Biomedical subjects

Greg L Plosker

Publications and source records attributed to Greg L Plosker.

At least 55 records · Page 3Linked to original sources

PubMed2005

Linezolid: a pharmacoeconomic review of its use in serious Gram-positive infections.

Linezolid (Zyvox), the first available oxazolidinone antibacterial agent, has good activity against Gram-positive pathogens, including multidrug-resistant organisms such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium. Randomised multicentre trials in patients with various types of serious Gram-positive infections showed that clinical cure rates with linezolid were similar to those with vancomycin or teicoplanin. In some subgroup analyses, which must be interpreted with a degree of caution, clinical advantages were noted for linezolid (e.g. versus vancomycin in confirmed MRSA nosocomial pneumonia and MRSA-complicated skin and soft tissue infections). Although generally well tolerated, gastrointestinal adverse effects are relatively common with linezolid and it has been associated with thrombocytopenia and myelosuppression. The oral bioavailability of linezolid is approximately 100%, thus allowing sequential intravenous-to-oral administration without changing the drug or dosage regimen. Healthcare resource use data from various countries indicate that this practical advantage translates into at least a trend towards reduced length of hospital stay compared with vancomycin, which may offset its several-fold higher acquisition cost. Modelled analyses from the US, despite some limitations, indicate that, compared with vancomycin, linezolid is associated with lower total hospitalisation costs for the treatment of patients with cellulitis and has a favourable incremental cost-effectiveness ratio of approximately US30,000 dollars per QALY gained (2001 value) for patients with ventilator-associated pneumonia. Broadly similar results have also been reported in modelled analyses from other countries. In conclusion, for patients with serious Gram-positive infections, including those caused by suspected or proven multidrug-resistant pathogens such as MRSA, linezolid is an effective and generally well tolerated therapeutic option. Linezolid is currently the only antibacterial agent with good activity against MRSA that can be administered orally (as well as intravenously). It may be particularly useful as an alternative to vancomycin in patients who have impaired renal function, poor or no intravenous access, require outpatient therapy, or who have been unable to tolerate glycopeptides. Healthcare resource use studies and pharmacoeconomic analyses generally support the use of linezolid in some subgroups of patients, although results should be interpreted with due consideration of the study limitations.

Acetamides↗

PubMed2005

Eplerenone : a pharmacoeconomic review of its use in patients with post-myocardial infarction heart failure.

Eplerenone (Inspra) is a selective aldosterone blocker. When added to standard medical therapy, eplerenone significantly improved morbidity and mortality in patients with left ventricular (LV) systolic dysfunction and clinical evidence of heart failure following acute myocardial infarction (MI), in a well designed, placebo-controlled trial known as EPHESUS (Eplerenone Post-acute myocardial infarction Heart failure Efficacy and SUrvival Study). Although eplerenone was generally well tolerated, it was associated with a higher incidence of hyperkalaemia than placebo.Cost-effectiveness analyses based on this trial have been performed in the US, The Netherlands, Germany, France and Spain. Direct medical costs were analysed based on prospectively collected resource-use data with local costs applied; modelling was conducted to calculate incremental costs per life-year or QALY gained, with survival curves assumed to remain parallel after treatment ended. Eplerenone was associated with a gain of 0.0304 life-years (approximately 11 days) compared with placebo during the study period. Based on these analyses, eplerenone was cost effective compared with placebo in patients with LV systolic dysfunction and heart failure after an MI when added to standard therapy for 16 months. The incremental cost per life-year gained for eplerenone versus placebo (for a range of three different life-expectancy projections) was 10,402-21,876 US dollars in the US (year 2001 costs, except for eplerenone [2004]) [equivalent to 12,274-25,814 euro; mid-2001 exchange rate], 5,365-12,795 euro for The Netherlands (year 2003 costs), 6,956-14,628 euro for Germany, 5,432-11,423 euro for France and 8,626-18,141 euro for Spain (year of costing not reported). The US, Dutch, French and Spanish analyses estimated that >90% of observations for incremental cost per life-year gained were below a threshold of 50,000 US dollars or 50,000 euro. Incremental costs per QALY gained for eplerenone versus placebo in the US, Dutch, French and Spanish analyses were 15,330-32,405 US dollars (18,089-38,238 euro), 12,148, 8,005-16,922 euro and 12,713-26, 873 euro, respectively. Clinical and pharmacoeconomic data comparing eplerenone with another active drug, such as spironolactone, in this patient population are not available. In conclusion, when added to standard therapy in patients with LV systolic dysfunction and heart failure after an acute MI, eplerenone was associated with significant reductions in mortality and morbidity compared with placebo. Despite some inherent limitations, available pharmacoeconomic data from Europe and the US indicate that eplerenone is a cost-effective treatment compared with placebo in terms of incremental cost per life-year gained in this patient population.

Aged↗

PubMed2005

The Novolizer: a multidose dry powder inhaler.

The Novolizer is a multidose, refillable, breath-actuated dry powder inhaler that delivers up to 200 metered doses of drug from a single cartridge. It has a multiple-feedback control mechanism to ensure that the inhalation was performed correctly. In randomized studies, almost all patients with asthma or COPD using the Novolizer, including those using the device for the first time and children, were able to generate sufficient peak inspiratory flow rates (PIFRs) to overcome the trigger threshold of the device. Comparative studies have shown that patients generate significantly higher PIFR through the Novolizer than through the Turbuhaler. At PIFR of 54-99 L/min through the Novolizer, the median deposition of budesonide in the lungs of healthy volunteers was 19.9-32.1%. Two randomized, double-blind trials in patients with asthma showed that the clinical efficacy of drugs delivered through the Novolizer in terms of improvement in FEV(1) was at least as good as that of an identical treatment regimen delivered through the Aerolizer (for formoterol) or the Sultanol (for albuterol [salbutamol]). Similarly, therapeutic equivalence was also shown between budesonide delivered through the Novolizer and that through the Turbuhaler in patients with COPD or asthma in a randomized, nonblind study. Device-related adverse events were not reported in patients using the Novolizer in therapeutic trials and in a large (n > 3000) post-marketing surveillance study. Overall, the Novolizer was well accepted, with an improved compliance in 80% of patients that was attributable to the control mechanisms of the device.

Asthma↗

PubMed2004

Atomoxetine: a review of its use in adults with attention deficit hyperactivity disorder.

UNLABELLED: Atomoxetine (Strattera) is a selective norepinephrine reuptake inhibitor and nonstimulant that has shown greater efficacy than placebo in attention deficit hyperactivity disorder (ADHD) in adults. In two large, well controlled, 10-week trials in adults with ADHD, improvements in ADHD symptoms, as assessed by investigator- and patient-rated scores, were greater with oral atomoxetine (60, 90 or 120 mg/day) than with placebo. Mean reductions in the total ADHD symptom score on the investigator-rated Conners' Adult ADHD Rating Scale (CAARS) in atomoxetine versus placebo recipients were 28.3% versus 18.1% and 30.1% versus 19.6%, respectively. Mean reductions in the scores on the Clinician Global Impression of Severity Scale, patient-rated CAARS and Wender-Reimherr Adult Attention Deficit Disorder Scale were also significantly greater with atomoxetine than with placebo. Continued efficacy was demonstrated in a noncomparative, 34-week extension phase. Atomoxetine was generally well tolerated in clinical trials; withdrawal rates due to adverse events in atomoxetine-treated versus placebo-treated patients participating in the two major trials were 7.8% versus 4.3% and 9.3% versus 2.4% (p<0.05 for the latter trial). Adverse events reported significantly more frequently with atomoxetine than placebo included dry mouth, insomnia, nausea, decreased appetite, constipation, dizziness, sweating, dysuria, sexual problems and palpitations. Modest increases in heart rate and blood pressure were well tolerated and gradually decreased on cessation of treatment. Atomoxetine was not associated with QT interval prolongation. Atomoxetine can be administered once or twice daily. Its subjective-effects profile is different to that of methylphenidate and atomoxetine is not associated with abuse or diversion; it is therefore not a controlled substance in the US. This also means repeat prescriptions during long-term treatment can be more conveniently processed. CONCLUSION: Atomoxetine is an effective and generally well tolerated treatment for adults with ADHD. It is a nonstimulant and is the first ADHD treatment to be approved specifically for adult use based on its efficacy in well controlled adult trials. It can be administered as a single daily dose or split into two evenly divided doses. It carries negligible risk of abuse or diversion and is not a controlled substance. Atomoxetine is a valuable new treatment option for adults with ADHD and is particularly useful in patients who are at risk for substance abuse or who do not wish to take a controlled substance.

Adrenergic Uptake Inhibitors↗

PubMed2004

Fulvestrant: a review of its use in hormone receptor-positive metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy.

Fulvestrant (Faslodex) is a novel estrogen receptor (ER) antagonist that competitively binds to the ER with a much greater affinity than that of tamoxifen. The downregulation of cellular levels of the ER protein results in complete abrogation of estrogen-sensitive gene transcription. This distinct mechanism of action ensures a lack of cross resistance with other hormonal agents and, in contrast to tamoxifen, fulvestrant has no known estrogen-agonist effects. Fulvestrant is administered via monthly intramuscular injections (250mg) and is recommended for the treatment of hormone receptor-positive metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy. The efficacy of fulvestrant was similar to that of the aromatase inhibitor anastrozole (1 mg/day) in two, well designed studies in postmenopausal women with locally advanced or metastatic breast cancer that had progressed during prior antiestrogen therapy. Time to disease progression (primary endpoint) and treatment failure, rates of objective response and clinical benefit, overall survival and quality of life were similar in patients treated with fulvestrant or anastrozole. In retrospective noninferiority analyses, fulvestrant was at least as effective as anastrozole in all randomised patients, and in those with or without visceral metastases. Fulvestrant is generally well tolerated and was tolerated as well as anastrozole in clinical trials. Treatment-related adverse events were mostly mild to moderate and led to treatment withdrawal in about 1% of patients who received fulvestrant or anastrozole. The main adverse effects associated with therapy are nausea, asthenia, pain, vasodilation and headache.In conclusion, monthly intramuscular injections of fulvestrant are at least as effective and as well tolerated as oral anastrozole once daily in the treatment of postmenopausal women with advanced breast cancer that has progressed on prior antiestrogen therapy. Because of a different mode of action to that of other hormonal agents, fulvestrant is effective in the treatment of tamoxifen-resistant disease and, unlike tamoxifen, has no known estrogen agonist effects. Thus, fulvestrant provides an effective and well tolerated option for the treatment of hormone receptor-positive metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy.

Anastrozole↗

PubMed2004

Fixed-dose combination enalapril/nitrendipine: a review of its use in mild-to-moderate hypertension.

The fixed-dose combination of enalapril 10mg with nitrendipine 20mg combines an ACE inhibitor with a calcium channel antagonist (CCA) and is indicated for the treatment of patients with mild-to-moderate hypertension whose blood pressure (BP) is inadequately controlled with enalapril or nitrendipine monotherapy. In randomised, double-blind clinical trials, enalapril/nitrendipine 10/20 mg/day was significantly more effective than its individual components in reducing diastolic BP (DBP) in patients with mild-to-moderate hypertension inadequately controlled with enalapril 10 mg/day or nitrendipine 20 mg/day. The fixed-dose combination was similar in efficacy at reducing DBP to amlodipine 10 mg/day in patients who failed to achieve BP control with amlodipine 5 mg/day, and to losartan/hydrochlorothiazide 50/12.5 mg/day in patients who received the combinations as first-line therapy. Enalapril/nitrendipine 10/20 mg produced a consistent antihypertensive effect that persisted for the entire 24-hour dosage interval as shown by ambulatory BP monitoring. Enalapril/nitrendipine 10/20 mg was well tolerated in clinical trials where it was administered to patients with mild-to-moderate hypertension for up to 12 weeks. The adverse events were those expected of ACE inhibitors and CCAs and included cough, headache and flushing. Evidence from clinical trials, including a pooled analysis, suggests that the incidence of oedema may be significantly lower with the fixed-dose combination than with CCA monotherapy. In conclusion, enalapril/nitrendipine 10/20 mg is a well tolerated fixed-dose combination of two established antihypertensive agents administered once daily that effectively lowers BP throughout the 24-hour dosage interval. Importantly, the fixed-dose combination may have a lower incidence of oedema than CCA monotherapy. Enalapril/nitrendipine 10/20 mg provides an additional treatment option for patients with mild-to-moderate hypertension for whom combination therapy is appropriate.

Antihypertensive Agents↗

PubMed2004

Oral sodium phosphate solution: a review of its use as a colorectal cleanser.

Oral sodium phosphate solution (Fleet Phospho-soda, Casen-Fleet Fosfosoda is a low-volume, hyperosmotic agent used as part of a colorectal-cleansing preparation for surgery, x-ray or endoscopic examination. The efficacy and tolerability of oral sodium phosphate solution was generally similar to, or significantly better than, that of polyethylene glycol (PEG) or other colorectal cleansing regimens in patients preparing for colonoscopy, colorectal surgery or other colorectal-related procedures. Generally, oral sodium phosphate solution was significantly more acceptable to patients than PEG or other regimens. The use of this solution should be considered in most patients (with the exception of those with contraindications) requiring colorectal cleansing. PHARMACOLOGICAL PROPERTIES: After the first and second 45 mL dose of oral sodium phosphate solution, the mean time to onset of bowel activity was 1.7 and 0.7 hours and the mean duration of activity was 4.6 and 2.9 hours. Bowel activity ceased within 4 hours of administration of the second dose in 83% of patients. Elevations in serum phosphorus and falls in serum total and ionised calcium from baseline occurred during the 24 hours after administration of oral sodium phosphate solution in seven healthy volunteers. These changes were not associated with significant changes in clinical assessments. The decrease in serum potassium levels after administration of oral sodium phosphate solution was negatively correlated with baseline intracellular potassium levels. THERAPEUTIC USE: A regimen that administered the first dose of sodium phosphate on the previous evening and a second dose on the morning of the procedure (10-12 hours apart) was significantly more effective than PEG-based regimens for colorectal cleansing in preparation for colonoscopy, sigmoidoscopy or colorectal surgery. A regimen that administered both doses of oral sodium phosphate on the day prior to the procedure offered no colorectal cleansing advantage over PEG-based regimens and was significantly less effective than an oral sodium phosphate solution regimen that administered one dose on the previous evening and a second dose on the morning of the procedure. Oral sodium phosphate solution was generally as effective as other colorectal cleansing solutions (including magnesium citrate-containing regimens with sodium picosulfate). The direct costs of a diagnostic colonic examination with oral sodium phosphate solution were less than those with PEG (US465 dollars vs US503 dollars per patient; 1995 values), according to data from a US study. Oral sodium phosphate solution was significantly more effective than a commercially available tablet formulation as a colorectal cleanser prior to colonoscopy (data from one study only). TOLERABILITY: Oral sodium phosphate solution administered as two 45 mL doses (generally 10-12 hours apart) was well tolerated in well designed trials in which adults with major comorbid conditions were excluded. Sodium phosphate-associated adverse events were mostly gastrointestinal (including abdominal pain/cramping, abdominal fullness and/or bloating, anal or perianal irritation or soreness, nausea, vomiting or hunger pains), although dizziness, weakness/fatigue, thirst, chest pain, chills, headache and sleep loss were also reported. Faecal incontinence was commonly reported in the elderly. Three doses (administered 10 minutes apart) of 15 mL of oral sodium phosphate solution, each diluted in 250 mL of clear fluid was associated with less vomiting than one 45 mL dose of the solution diluted in 250 mL of clear fluid (data from one study). In patients without major comorbid conditions, oral sodium phosphate has been associated with transient and clinically inconsequential changes in intravascular volume and electrolyte disturbances. Serious electrolyte disturbances have been associated with oral sodium phosphate administration in patients in whom sodium phosphate is contraindicated or should be use with caution (the elderly and those with bowel obstructions, small intestinal disorders, poor gut motilderly and those with bowel obstructions, small intestinal disorders, poor gut motility, renal insufficiency, cardiovascular disease or taking concomitant medication) or in patients ingesting more than the recommended dosage. Changes in the colonic mucosa have been reported in patients treated with oral sodium phosphate solution; however, the exact role of this agent in the appearance of these changes has not been fully clarified. The tolerability profile of oral sodium phosphate solution was similar to, or significantly better than, that of PEG or other colorectal cleansing regimens. Oral sodium phosphate solution was generally significantly more acceptable than PEG or other colorectal cleansing regimens. Oral sodium phosphate solution had similar tolerability, but was considered to be more acceptable than commercially available oral sodium phosphate tablets prior to colonoscopy (data from one study).

Administration, Oral↗

PubMed2004

Paclitaxel: as adjuvant or neoadjuvant therapy in early breast cancer.

Paclitaxel is a antimicrotubule agent with established antitumour activity in a variety of cancers including breast cancer. The efficacy of intravenous paclitaxel as adjuvant therapy for early breast cancer has been investigated in two large, randomised trials; it was administered sequentially to standard doxorubicin-cyclophosphamide (AC) combination therapy and compared with cycles of AC alone. In both trials, the addition of sequentially administered paclitaxel to the AC regimen significantly improved disease-free survival at 5 years compared with AC alone. In one of the trials, women who received paclitaxel also had a significant improvement in overall 5-year survival time. In randomised trials of neoadjuvant therapy for women with early breast cancer, paclitaxel or paclitaxel-containing regimens showed efficacy in terms of response/remission rates, local breast tumour recurrence and proportion of patients eligible for breast-conserving surgery. The most frequently reported grade 3-4 adverse events with paclitaxel administered sequentially to AC were haematological events (neutropenia, thrombocytopenia, anaemia) and nausea/vomiting.

Antineoplastic Agents, Phytogenic↗

PubMed2004

Intravenous lansoprazole: in erosive oesophagitis.

An intravenous formulation of lansoprazole, a proton pump inhibitor, is approved for use in patients with erosive oesophagitis who are temporarily unable to take oral lansoprazole. In healthy volunteers, oral and intravenous lansoprazole 30 mg/day were equivalent in suppressing basal and pentagastrin-stimulated maximum gastric acid output. Moreover, the mean 24-hour intragastric pH did not differ significantly following oral or intravenous administration of lansoprazole and was significantly higher with both formulations than with intravenous polyethylene glycol vehicle. After treatment for 7 days in patients with erosive oesophagitis, intravenous lansoprazole (30 mg/day) recipients had significantly lower median stimulated and basal gastric acid output measurements than placebo recipients. Median pentagastrin-stimulated gastric acid output levels were equivalent after 7 days treatment with intravenous or oral lansoprazole. Intravenous lansoprazole is generally well tolerated. All adverse events experienced by patients with erosive oesophagitis who received intravenous lansoprazole were mild or moderate in severity.

2-Pyridinylmethylsulfinylbenzimidazoles↗

PubMed2004

Fosamprenavir: a review of its use in the management of antiretroviral therapy-naive patients with HIV infection.

Fosamprenavir (GW433908, Lexiva, Telzir) is an oral prodrug of the protease inhibitor (PI) amprenavir, with a reduced daily pill burden. Fosamprenavir, in combination with other antiretroviral agents, is indicated for the treatment of patients with HIV infection, particularly those who have not previously received antiretroviral therapy. Viral load reductions were at least as great with fosamprenavir-based regimens as those achieved with nelfinavir-based regimens in two large, 48-week, randomised, multicentre trials in antiretroviral therapy-naive patients with HIV infection. In the NEAT study, more patients receiving twice-daily fosamprenavir in combination with abacavir and lamivudine achieved HIV RNA levels <400 copies/mL than those receiving a similar nelfinavir-based regimen. Results of the SOLO study showed similar reductions in viral load among patients who received once-daily ritonavir-boosted fosamprenavir and those treated with twice-daily nelfinavir, both in combination with twice-daily abacavir and lamivudine. In both trials, virological failure rates were at least twice as high with the nelfinavir-based regimen as they were with the fosamprenavir-based regimen. Fosamprenavir was generally well tolerated in clinical trials. The most common adverse events among patients treated with fosamprenavir, with or without ritonavir, plus abacavir and lamivudine were diarrhoea, nausea, vomiting, abdominal pain, drug hypersensitivity and skin rash. The incidence of diarrhoea was significantly lower with fosamprenavir-based therapy than with nelfinavir-based therapy in the NEAT and SOLO trials. The resistance profile of fosamprenavir is consistent with that of amprenavir. Amprenavir-resistant viral isolates from patients experiencing treatment failure with fosamprenavir-based therapy in the NEAT study showed little or no cross-resistance to several other PIs, and protease mutations commonly selected for by various other PIs were not observed. In the SOLO study, protease resistance mutations were not observed in viral isolates from patients experiencing treatment failure with ritonavir-boosted fosamprenavir-based therapy. In conclusion, fosamprenavir-based regimens have shown good antiviral efficacy and are generally well tolerated in antiretroviral therapy-naive patients with HIV infection. Available data on the resistance profile of the drug suggest that it may be used early in the course of therapy without compromising a range of future treatment options. The relatively low pill burden and lack of food restrictions with fosamprenavir may improve adherence to therapy. Further studies are needed to compare fosamprenavir with other PIs and to establish the long-term efficacy of fosamprenavir-based regimens. In conclusion, fosamprenavir appears to be a promising agent for the treatment of antiretroviral therapy-naive patients with HIV infection.

Anti-Retroviral Agents↗

PubMed2004

Anidulafungin.

Anidulafungin is a novel antifungal agent which, like other echinocandins, inhibits beta-(1,3)-D-glucan synthase and disrupts fungal cell-wall synthesis. It has marked antifungal activity against a broad spectrum of Candida spp. and Aspergillus spp., including amphotericin B- and triazole-resistant strains. In clinical trials, anidulafungin has primarily been evaluated in patients with oesophageal and invasive candidiasis. Preliminary data are emerging for other indications such as invasive aspergillosis. In a large, multicentre, double-blind, double-dummy, randomised trial in patients with oesophageal candidiasis, intravenous anidulafungin 50 mg/day was as effective as oral fluconazole 100 mg/day regarding end-of-treatment rates of endoscopic cure and clinical and microbiological success. Duration of treatment was approximately 2-3 weeks, and patients in both groups received a loading dose of study drug (twice the daily maintenance dose) on day 1. Anidulafungin is generally well tolerated. Across the dosage range 50-100 mg/day, adverse events appear not to be dose- or infusion-related. In the largest clinical trial to date, the most common treatment-related adverse events were phlebitis/thrombophlebitis, headache, nausea, vomiting and pyrexia.

Anidulafungin↗

PubMed2004

Eplerenone : a review of its use in left ventricular systolic dysfunction and heart failure after acute myocardial infarction.

Eplerenone (Inspra) is a selective aldosterone blocker. Oral eplerenone is approved for use in patients with left ventricular (LV) systolic dysfunction and clinical evidence of heart failure following acute myocardial infarction (MI) in the US and in European countries (e.g. the UK and The Netherlands). The addition of eplerenone to standard medical therapy significantly improved mortality and morbidity in patients with LV systolic dysfunction and clinical evidence of heart failure following acute MI in the large, well designed EPHESUS (Eplerenone Post-acute myocardial infarction Heart failure Efficacy and SUrvival Study) trial. The beneficial effects of eplerenone on all-cause mortality and cardiovascular mortality were seen within 30 days of randomisation. Eplerenone was generally well tolerated. Although a higher incidence of hyperkalaemia occurred with eplerenone than with placebo, the incidence of hypokalaemia was significantly lower with eplerenone treatment. Thus, the addition of eplerenone to standard medical therapy is an important new strategy for further improving mortality and morbidity in post-MI patients with LV systolic dysfunction and heart failure.

Animals↗

PubMed2004

Peginterferon-alpha-2a (40kD) plus ribavirin: a review of its use in hepatitis C Virus And HIV co-infection.

Pegylated interferon plus ribavirin is the standard first-line treatment in patients with chronic hepatitis C virus (HCV) mono-infection. Although the optimal anti-HCV regimen is not established in the more difficult-to-treat population with HIV-HCV co-infection, much of the data in this clinical setting have been derived from studies evaluating peginterferon-alpha-2a (40kD) [Pegasys] plus ribavirin (Copegus), most notably the APRICOT (AIDS Pegasys Ribavirin International Co-Infection Trial) and the ACTG (AIDS Clinical Trial Group) A5071 study. In particular, results of APRICOT - the largest study conducted to date with a pegylated interferon plus ribavirin in patients with HIV-HCV co-infection - indicate that a substantial proportion of patients will achieve sustained virological response (SVR) at week 72 when these drugs are administered for 48 weeks in an appropriate dosage regimen. In general, the tolerability profile of peginterferon-alpha-2a plus ribavirin in APRICOT was similar to that previously reported in patients with HCV mono-infection.

Antiviral Agents↗

PubMed2004

Repaglinide : a pharmacoeconomic review of its use in type 2 diabetes mellitus.

Repaglinide (Prandin), NovoNorm, GlucoNorm, an oral insulin secretagogue, was the first meglitinide analogue to become available for use in patients with type 2 diabetes mellitus. The drug lowers postprandial glucose excursions by targeting early-phase insulin release, an effect thought to be important in reducing long-term cardiovascular complications of diabetes. Repaglinide provided similar overall glycaemic control to that achieved with glibenclamide (glyburide), as assessed by glycosylated haemoglobin (HbA(1c)) and fasting blood glucose levels, and was generally well tolerated in well designed clinical trials. Its rapid onset and relatively short duration of action allow for flexible meal schedules. Two modelled US cost-effectiveness analyses projected lifetime costs and outcomes for a hypothetical cohort of patients with type 2 diabetes. Both analyses projected long-term complications using data on HbA(1c) level changes from short-term clinical trials. Repaglinide plus rosiglitazone was dominant over rosiglitazone in one analysis, and repaglinide plus metformin was dominant over nateglinide plus metformin in the other. A similar Canadian analysis showed a favourable incremental cost-effectiveness ratio (<dollars US 1000 per QALY gained; 2001 values) for patients who switched from a sulphonylurea to repaglinide versus those who remained on sulphonylurea therapy. Long-term outcomes were projected using short-term clinical trial data on postprandial blood glucose level changes in the Canadian study. All three cost-effectiveness analyses are available as abstracts/posters. Two US cost analyses (both published in full) have also been conducted comparing the short-term costs (<or=3 years) of repaglinide, with or without metformin, versus other oral antidiabetic regimens. Results of these analyses are somewhat equivocal because of study design issues and/or a lack of statistically significant differences between treatment groups. In conclusion, repaglinide as monotherapy or in combination with other antidiabetic agents, such as metformin or rosiglitazone, achieves good metabolic control, similar to that achieved with comparable glibenclamide regimens. Severe hypoglycaemic episodes are less common with repaglinide than some sulphonylureas, including glibenclamide. Modelled cost-effectiveness analyses conducted in North America showed favourable results for repaglinide-containing regimens versus comparators, largely attributed to projected reductions in long-term cardiovascular complications using short-term data on changes in glycaemic parameters from clinical trials. Results of these cost-effectiveness analyses (all of which have been published as abstracts/posters) should be interpreted with caution since various assumptions regarding long-term costs and outcomes were necessarily incorporated into the economic models. While repaglinide is a useful addition to the available treatment options in type 2 diabetes, potential long-term advantages versus other agents, such as reducing cardiovascular complications, require confirmation. The prevalence of diabetes mellitus is projected to increase to over 3% of the world's population ( approximate, equals 220 million people) by the year 2010. Globally, 97% of patients with diabetes have type 2 disease, although in industrialised countries the proportion of type 2 disease is about 90%. In 2010, an estimated 14.85 million individuals in the US and 2.88 million in the UK will be diagnosed with type 2 diabetes. In addition, approximately one-third to one-half of individuals with diabetes are unaware that they have the disease, and are therefore undiagnosed. Diabetes is associated with significant morbidity, mortality and economic consequences. For the year 2002 in the US, direct medical costs associated with diabetes (type 1 and 2) were estimated at dollars US 91.8 billion (70% of total costs) and indirect costs at dollars US 39.8 billion (30%), for a total of dollars US 132 billion. Data from more than 7000 patients in eight European countries indicate tha the mean cost per patient with diabetes was dollars US 2928 annually (1999 values), and the proportion of total healthcare expenditure directed toward diabetes ranged from 1.6% to 6.6% depending on the country. Several analyses focusing specifically on type 2 disease showed, not surprisingly, that costs were higher among patients with diabetic complications than in those without complications. Repaglinide, a meglitinide analogue, is an oral insulin secretagogue that reduces postprandial glucose excursions by targeting postprandial insulin release. In clinical trials in patients with type 2 diabetes, repaglinide was usually administered at a dosage of 0.5-4 mg three times daily before meals as monotherapy or in combination with other agents. In placebo-controlled trials of up to 24 weeks' duration in patients with type 2 diabetes, repaglinide achieved statistically significant improvements in glycaemic control, as assessed by glycosylated haemoglobin (HbA(1c)), fasting blood glucose (FBG) and/or postprandial blood glucose (PPBG) levels compared with placebo. Preprandial administration of repaglinide achieved similar glycaemic control to glibenclamide (glyburide) 1.75-15 mg/day and better glycaemic control than glipizide 5-15 mg/day in 1-year, double-blind, randomised trials in patients with type 2 disease, the vast majority of whom had previously received oral antidiabetic therapy. Several randomised, open-label studies have evaluated repaglinide as part of combination therapy over 3-6 months in patients with type 2 diabetes who had inadequate glycaemic control with previous drug therapy. In general, results showed statistically significant improvements in glycaemic control when repaglinide was used in combination with metformin, various thiazolidinediones, or metformin plus bedtime insulin compared with monotherapy with either comparator drug in each study (or metformin plus bedtime insulin in one trial). Other studies in this patient population indicate that metformin plus repaglinide is associated with significantly better glycaemic control than metformin plus nateglinide 60-120 mg three times daily over 16 weeks, and similar glycaemic control to that achieved with metformin in combination with either glibenclamide or glimepiride for up to 1 year. Good glycaemic control has also been achieved with preprandial administration of repaglinide in flexible meal schedules. This was demonstrated in a placebo-controlled trial and in a large, prospective survey of patients receiving repaglinide in a clinical setting. The tolerability profile of repaglinide is characterised by adverse events of mild-to-moderate intensity similar to those associated with sulphonylureas. The most frequently reported adverse events with repaglinide include hypoglycaemia, upper respiratory infection, headache, other respiratory events, musculoskeletal events and gastrointestinal events. Severe episodes of hypoglycaemia are rare with repaglinide and occur approximately 2-2.5 times less frequently than with sulphonylureas. In addition, available data indicate that repaglinide may be less likely to increase bodyweight than various commonly used sulphonylurea agents. In general, repaglinide is also well tolerated when used as part of combination therapy. Repaglinide is metabolised by the cytochrome P450 (CYP) 3A4 enzyme system and therefore has the potential to interact with other CYP3A4 substrates when administered concurrently. A number of studies in healthy volunteers have shown no clinically significant pharmacokinetic drug interactions when repaglinide was administered concomitantly with digoxin, theophylline, warfarin, cimetidine, ketoconazole, rifampicin (rifampin), ethinylestradiol, simvastatin or nifedipine. However, a clinically significant increase in systemic exposure to repaglinide occurs when clarithromycin and repaglinide are administered concurrently, which may necessitate a reduction in repaglinide dosage. Moreover, a potentially hazardous interaction occurs when gemfibrozil (alone or with itraconazole) is used concomitantly with repaglinide. In view of the marked increase in systemic exposure to repaglinide, the combination of repaglinide and gemfibrozil should be avoided if possible. Pharmacoeconomic Analyses of RepaglinideTwo US cost analyses have been conducted with repaglinide in patients with type 2 diabetes (both published in full). One was a retrospective analysis of pharmacy and medical claims data from a large managed care organisation in which costs were adjusted for age, gender and comorbidities. Total adjusted (year 2000) cost per patient over a 9-month period was numerically lower for those treated with a combination of repaglinide plus metformin (dollars US 8924) than for patients who received metformin only (dollars US 9448), metformin plus glibenclamide (dollars US 9576) or repaglinide only (dollars US 11910), although there were no statistically significant differences between treatment groups. The other study, a literature-based decision-tree analysis, projected the proportion of patients achieving a target HbA(1c) level (<7%) and the associated direct medical costs over a 3-year period from the time of diagnosis. Among six different treatment regimens evaluated, costs ranged from dollars US 6106 with glipizide gastrointestinal therapeutic system (GITS) to dollars US 9298 with repaglinide monotherapy (2001/2002 values). Probabilistic sensitivity analysis indicated that first-line therapy with glipizide GITS or metformin would be associated with lower total medical costs than rosiglitazone or repaglinide monotherapy. Three cost-effectiveness analyses, all of which are modelled studies published as abstracts and/or posters, have been conducted with repaglinide in patients with type 2 diabetes. (ABSTRACT TRUNCATED)

Administration, Oral↗

PubMed2004

Etanercept: a pharmacoeconomic review of its use in rheumatoid arthritis.

Etanercept (Enbrel), which inhibits the activity of tumour necrosis factor-alpha, is indicated in the treatment of patients with active rheumatoid arthritis (RA). A lifetime cost-utility analysis in patients with severe disease-modifying antirheumatic drug (DMARD)-resistant RA in the UK suggested that etanercept is associated with acceptable cost-utility ratios relative to traditional nonbiological DMARDs. In a 12-month cost-utility study in Spain, etanercept was predicted to be dominant over infliximab plus methotrexate in patients with active, refractory RA with regards to the cost per QALY gained and cost per American College of Rheumatology (ACR) 20 response achieved. In short-term cost-effectiveness analyses conducted in the US, the cost effectiveness of etanercept relative to other treatments in patients with methotrexate-naive or -resistant RA depends on whether predicted incremental cost-effectiveness ratios of at least USD 41,900 per ACR 20 response or USD 34,800 per ACR 70 weighted response over a 6-month period are considered acceptable (1999 values). The relative efficacy and cost effectiveness of etanercept and other biological DMARDs will be clarified when appropriate data from directly comparative clinical and/or long-term pharmacoeconomic studies become available. Etanercept may prevent or delay disability, which may produce reductions in nondrug costs that could help offset its acquisition cost.

Antirheumatic Agents↗

PubMed2004

Spotlight on atomoxetine in adults with attention-deficit hyperactivity disorder.

UNLABELLED: Atomoxetine (Strattera) is a selective noradrenaline (norepinephrine) reuptake inhibitor and nonstimulant that has shown greater efficacy than placebo in attention-deficit hyperactivity disorder (ADHD) in adults. In two large, well controlled, 10-week trials in adults with ADHD, improvements in ADHD symptoms, as assessed by investigator- and patient-rated scores, were greater with oral atomoxetine (60, 90 or 120 mg/day) than with placebo. Mean reductions in the total ADHD symptom score on the investigator-rated Conners' Adult ADHD Rating Scale (CAARS) in atomoxetine versus placebo recipients were 28.3% versus 18.1% and 30.1% versus 19.6%, respectively. Mean reductions in the scores on the Clinician Global Impression of Severity Scale, patient-rated CAARS and Wender-Reimherr Adult Attention Deficit Disorder Scale were also significantly greater with atomoxetine than with placebo. Continued efficacy was demonstrated in a noncomparative, 34-week extension phase. Atomoxetine was generally well tolerated in clinical trials; withdrawal rates due to adverse events in atomoxetine- versus placebo-treated patients participating in the two major trials were 7.8% versus 4.3% and 9.3% versus 2.4% (p < 0.05 for the latter trial). Adverse events reported significantly more frequently with atomoxetine than placebo included dry mouth, insomnia, nausea, decreased appetite, constipation, dizziness, sweating, dysuria, sexual problems and palpitations. Modest increases in heart rate and blood pressure were well tolerated and gradually decreased on cessation of treatment. Atomoxetine was not associated with QT interval prolongation. Atomoxetine can be administered once or twice daily. Its subjective-effects profile is different to that of methylphenidate and atomoxetine is not associated with abuse or diversion; it is therefore not a controlled substance in the US. This also means repeat prescriptions during long-term treatment can be more conveniently processed. CONCLUSION: Atomoxetine is an effective and generally well tolerated treatment for adults with ADHD. It is a nonstimulant and is the first ADHD treatment to be approved specifically for adult use based on its efficacy in well controlled adult trials. It can be administered as a single daily dose or split into two evenly divided doses. It carries negligible risk of abuse or diversion and is not a controlled substance. Atomoxetine is a valuable new treatment option for adults with ADHD and is particularly useful in patients who are at risk for substance abuse or who do not wish to take a controlled substance.

Administration, Oral↗

PubMed2004

Spotlight on the pharmacoeconomics of escitalopram in depression.

UNLABELLED: Escitalopram (Cipralex), a new highly selective inhibitor of serotonin reuptake, is the active S-enantiomer of RS-citalopram. It is effective in the treatment of patients with major depressive disorder (MDD) and may have a faster onset of therapeutic effect than citalopram. It has also been shown to lead to improvements in measures of quality of life (QOL). Escitalopram is generally well tolerated, with nausea being the most common adverse event associated with its use. Modelled pharmacoeconomic analyses found escitalopram to have a cost-effectiveness and cost-utility advantage over other SSRIs, including generic citalopram and fluoxetine and branded sertraline, and also over the serotonin-noradrenaline reuptake inhibitor (SNRI) venlafaxine extended-release (XR). These studies used a decision-analytic approach with a 6-month time horizon and were performed in Western Europe (year of costing 2000 or 2001). Cost-effectiveness ratios for escitalopram, in terms of cost per successfully treated patient over 6 months, ranged from euro871 to euro2598 in different countries, based on direct costs and remission rates, and were consistently lower (i.e. more favourable) than the ratios for comparators (euro970-euro3472). Outcomes similarly favoured escitalopram when indirect costs (represented by those associated with sick leave and loss of productivity) were included. The results of comparisons with citalopram, fluoxetine and sertraline were not markedly affected by changes to assumptions in sensitivity analyses, although comparisons with venlafaxine XR were sensitive to changes in the remission rate. The mean number of quality-adjusted life years gained during the 6-month period was similar for all drugs evaluated, but direct costs were lower with escitalopram, leading to lower cost-utility ratios than for comparators. Incremental analyses performed in two of the studies confirmed the cost-effectiveness and cost-utility advantage of escitalopram. A prospective, 8-week comparative pharmacoeconomic analysis found that escitalopram achieved similar efficacy to venlafaxine XR, but was associated with 40% lower direct costs (euro85 vs euro142 per patient over 8 weeks; 2001 costs), although this difference did not reach statistical significance. In both the modelled and prospective analyses, the differences in overall direct costs were mainly due to lower secondary care costs (in particular those related to hospitalisation) with escitalopram. In the prospective analysis, escitalopram had lower estimated drug acquisition costs than venlafaxine XR. CONCLUSION: Escitalopram, the S-enantiomer of RS-citalopram and a highly selective inhibitor of serotonin reuptake, is an effective antidepressant in patients with MDD, has a favourable tolerability profile, and, on the basis of available data, appears to have a rapid onset of therapeutic effect. Modelled pharmacoeconomic analyses from Western Europe suggest that it may be a cost-effective alternative to generic citalopram, generic fluoxetine and sertraline. Although the available data are less conclusive in comparison with venlafaxine XR, escitalopram is at least as cost effective as the SNRI based on a prospective study, and potentially more cost effective based on modelled analyses. Overall, clinical and pharmacoeconomic data support the use of escitalopram as first-line therapy in patients with MDD.

Citalopram↗

PubMed2004

Amisulpride: a review of its use in the management of schizophrenia.

Amisulpride (Solian), a substituted benzamide derivative, is a second-generation antipsychotic that preferentially binds to dopamine D2/D3 receptors in limbic rather than striatal structures. High dosages preferentially antagonise postsynaptic D2/D3 receptors, resulting in reduced dopamine transmission, and low dosages preferentially block presynaptic D2/D3 receptors, resulting in enhanced dopamine transmission. Amisulpride (200-1200 mg/day) was at least as effective as haloperidol and as effective as risperidone or olanzapine, in studies of up to 1 year in patients with schizophrenia manifesting predominantly positive symptoms. Amisulpride (50-300 mg/day) was significantly more effective than placebo in studies of up to 6 months in patients manifesting predominantly negative symptoms. Quality of life was also improved significantly more in patients receiving amisulpride than in those receiving haloperidol in 4- and 12-month studies in patients with predominantly mixed symptoms. Amisulpride was generally well tolerated in clinical trials. In patients with predominantly positive symptoms, amisulpride appeared to be better tolerated than haloperidol and was tolerated as well as risperidone and olanzapine. The incidence of extrapyramidal adverse effects with amisulpride was lower than with haloperidol but was generally similar to risperidone or olanzapine. Weight gain with amisulpride was less than that with risperidone or olanzapine and, unlike these agents, amisulpride does not seem to be associated with diabetogenic effects. Plasma prolactin levels are increased during amisulpride therapy and amenorrhoea occurs in about 4% of women. The incidence of adverse events with low dosages of amisulpride (< or = 300 mg/day) in patients with predominantly negative symptoms was similar to that observed with placebo. In conclusion, oral amisulpride (200-1200 mg/day) is at least as effective as haloperidol, and as effective as risperidone or olanzapine, in the treatment of patients with schizophrenia manifesting predominantly positive symptoms. In the treatment of patients manifesting predominantly negative symptoms, low dosages of amisulpride (50-300 mg/day) are significantly more effective than placebo. Amisulpride appears to be better tolerated than haloperidol, causing a lower incidence of extrapyramidal adverse effects and an improved quality of life. Compared with risperidone or olanzapine, amisulpride is more likely to cause hyperprolactinaemia, but has a lower propensity to cause weight gain and does not seem to be associated with diabetogenic effects. Thus, amisulpride is an effective and well tolerated option for the first-line treatment of patients with acute schizophrenia as well as for those requiring long-term maintenance therapy.

Amisulpride↗