereby precipitating thrombolysis. It is a third-generation recombinant form of t-PA that operates in the presence of fibrin (i.e. it is fibrin specific).

Famciclovir (Famvir) is the oral prodrug of penciclovir, an agent that has demonstrated antiviral activity against herpes simplex viruses, type 1 (HSV-1) and 2 (HSV-2) [which cause orolabial and/or genital herpes simplex], and against varicella zoster virus (VZV) [a reactivation of which leads to herpes zoster]. Famciclovir has efficacy similar to that of aciclovir (in immunocompetent or immunocompromised patients) or valaciclovir (in immunocompetent patients) in the treatment of herpes zoster, and efficacy similar to aciclovir in the treatment of first or recurrent episodes of genital herpes (in immunocompetent or immunocompromised patients). Famciclovir also has efficacy in the suppression of recurrent episodes of genital herpes, and in the treatment of orolabial herpes, in immunocompetent patients. As such, famciclovir is a well tolerated first-line option for the treatment of herpes zoster and the treatment and suppression of genital herpes, and is approved for the treatment of recurrent orolabial herpes. Convenient patient-initiated single-day (for recurrent genital herpes) and single-dose (for orolabial herpes) dosage regimens may contribute to treatment compliance, patient acceptability and subsequent treatment outcomes.

Perindopril (Coversyl) is a prodrug ester of perindoprilat, an ACE inhibitor. This agent has shown pharmacodynamic effects beyond those responsible for lowering blood pressure (BP), including the improvement of endothelial function and the normalisation of vascular and cardiac structure and function. Perindopril has a well established role in the treatment of patients with hypertension or heart failure. In the EUROPA trial, once-daily perindopril 8 mg prevented cardiovascular events in patients with stable coronary artery disease (CAD) without any apparent heart failure receiving standard recommended therapy. In the ASCOT-BPLA trial, a calcium channel antagonist +/- perindopril regimen demonstrated significant cardiovascular benefits compared with a conventional beta-blocker +/- diuretic regimen in patients with hypertension who were at risk of developing cardiovascular events. These trials demonstrate that while perindopril, in addition to standard recommended therapy, has a potential role in preventing cardiovascular events in hypertensive patients, its role in the management of patients with stable CAD is clearly established.

Although the incidence of new hepatitis C virus (HCV) infections may be declining, the prevalence of the diagnosed and treated chronic infection is set to increase over the next 2 decades because of the emergence of hepatic complications of the disease and the increased public awareness of hepatitis C and its transmission, which will prompt diagnosis and treatment of already infected individuals.

Adalimumab, a fully human monoclonal antibody, is a tumour necrosis factor antagonist that has been investigated for efficacy in psoriatic arthritis, based on well-established use of the drug in rheumatoid arthritis.In well-controlled Phase III trials, adalimumab (40 mg administered subcutaneously every other week) has shown efficacy in adult patients with psoriatic arthritis who had an inadequate response to previous treatment with NSAIDs (24-week ADEPT trial; n = 313) or disease-modifying antirheumatic drugs (12-week study; n = 100).In these trials, adalimumab recipients experienced a significantly greater improvement in arthritis response (p < 0.001 in die ADEPT trial, and p <= 0.05 in the smaller study) than placebo recipients, as assessed by the ACR20, ACR50 and ACR70 response rates.There was radiographic evidence of progressive joint damage in the placebo group but not the adalimumab group at 24 weeks in the ADEPT trial, according to the mean total Sharp score modified for psoriatic arthritis.The signs and symptoms of psoriasis in patients with psoriatic arthritis were clinically and statistically more improved with adalimumab than with placebo, according to the PASI responses, at 12 and 24 weeks in the ADEPT trial (e.g. PASI50 rate 75% vs 12% at 24 weeks; p < 0.001).Adalimumab was generally well-tolerated in clinical trials of psoriatic arthritis; the adverse event profile appears to be similar to that associated with use of the drug in rheumatoid arthritis.

Droperidol (Dehydrobenzperidol, Dehidrobenzoperidol, Dridol, Droleptan, Inapsine) is a dopamine D(2) receptor antagonist that has been widely used in adults and children for the prevention and treatment of postoperative nausea and vomiting (PONV) over several decades and, more recently, for the prevention of opioid-induced PONV during patient-controlled analgesia (PCA) in adults. In well controlled clinical trials of patients undergoing surgery, the efficacy of single-dose intravenous (IV) droperidol in preventing PONV was similar to that of ondansetron and dexamethasone. Droperidol significantly reduced opioid-induced PONV in adults during PCA and had a morphine-sparing effect. Droperidol is generally well tolerated and the incidence of adverse effects is similar to that observed with placebo and the serotonin 5-HT(3) receptor antagonists (setrons). Guidelines recommend that, in adults, droperidol monotherapy be considered for those at moderate risk of PONV, and droperidol in combination with a setron and/or dexamethasone be considered for patients at moderate or high risk of PONV. In children with moderate or high risk of PONV, droperidol is recommended for first-line use in some countries, and second-line use in others.

Reteplase (Retavase) is a plasminogen activator, mimicking endogenous tissue plasminogen activator (t-PA), a serine protease, converting plasminogen to plasmin and thereby precipitating thrombolysis. It is a third-generation recombinant form of t-PA that operates in the presence of fibrin (i.e. it is fibrin specific). Reteplase can be administered as a bolus dose (nonweight-based) rather than an infusion, which promotes rapid and safe administration. The ease of administration of this reteplase dosage regimen (two 10U bolus doses, each over 2 minutes, 30 minutes apart) is conducive to prehospital initiation of thrombolytic treatment in patients with ST-segment elevation myocardial infarction (STEMI), which reduces the time to treatment, a critical factor in improving long-term survival. In large randomized clinical trials of patients with STEMI, reteplase was superior to alteplase for coronary artery patency (according to TIMI [thrombolysis in myocardial infarction] flow) at 60 and 90 minutes, but there was no significant difference between agents for mortality rate and incidence of intracranial bleeding. The 35-day mortality rates were equivalent for reteplase and streptokinase recipients; there was reduced incidence of some cardiac events with reteplase versus streptokinase, but a greater incidence of hemorrhagic stroke. Reteplase has also shown thrombolytic efficacy (in nonapproved indications) as a catheter-directed intra-arterial or intravenous infusion for peripheral vessel occlusions, as 5-minute bolus doses (in 1U increments) for acute ischemic stroke, as a low-dose solution for occluded catheters or grafts, and as an intravenous double bolus for massive pulmonary embolism. Across studies in these indications, the incidence of bleeding complications associated with reteplase treatment appeared to be similar to that associated with other thrombolytic agents. With its efficacy, and the ease of administration of the bolus doses potentially minimizing dosage errors when treatment is administered under time pressure, reteplase is a valuable option for pre- or in-hospital thrombolytic treatment in patients with STEMI, and is a useful thrombolytic for the treatment of the other thrombotic occlusive disorders described.

Droperidol (Dehydrobenzperidol®, Dehidrobenzoperidol®, Dridol®, Droleptan®, Inapsine®) is a dopamine D2 receptor antagonist that has been widely used in adults and children for the prevention and treatment of postoperative nausea and vomiting (PONV) over several decades and, more recently, for the prevention of opioid-induced PONV during patient-controlled analgesia (PCA) in adults. In well controlled clinical trials of patients undergoing surgery, the efficacy of single-dose intravenous (IV) droperidol in preventing PONV was similar to that of ondansetron and dexamethasone. Droperidol significantly reduced opioid-induced PONV in adults during PCA and had a morphine-sparing effect. Droperidol is generally well tolerated and the incidence of adverse effects is similar to that observed with placebo and the serotonin 5-HT3 receptor antagonists (setrons). Guidelines recommend that, in adults, droperidol monotherapy be considered for those at moderate risk of PONV, and droperidol in combination with a setron and/or dexamethasone be considered for patients at moderate or high risk of PONV. In children with moderate or high risk of PONV, droperidol is recommended for first-line use in some countries, and second-line use in others.

Adalimumab, a fully human monoclonal antibody, is a tumour necrosis factor antagonist that has been investigated for efficacy in psoriatic arthritis, based on well-established use of the drug in rheumatoid arthritis. In well-controlled Phase III trials, adalimumab (40 mg administered subcutaneously every other week) has shown efficacy in adult patients with psoriatic arthritis who had an inadequate response to previous treatment with NSAIDs (24-week ADEPT trial; n = 313) or disease-modifying antirheumatic drugs (12-week study; n = 100). In these trials, adalimumab recipients experienced a significantly greater improvement in arthritis response (p < 0.001 in the ADEPT trial, and p <or= 0.05 in the smaller study) than placebo recipients, as assessed by the ACR20, ACR50 and ACR70 response rates. There was radiographic evidence of progressive joint damage in the placebo group but not the adalimumab group at 24 weeks in the ADEPT trial, according to the mean total Sharp score modified for psoriatic arthritis. The signs and symptoms of psoriasis in patients with psoriatic arthritis were clinically and statistically more improved with adalimumab than with placebo, according to the PASI responses, at 12 and 24 weeks in the ADEPT trial (e.g. PASI50 rate 75% vs 12% at 24 weeks; p < 0.001). Adalimumab was generally well-tolerated in clinical trials of psoriatic arthritis; the adverse event profile appears to be similar to that associated with use of the drug in rheumatoid arthritis.