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Biomedical subjects

Greg L Plosker

Publications and source records attributed to Greg L Plosker.

At least 19 recordsLinked to original sources

PubMed2003

Rituximab: a review of its use in non-Hodgkin's lymphoma and chronic lymphocytic leukaemia.

Rituximab is an anti-CD20 monoclonal antibody that has demonstrated efficacy in patients with various lymphoid malignancies, including indolent and aggressive forms of B-cell non-Hodgkin's lymphoma (NHL) and B-cell chronic lymphocytic leukaemia (CLL). While the optimal use of the drug in many clinical settings has yet to be clarified, two pivotal trials have established rituximab as a viable treatment option in patients with relapsed or refractory indolent NHL, and as a standard first-line treatment option when combined with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) chemotherapy in elderly patients with diffuse large B-cell lymphoma (the most common type of aggressive NHL). The former was a noncomparative trial in relapsed indolent NHL (follicular and small lymphocytic subtypes) with clinical responses achieved in about half of patients treated with rituximab 375 mg/m(2) intravenously once weekly for 4 weeks, which was similar to some of the most encouraging results reported with traditional chemotherapeutic agents. The latter was a randomised comparison of eight cycles of CHOP plus rituximab 375 mg/m(2) intravenously (one dose per cycle) versus CHOP alone in previously untreated elderly patients (60 to 80 years of age) with diffuse large B-cell lymphoma. In this pivotal trial, 2-year event-free and overall survival were significantly higher with rituximab plus CHOP, and there was no increase in clinically significant adverse effects compared with CHOP alone. Treatment with rituximab is generally well tolerated, particularly in terms of adverse haematological effects and serious or opportunistic infections relative to standard chemotherapy. Infusion-related reactions occur in the majority of patients treated with rituximab; these are usually mild to moderate flu-like symptoms that decrease in frequency with subsequent infusions. In approximately 10% of patients, however, severe infusion-related reactions develop (e.g. bronchospasm, hypotension). These reactions are usually reversible with appropriate interventions and supportive care but there have been rare reports of fatalities. CONCLUSIONS: Clinical trials with rituximab indicate that the drug has broad application to B-cell malignancies, although further clarification is needed to determine its optimal use in many of these clinical settings. Importantly, rituximab in combination with CHOP chemotherapy has emerged as a new treatment standard for previously untreated diffuse large B-cell lymphoma, at least in elderly patients. Compared with conventional chemotherapy, rituximab is associated with markedly reduced haematological events such as severe neutropenia, as well as associated infections. Rituximab may be particularly suitable for elderly patients or those with poor performance status, and its tolerability profile facilitates its use in combination with cytotoxic drugs. PHARMACODYNAMIC PROPERTIES: Rituximab is a mouse/human chimaeric IgG(1)-kappa monoclonal antibody that targets the CD20 antigen found on the surface of malignant and normal B lymphocytes. Although treatment with rituximab induces lymphopenia in most patients, typically lasting about 6 months, a full recovery of B lymphocytes in the peripheral blood is usually seen 9-12 months after therapy, as CD20 is not expressed on haematopoietic stem cells. CD20 is, however, expressed on >90% of B-cell non-Hodgkin's lymphomas (NHL) and to a lesser degree on B-cell chronic lymphocytic leukaemia (CLL) cells. Although not fully elucidated, the cytotoxic effects of rituximab on CD20-positive malignant B cells appears to involve complement-dependent cytotoxicity, complement-dependent cellular cytotoxicity, antibody-dependent cellular cytotoxicity and induction of apoptosis. In addition, in vitro data indicate that rituximab sensitises tumour cells to the effects of conventional chemotherapeutic drugs. PHARMACOKINETIC PROPERTIES: Serum rituximab concentrations increased in proportion to dose across a wide range of single- and multiple-dose intravenous regimens in patients with B-cell NHL. When administll NHL. When administered at a dose of 375 mg/m(2) once weekly for 4 weeks in a pivotal trial in patients with relapsed or refractory indolent B-cell NHL (follicular or small lymphocytic subtypes), peak serum concentrations essentially doubled from the first (239.1 mg/L) to the fourth (460.7 mg/L) infusion, while elimination half-life (t(1/2)) increased from 76.3 to 205.8 hours (3.2 to 8.6 days). The concomitant increase in serum rituximab concentrations and t(1/2) with each successive infusion may be due, at least in part, to the elimination of circulating CD20-positive B cells and reduction or saturation of CD20-binding sites after the initial infusions of rituximab. The pharmacokinetic properties of rituximab are also characterised by wide inter-individual variability, and serum drug concentrations that are correlated with clinical response. Although pharmacokinetic data are limited in patients with aggressive forms of NHL, such as diffuse large B-cell lymphoma, rituximab appears to have a similar pharmacokinetic profile in these patients to that in patients with indolent B-cell NHL. The pharmacokinetics of rituximab are also reported to be similar whether the drug is administered with or without cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) chemotherapy. THERAPEUTIC USE: A number of studies have demonstrated efficacy of intravenous rituximab in patients with various lymphoid malignancies of B-cell origin, including indolent (e.g. follicular lymphoma) and aggressive (e.g. diffuse large B-cell lymphoma) forms of NHL, and CLL, but the drug has not yet been approved for use in CLL, and approved indications in NHL vary between countries. In the US, for example, rituximab is available for the treatment of patients with low-grade or follicular, relapsed or refractory, CD20-positive B-cell NHL. In Europe, the drug has similar approval for relapsed or refractory follicular NHL as in the US, but has also been approved for use in combination with CHOP chemotherapy for the most common aggressive form of NHL (CD20-positive, diffuse large B-cell lymphoma). Rituximab was approved for these indications primarily on the basis of results from two pivotal trials. In Japan, rituximab has been approved for indolent B-cell NHL and mantle cell lymphoma (an aggressive form of B-cell NHL), primarily on the basis of results of a Japanese phase II trial. Indolent NHL: Results of several studies evaluating rituximab 375 mg/m(2) once weekly for 4 weeks in patients with indolent forms of B-cell NHL (primarily follicular and small lymphocytic lymphomas) showed objective response (OR) rates ranging from approximately 40-60% in those receiving the drug for relapsed or refractory indolent B-cell NHL, and slightly higher (50-70%) for those receiving rituximab as first-line therapy. In a pivotal trial in 166 patients with relapsed or refractory low-grade or follicular B-cell NHL, intent-to-treat (ITT) analysis showed an OR rate of 48%, and a projected median time to progression of 13 months. Encouraging data are also emerging on the use of rituximab in combination with chemotherapeutic agents (e.g. CHOP, fludarabine-containing regimens) or other drugs (e.g. interferon-alpha2a) in previously untreated patients with indolent forms of B-cell NHL (primarily follicular and small lymphocytic subtypes). Rates for OR were consistently around 95%, with the majority being complete responses (CRs). Follow-up data from a study in 40 patients with low-grade or follicular B-cell NHL treated with rituximab plus CHOP as first-line therapy showed that responses were durable with a progression-free survival and median duration of response >5 years.Bcl-2 gene rearrangement (t14;18) occurs in malignant cells in up to 85% of patients with follicular lymphoma, and minimal residual disease in peripheral blood and bone marrow can be monitored using polymerase chain reaction (PCR). In several studies assessing blood and/or bone marrow, rituximab has achieved molecular response (conversion from PCR-positive to PCR-negative bcl-2 status) in at least half of the patients. Aggressive NHL: Studies with rituximab as monotherapy in aggressive B-cell NHL, a potentially curable disorder, have generally been restricted to patients with relapsed or recurrent disease, since CHOP has traditionally been the standard first-line treatment regimen. However, promising results from phase II monotherapy studies prompted further clinical investigation of rituximab in conjunction with chemotherapy. Thus, most studies with rituximab in patients with aggressive forms of B-cell NHL have involved combination therapy, including a pivotal randomised trial comparing eight cycles of standard CHOP therapy plus rituximab 375 mg/m(2) (one dose per cycle) versus CHOP alone in 399 previously untreated elderly patients (60-80 years of age) with diffuse large B-cell lymphoma. Results of the pivotal trial showed a clear advantage for rituximab plus CHOP versus CHOP in terms of event-free survival (primary endpoint) at 2 years (57% vs 38%, p < 0.001). Overall survival at 2 years (70% vs 57%, p < 0.01) and CR rate (76% vs 63%, p < 0.01) were also higher with the rituximab-CHOP combination. Other, smaller trials with rituximab in combination with CHOP or other chemotherapeutic regimens, either as first-line therapy or for patients with relapsed or refractory aggressive B-cell NHL, have also shown promising results in terms of clinical response rates.CLL: In relatively small trials (n < 40) conducted primarily in patients with relapsed or refractory B-cell CLL, rituximab monotherapy (various regimens) achieved OR rates of 23-45%, with median duration of response ranging from approximately 3-10 months. (ABSTRACT TRUNCATED)

Antibodies, Monoclonal↗

PubMed2003

Tacrolimus: a further update of its use in the management of organ transplantation.

UNLABELLED: Extensive clinical use has confirmed that tacrolimus (Prograf) is a key option for immunosuppression after transplantation. In large, prospective, randomised, multicentre trials in adults and children receiving solid organ transplants, tacrolimus was at least as effective or provided better efficacy than cyclosporin microemulsion in terms of patient and graft survival, treatment failure rates and the incidence of biopsy-proven acute and corticosteroid-resistant rejection episodes. Notably, the lower incidence of rejection episodes after renal transplantation in tacrolimus recipients was reflected in improved cost effectiveness. In bone marrow transplant (BMT) recipients, the incidence of tacrolimus grade II-IV graft-versus-host disease was significantly lower with tacrolimus than cyclosporin treatment. Efficacy was maintained in renal and liver transplant recipients after total withdrawal of corticosteroid therapy from tacrolimus-based immunosuppression, with the incidence of acute rejection episodes at up to 2 years' follow-up being similar with or without corticosteroids. Tacrolimus provided effective rescue therapy in transplant recipients with persistent acute or chronic allograft rejection or drug-related toxicity associated with cyclosporin treatment. Typically, conversion to tacrolimus reversed rejection episodes and/or improved the tolerability profile, particularly in terms of reduced hyperlipidaemia. In lung transplant recipients with obliterative bronchiolitis, conversion to tacrolimus reduced the decline in and/or improved lung function in terms of forced expiratory volume in 1 second. Tolerability issues may be a factor when choosing a calcineurin inhibitor. Cyclosporin tends to be associated with a higher incidence of significant hypertension, hyperlipidaemia, hirsutism, gingivitis and gum hyperplasia, whereas the incidence of some types of neurotoxicity, disturbances in glucose metabolism, diarrhoea, pruritus and alopecia may be higher with tacrolimus treatment. Renal function, as assessed by serum creatinine levels and glomerular filtration rates, was better in tacrolimus than cyclosporin recipients at up to 5 years' follow-up. CONCLUSION: Recent well designed trials have consolidated the place of tacrolimus as an important choice for primary immunosuppression in solid organ transplantation and in BMT. Notably, in adults and children receiving transplants, tacrolimus-based primary immunosuppression was at least as effective or provided better efficacy than cyclosporin microemulsion treatment in terms of patient and graft survival, treatment failure and the incidence of acute and corticosteroid-resistant rejection episodes. The reduced incidence of rejection episodes in renal transplant recipients receiving tacrolimus translated into a better cost effectiveness relative to cyclosporin microemulsion treatment. The optimal immunosuppression regimen is ultimately dependent on balancing such factors as the efficacy of the individual drugs, their tolerability, potential for drug interactions and pharmacoeconomic issues.

Adolescent↗

PubMed2003

Saquinavir: a review of its use in boosted regimens for treating HIV infection.

UNLABELLED: Protease inhibitor boosting involves concurrent administration of a protease inhibitor, such as saquinavir, plus a potent inhibitor of cytochrome P450 (CYP) 3A4, usually ritonavir in subtherapeutic doses. Since protease inhibitors are extensively metabolised by CYP3A4, this results in a marked increase in systemic exposure of saquinavir or other protease inhibitors boosted by ritonavir. As with traditional protease inhibitor regimens, boosted regimens are typically used in combination with nucleoside reverse transcriptase inhibitors (NRTIs). In protease inhibitor-experienced and -naive patients with HIV infection, twice-daily and once-daily boosted saquinavir regimens achieved good rates of viral suppression, improved CD4+ cell counts and were generally well tolerated in clinical trials. Encouraging results have also been reported in a number of small studies in heavily pretreated HIV-infected patients who received salvage therapy comprising double-boosted regimens of saquinavir plus lopinavir with subtherapeutic doses of ritonavir, along with other agents. The largest clinical trials have been multicentre, randomised comparisons of twice-daily boosted saquinavir versus twice-daily boosted indinavir (MaxCmin1) or lopinavir (MaxCmin2) regimens. In the MaxCmin1 study, >90% of patients in both groups had an undetectable viral load (<400 copies/mL) after 48 weeks of therapy in the on-treatment analysis. However, viral suppression was achieved in significantly more saquinavir than indinavir recipients in the intention-to-treat analysis, which appeared to be due to the significantly greater percentage of patients in the indinavir group who switched from randomised therapy because of adverse events. Interim 24-week results of the MaxCmin2 trial indicate that 90% of patients in both groups combined had plasma HIV RNA levels <400 copies/mL; final results at 48 weeks will report data separately for the boosted regimens of saquinavir and lopinavir. CONCLUSION: Boosted protease inhibitor regimens (including two NRTIs) are recommended as a first-line option in current HIV treatment guidelines and are used extensively in clinical practice. The convenient administration schedule and good pharmacokinetic profile associated with boosted saquinavir regimens have the potential to increase adherence to therapy and improve antiretroviral effects through increased drug exposure. Twice-daily boosted saquinavir is one of the most extensively evaluated boosted protease inhibitor regimens and has been shown to have good efficacy on surrogate markers of HIV disease as well as significant tolerability advantages over boosted indinavir. Once-daily boosted saquinavir regimens may be most suitable for HIV-infected patients with busy lifestyles and those who would benefit from directly observed therapy.

Area Under Curve↗

PubMed2003

Tipranavir.

Tipranavir is a potent and selective non-peptidic HIV-1 protease inhibitor with a markedly improved resistance profile compared with traditional, peptidomimetic protease inhibitors. The presence of five or fewer protease gene mutations or one or two protease inhibitor resistance-associated mutations (PRAMs) is associated with reduced susceptibility to currently available protease inhibitors. However, 16-20 mutations (including three or more PRAMs) may be needed to confer resistance to tipranavir. Tipranavir-based therapy achieved sustained viral suppression for more than 48 weeks in a small phase II trial in multiple protease inhibitor-experienced HIV-infected patients. A large dose-finding study demonstrated potent virological reduction through 14 days of functional monotherapy in heavily pretreated HIV-infected patients with 6 to >20 protease gene mutations at baseline. Two large, ongoing, phase III trials in patients with multi-drug resistant HIV infection are comparing the efficacy of tipranavir/ritonavir 500/200mg twice daily plus a patient-individualised background antiretroviral regimen versus other ritonavir-boosted protease inhibitor regimens. In general, tipranavir has been well tolerated in clinical trials. As with other protease inhibitors, the most common adverse events with tipranavir have been gastrointestinal disturbances.

Clinical Trials as Topic↗

PubMed2003

Insulin glargine: an updated review of its use in the management of diabetes mellitus.

Insulin glargine is a human insulin analogue prepared by recombinant DNA technology. Modification of the human insulin molecule at position A21 and at the C-terminus of the B-chain results in the formation of a stable compound that is soluble at pH 4.0, but forms amorphous microprecipitates in subcutaneous tissue from which small amounts of insulin glargine are gradually released. The plasma concentration versus time profile of insulin glargine is therefore relatively constant in relation to conventional human insulins, with no pronounced peak over 24 hours. This allows once-daily administration as basal therapy. Early randomised trials with insulin glargine generally showed greater reductions in fasting blood or plasma glucose levels and a reduced frequency of nocturnal hypoglycaemia relative to neutral protamine Hagedorn (NPH) insulin in patients with type 1 diabetes mellitus. In addition to this basal therapy, patients continued to use the regular mealtime insulin regimen to which they were accustomed. More recent data with insulin glargine have included evidence of improved glycaemic control, with improvements in satisfaction with treatment over NPH insulin. Furthermore, the time of day at which insulin glargine is injected has no clinically relevant effect on glycaemic control in these patients. There are also data from small, nonblind studies to suggest comparable glycaemic control with insulin glargine and continuous subcutaneous insulin infusion. Results from comparative studies and meta-analyses in individuals with type 2 diabetes show lower incidences of nocturnal hypoglycaemia with insulin glargine than with NPH insulin, with two studies showing a significantly greater improvement in glycosylated haemoglobin levels with insulin glargine than with NPH. Insulin glargine is well tolerated, and is not associated with greater immunogenicity or increases in bodyweight than NPH insulin. Long-term data show maintenance of glycaemic control with insulin glargine for up to 39 months in adults and children with type 1 and adults with type 2 diabetes. In conclusion, insulin glargine is an effective and well tolerated basal insulin therapy when given as a single daily subcutaneous injection to patients with diabetes, with benefits in terms of glycaemic control and reduced frequency of hypoglycaemia over regimens based on conventional basal insulins. Accumulating data and official recommendations show the suitability of insulin glargine for first-line use in selected patients with type 2 diabetes who require insulin treatment, as well as in patients with type 1 disease, and confirm its use in children and adolescents.

Adolescent↗

PubMed2003

Icodextrin: a review of its use in peritoneal dialysis.

UNLABELLED: Icodextrin (Extraneal) is a high molecular weight glucose polymer developed specifically for use as an alternative osmotic agent to dextrose during the once-daily long-dwell exchange in peritoneal dialysis (PD). Isosmotic 7.5% icodextrin solution induces transcapillary ultrafiltration (UF) by a mechanism resembling 'colloid' osmosis (unlike hyper-osmolar dextrose-based solutions, which induce UF by crystalline osmosis). In addition, absorption of icodextrin from the peritoneal cavity is relatively slow compared with that of dextrose; this results not only in UF of longer duration, but also a lower carbohydrate load compared with medium (2.5%) and strong (4.25%) dextrose exchanges. In randomised clinical trials of up to 2 years in duration, administration of icodextrin for the long (8- to 16-hour) overnight exchange in continuous ambulatory peritoneal dialysis (CAPD) or daytime exchange in automated peritoneal dialysis (APD) produced net UF which exceeded that with 1.5% and 2.5% dextrose solutions (thereby improving fluid balance), and was equivalent to that with 4.25% dextrose solution. Icodextrin also increased peritoneal clearances of creatinine and urea nitrogen compared with 2.5% dextrose solution. The increase in UF volume with icodextrin was enhanced in CAPD patients with high peritoneal membrane permeability (i.e. high and high-average transporters), maintained in the small number of patients followed-up for 2 years and sustained during episodes of peritonitis. Icodextrin reduced the percentage of patients with net negative UF in contrast to 1.5% and 2.5% dextrose and, in noncomparative studies, extended PD technique survival in patients who had failed dextrose-based dialysis. The use of icodextrin was also associated with some symptomatic improvements and health-related quality of life advantages, and no adverse effect on patient survival, compared with dextrose, although confirmation of these findings is ideally required in appropriately designed studies. The tolerability of icodextrin was generally similar to that of dextrose-based solutions in controlled clinical trials, although there was an approximate three-fold increase in the risk of new skin rash (5.5% vs 1.7%). However, reports of severe cutaneous hypersensitivity reactions remain rare; this possibility should not preclude the use of the polymer. CONCLUSION: 7.5% icodextrin solution offers the first feasible alternative to conventional dextrose solutions for the once-daily long-dwell exchange in PD. It is effective, generally well tolerated and appears to be most useful in situations of reduced or inadequate UF with dextrose, including in high and high-average transporters, during episodes of peritonitis and patients who have failed dextrose-based dialysis.

Clinical Trials as Topic↗

PubMed2003

Eptifibatide: a pharmacoeconomic review of its use in percutaneous coronary intervention and acute coronary syndromes.

UNLABELLED: Eptifibatide (Integrilin) is a selective inhibitor of platelet glycoprotein (GP) IIb/IIIa receptors used as adjunctive therapy for patients undergoing percutaneous coronary intervention (PCI) and for patients with acute coronary syndromes (ACS), particularly those requiring PCI. Most economic analyses of eptifibatide have incorporated clinical and healthcare resource use data from either the ESPRIT (Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy) study in low- to moderate-risk patients undergoing selective PCI with stent implantation or the PURSUIT (Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy) trial in patients with ACS. Eptifibatide achieved statistically significant reductions in combined endpoints of death and ischaemic complications in both of these large multicentre clinical trials, in which patients were randomised to receive intravenous eptifibatide or placebo as adjunctive therapy to heparin and aspirin (plus a thienopyridine in ESPRIT). In US economic analyses using ESPRIT trial data, approximately 40% and 70% of the acquisition cost of eptifibatide was offset by reduced medical resource consumption during the initial hospitalisation period and over a 1-year period, respectively. Eptifibatide was associated with a favourable cost-effectiveness ratio of $US1407 (year 2000 costs) per life-year gained (LYG) in a retrospective US cost-effectiveness analysis that incorporated data from the ESPRIT trial and modelled life expectancy using a large cardiovascular database.Several cost-effectiveness analyses used prospectively collected data from the PURSUIT trial and modelled survival projections using similar methods. These analyses, conducted in the US, Canada and Western Europe, also showed favourable results ($US3761-$US18 774 per LYG; various years of costing). Cost-utility ratios reported in US analyses varied somewhat, but remained <$US20 000 per quality-adjusted life-year gained (1996 values) when clinical efficacy data were derived from the US cohort of PURSUIT. CONCLUSION: Significant clinical benefits have been demonstrated with eptifibatide as adjunctive therapy in patients undergoing selective PCI with stent implantation in the ESPRIT trial and in patients with ACS in the PURSUIT trial. Pharmacoeconomic analyses using data from either ESPRIT or PURSUIT have demonstrated favourable cost-effectiveness ratios for both indications in various countries. ESPRIT-based results from the limited number of available economic analyses are particularly favourable. The cost-effectiveness of eptifibatide in ACS (i.e. PURSUIT-based results) may be further improved by targeting the drug for patients in whom catheterisation and PCI are planned, although further analyses are required to confirm this.

Angina, Unstable↗

PubMed2003

Inhaled salmeterol/fluticasone propionate combination: a pharmacoeconomic review of its use in the management of asthma.

UNLABELLED: Asthma guidelines recommend an inhaled corticosteroid plus a long-acting inhaled beta(2)-agonist (beta(2)-adrenoceptor agonist) as the preferred maintenance therapy for moderate and severe persistent asthma. Advair/Seretide Diskus also registered as Accuhaler is fixed-dose salmeterol (a long-acting inhaled beta(2)-agonist) and fluticasone propionate (a corticosteroid) administered via a single powder inhalation device. The clinical effectiveness of salmeterol/fluticasone propionate in patients with persistent asthma symptoms has been established in comparative clinical trials. Pharmacoeconomic analyses, based on data from these clinical trials, have been conducted from a healthcare payer perspective in various countries. In patients with asthma not controlled with inhaled corticosteroids, salmeterol/fluticasone propionate was associated with more favourable (lower) cost-effectiveness ratios than fluticasone propionate monotherapy, oral montelukast plus inhaled fluticasone propionate, inhaled budesonide, and inhaled formoterol plus budesonide. As the initial maintenance therapy in patients with persistent asthma symptoms while receiving short-acting beta(2)-agonists alone, salmeterol/fluticasone propionate was cost effective relative to montelukast monotherapy. Although the total cost of asthma management tended to be slightly higher with salmeterol/fluticasone propionate than with fluticasone propionate or montelukast monotherapy, salmeterol/fluticasone propionate consistently had a more favourable cost-effectiveness ratio in terms of per successfully treated week or symptom-free day and/or was associated with small incremental costs to achieve significant additional clinical benefits. In clinical practice, salmeterol plus fluticasone propionate was associated with lower asthma-related costs than treatment with other maintenance therapies.In patients with asthma symptoms despite treatment with inhaled corticosteroids, salmeterol/fluticasone propionate produced clinically meaningful improvements in overall Asthma Quality of Life Questionnaire (AQLQ) scores relative to salmeterol or placebo monotherapy, in emotional function domain scores relative to fluticasone propionate or budesonide, and in asthma symptoms domain scores relative to budesonide. In patients with persistent asthma symptoms while receiving short-acting beta(2)-agonists alone, salmeterol/fluticasone propionate produced clinically meaningful improvements in overall AQLQ scores compared with fluticasone propionate or montelukast. CONCLUSIONS: Pharmacoeconomic analyses indicate that salmeterol/fluticasone propionate administered via a single inhaler represents a cost-effective treatment option (relative to fluticasone propionate at the same nominal dosage, budesonide, formoterol plus budesonide and montelukast plus fluticasone propionate) in patients with asthma not controlled with inhaled corticosteroid therapy. In patients with asthma not controlled with short-acting beta(2)-agonists alone, salmeterol/fluticasone propionate is a cost effective treatment relative to monotherapy with montelukast. Importantly, salmeterol/fluticasone propionate is also associated with improvements in health-related quality of life.

Albuterol↗

PubMed2002

Sertraline: a review of its use in the management of major depressive disorder in elderly patients.

UNLABELLED: Sertraline is a selective serotonin reuptake inhibitor (SSRI) with well established antidepressant and anxiolytic activity. Results from several well designed trials show that sertraline (50 to 200 mg/day) is effective in the treatment of major depressive disorder in elderly patients (> or =60 years of age). Primary endpoints in most studies included the Hamilton Depression Rating Scale (HDRS), Clinical Global Impression (CGI) score and the Montgomery-Asberg Depression Rating Scale (MADRS). Sertraline was significantly more effective than placebo, and was as effective as fluoxetine, nortriptyline and imipramine in elderly patients. During one trial, amitriptyline was significantly more effective than sertraline [mean reduction from baseline on one of six primary outcomes (HDRS)], although no quantitative data were provided. Subgroup analysis of data from a randomised, double-blind trial in elderly patients with major depressive disorder suggests that vascular morbidity, diabetes mellitus or arthritis does not affect the antidepressant effect of sertraline. Secondary endpoints from these clinical trials suggest that sertraline has significant benefits over nortriptyline in terms of quality of life. In addition, significant differences favouring sertraline in comparison with nortriptyline and fluoxetine have been recorded for a number of cognitive functioning parameters. Sertraline is generally well tolerated in elderly patients with major depressive disorder, and lacks the marked anticholinergic effects that characterise the adverse event profiles of tricyclic antidepressants (TCAs). The most frequently reported adverse events in patients aged > or =60 years with major depressive disorder receiving sertraline 50 to 150 mg/day were dry mouth, headache, diarrhoea, nausea, insomnia, somnolence, constipation, dizziness, sweating and taste abnormalities. The tolerability profile of sertraline is generally similar in younger and elderly patients. Sertraline has a low potential for drug interactions at the level of the cytochrome P450 enzyme system. In addition, no dosage adjustments are warranted for elderly patients solely based on age. CONCLUSION: Sertraline is an effective and well tolerated antidepressant for the treatment of major depressive disorder in patients aged > or =60 years. Since elderly patients are particularly prone to the anticholinergic effects of TCAs as a class, SSRIs such as sertraline are likely to be a better choice for the treatment of major depressive disorder in this age group. In addition, sertraline may have advantages over the SSRIs paroxetine, fluoxetine and fluvoxamine in elderly patients because of the drug's comparatively low potential for drug interactions, which is of importance in patient groups such as the elderly who are likely to receive more than one drug regimen.

Adolescent↗

PubMed2002

Vinorelbine: a review of its use in elderly patients with advanced non-small cell lung cancer.

Vinorelbine is a semisynthetic vinca alkaloid that is effective as monotherapy in elderly patients with advanced non-small cell lung cancer (NSCLC). In the large comparative Elderly Lung Cancer Vinorelbine Italian Study (ELVIS), patients receiving vinorelbine monotherapy achieved an objective response rate of 19.7%. The median survival time and the 1-year survival rate were significantly higher in recipients of vinorelbine plus best supportive care than in recipients of best supportive care alone. Vinorelbine recipients generally scored better than recipients of best supportive care on quality-of-life (QOL) functioning scales and experienced significantly fewer lung cancer-related symptoms; however, QOL scores were worse with vinorelbine for parameters relating to drug tolerability. Comparative phase III trials investigating the efficacy of combination therapy with vinorelbine and other agents specifically in elderly patients with advanced NSCLC have been conducted only for the combination of vinorelbine and gemcitabine [the Southern Italy Cooperative Oncology Group (SICOG) trial and the Multicenter Italian Lung Cancer in the Elderly Study (MILES)]. Objective response rates for vinorelbine/gemcitabine combination therapy in these phase III trials were 22 and 20%, respectively. The SICOG trial was closed early when an interim analysis demonstrated a significant survival advantage for combination therapy with vinorelbine plus gemcitabine over vinorelbine monotherapy. However, a survival advantage for combination therapy versus vinorelbine monotherapy was not demonstrated in the larger MILES trial. The main adverse effect of vinorelbine monotherapy in the elderly is myelosuppression. Adverse events associated with most antineoplastic agents, such as mild alopecia, nausea, vomiting and mucositis, were reported in clinical trials; however, these events were rarely severe. Mild-to-moderate neurotoxicity, including constipation (presumably from autonomic neuropathy), was also reported. The addition of gemcitabine to vinorelbine increased the incidence of both haematological and nonhaematological adverse events. However, there was no significant increase in the incidence of life-threatening toxicity. Vinorelbine as a single agent is effective in elderly patients with NSCLC and is associated with improved survival and at least a trend towards improved QOL parameters compared with best supportive care alone. Vinorelbine was associated with a generally manageable tolerability profile. The benefit of adding gemcitabine to vinorelbine for the treatment of NSCLC in the elderly is equivocal; improved survival was reported in one comparative trial, but not in another larger one. Vinorelbine is an effective and well tolerated palliative treatment option for elderly patients with advanced NSCLC.

Age Factors↗

PubMed2002

Cefditoren pivoxil.

Cefditoren pivoxil is an orally absorbed prodrug that is rapidly hydrolysed by intestinal esterases to the microbiologically active cephalosporin cefditoren. Cefditoren has a broad spectrum of activity against Gram-positive and Gram-negative bacteria, including common respiratory and skin pathogens. Cefditoren has shown excellent in vitro activity against the Gram-positive pathogens penicillin-susceptible and -intermediate Streptococcus pneumoniae, S. pyogenes and methicillin-susceptible Staphylococcus aureus. Cefditoren was inactive against methicillin-resistant S. aureus. Of the important Gram-negative pathogens, cefditoren had potent antibacterial effects against beta-lactamase-positive and -negative Haemophilus influenzae, H. parainfluenzae and beta-lactamase-positive and -negative Moraxella catarrhalis. Cefditoren does not have antibacterial activity against Pseudomonas aeruginosa or atypical respiratory pathogens and has only variable activity against anaerobes. In healthy volunteers, single doses of cefditoren pivoxil 200 and 400mg achieved maximal plasma concentrations of 2.6 to 3.1 mg/L and 3.8 to 4.6 mg/L, respectively. Cefditoren penetrates rapidly into bronchopulmonary and tonsillar tissue as well as inflammatory and noninflammatory blister fluid. In two, randomised, double-blind trials involving patients with acute exacerbations of chronic bronchitis (AECB), cefditoren 200 and 400mg twice daily for 10 days produced clinical cure rates of 88 to 89% within 48 hours of treatment completion. Clinical cure rates in patients with AECB were similar to those of either clarithromycin 500mg twice daily or cefuroxime axetil 250mg twice daily. In patients with streptococcal pharyngitis, a 10-day course of cefditoren pivoxil 200mg twice daily produced clinical cure rates of 94% at 4 to 7 days after treatment, which were similar to those observed for phenoxymethylpenicillin potassium 250 mg four times daily. In uncomplicated skin and skin structure infections, a 10-day course of cefditoren pivoxil 200 or 400mg twice daily produced the same clinical cure rate of 89% within 48 hours of treatment completion. These cefditoren pivoxil dosage regimens were as effective as a 10-day course of either cefadroxil 500 mg twice daily or cefuroxime axetil 250mg twice daily in treating uncomplicated skin and skin structure infections, including those caused by S. aureus and S. pyogenes. The most common adverse events associated with therapeutic doses of cefditoren pivoxil are diarrhoea, nausea, headache, abdominal pain and vaginal candidiasis.

Animals↗

PubMed2002

Alfuzosin: a review of the therapeutic use of the prolonged-release formulation given once daily in the management of benign prostatic hyperplasia.

UNLABELLED: Alfuzosin, a quinazoline derivative, is a selective and competitive alpha(1)-adrenoceptor antagonist. It distributes preferentially in the prostate, compared with plasma, and decreases the sympathetically controlled tone of prostatic smooth muscle. As a result lower urinary tract symptoms suggestive of benign prostatic hyperplasia (BPH) are improved. The once-daily formulation of alfuzosin contains inactive barrier layers which have been added to the planar surfaces of compressed tablets. Drug release is sustained over 20 hours with a near constant dissolution rate between 2 and 12 hours. Mean values for area under the plasma concentration-time curve over 24 hours (AUC(24)) were similar after administration of prolonged-release alfuzosin 10mg once daily and immediate-release alfuzosin 2.5mg three times daily. Likewise, similar AUC(24) values were reported when prolonged-release alfuzosin 10mg once daily and sustained-release alfuzosin 5mg twice daily were compared. These data suggest that these alfuzosin regimens provide similar average systemic exposure. Data from short- (3 months) and long-term (up to 12 months) clinical trials show that the prolonged-release formulation of alfuzosin controls the symptoms associated with BPH as effectively as immediate-release alfuzosin 2.5mg three times daily and clinical improvement is maintained for up to 1 year. Improvements in International Prostate Symptom Score, maximum urinary flow rate and quality-of-life index were improved to a similar extent in patients treated with immediate- or prolonged-release alfuzosin and improvements were statistically significant compared with placebo. Prolonged-release alfuzosin 10mg is well tolerated and the overall incidence of adverse events is similar to that seen with placebo. The once-daily formulation of alfuzosin 10mg caused fewer vasodilatory adverse events than immediate-release alfuzosin 2.5mg three times daily and caused only slight decreases in systolic and diastolic blood pressure which were not clinically significant and did not differ significantly from those with placebo. No dosage titration is required. The incidence of ejaculatory disorders was <1%. CONCLUSION: Prolonged-release alfuzosin 10mg once daily controls symptoms associated with BPH throughout a 24-hour dosage interval as effectively as immediate-release alfuzosin 2.5mg three times daily but with fewer vasodilatory adverse events. A nonblind extension study showed that clinical benefits were maintained for up to 1 year and the once-daily 10mg formulation continued to be well tolerated, particularly in terms of cardiovascular effects and sexual function. Thus, for the medical management of men with BPH, prolonged-release alfuzosin 10mg is an effective, well tolerated and convenient treatment option.

Absorption↗

PubMed2002

Bivalirudin: a review of its potential place in the management of acute coronary syndromes.

UNLABELLED: Bivalirudin, a synthetic analogue of hirudin, is a specific and reversible inhibitor of thrombin which binds directly with both fluid-phase and clot-bound thrombin. In patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA), results from a large well designed study and its reanalysis (n = 4312) indicate that bivalirudin is more effective than heparin in the prevention of ischaemic complications for up to 90 days after the start of treatment. In addition, among patients undergoing PTCA for post myocardial infarction (MI) bivalirudin may be more effective than heparin in preventing ischaemic complications for up to 180 days after treatment was started. Data from dose-finding studies indicate bivalirudin has potential in the treatment of patients with unstable angina not undergoing percutaneous coronary intervention (PCI); however, well designed comparative studies are needed before firm conclusions can be made. Among patients with acute ST elevation MI, randomised trials have demonstrated bivalirudin to be significantly more effective than heparin in improving early patency in patients receiving thrombolytic therapy with streptokinase. Data from the Hirulog and Early Reperfusion/Occlusion (HERO)-1 trial (n = 412) indicate that bivalirudin recipients were significantly more likely to have Thrombin Inhibition in Myocardial Ischaemia (TIMI) grade 3 flow at 90 to 120 minutes than heparin recipients. In addition, data from the HERO-2 trial (n = 17 073) show bivalirudin was significantly more effective than heparin in reducing adjudicated 96-hour reinfarction and 30-day investigator-reported death/reinfarction than heparin. Bivalirudin was as effective as heparin in reducing 30-day mortality. Data from a meta-analysis of four randomised trials among patients undergoing PTCA or treatment for acute coronary syndromes indicate that, at after 30 to 50 days of follow-up, bivalirudin was significantly more effective than heparin in reducing the incidence of nonfatal MI and the combined endpoint of death or nonfatal MI. The most significant adverse events associated with bivalirudin are bleeding complications. In individual trials, bivalirudin was as well tolerated as heparin with, in general, a reduced incidence of bleeding complications. Additionally, bivalirudin provides a more consistent, predictable anticoagulant response. In 4312 patients with unstable angina undergoing PTCA the incidence of retroperitoneal bleeding, blood transfusion and major haemorrhage was significantly lower in bivalirudin than heparin recipients. Data from the HERO-2 trial in patients with acute MI indicate that although bivalirudin recipients had a significantly higher incidence of mild or moderate bleeding than heparin recipients, there was no difference in intracranial haemorrhage, severe bleeding or transfusions. Data from a meta-analysis among 5674 patients with ischaemic heart disease show bivalirudin recipients were at a significantly lower risk of haemorrhagic events than heparin recipients. CONCLUSIONS: Bivalirudin is an effective alternative to heparin in the prevention of ischaemic complications in patients with unstable angina undergoing PTCA. In addition, the drug has shown potential in the treatment of patients with unstable angina not undergoing PCI. For patients with MI, it is clear that bivalirudin can replace heparin in the management of MI where streptokinase is used as the thrombolytic agent. Further data are required on the efficacy of bivalirudin in patients undergoing thrombolysis with newer thrombolytics.

Angina, Unstable↗

PubMed2002

ET-743.

ET-743 is a novel antineoplastic DNA-binding agent derived from the marine tunicate Ecteinascidia turbinata. It has significant cytotoxic activity against soft tissue sarcomas (STS). It also has in vitro activity against melanoma, breast, ovarian, colon, renal, non-small cell lung and prostate carcinomas. The drug has unique mechanism of action which includes in vitro inhibition of transcription-dependent nucleotide excision repair pathways and inhibition of cell cycle progression leading to p53-independent apoptosis. It also selectively inhibits transcriptional activation of multidrug-resistance (MDR1) gene in human sarcoma cells in vivo. The efficacy of ET-743 has been investigated in patients with advanced STS in three multicentre phase II clinical trials. Patients receiving ET-743 as second- or third-line treatment had partial tumour response rates of 6 to 8%. Patients receiving ET-743 as first-line chemotherapy had a partial response rate of 18%. Forty-two to 50% of all patients in these trials achieved stable disease. All responses were durable up to 14 months. A pooled analysis of the three multicentre phase II trials showed the following: median overall survival time of 10.2 months, 1-year survival rate of 40% and 6-month progression-free rate of 27.2%. ET-743 is generally well tolerated. The most common adverse events in clinical trials were non-cumulative haematological and hepatic toxicities. Transient and reversible elevation of hepatic transaminases, nausea, vomiting and asthenia were common but seldom severe and never treatment-limiting. Mucositis, alopecia and cardiac or neurotoxicities were not observed.

Antineoplastic Agents, Alkylating↗

PubMed2002

Rizatriptan: an update of its use in the management of migraine.

UNLABELLED: Rizatriptan is an orally active serotonin 5-HT(1) receptor agonist that potently and selectively binds to 5-HT(1B/1D) subtypes. Earlier clinical trials demonstrated that rizatriptan 5 or 10mg is more effective than placebo at providing pain relief and a pain-free state, relieving associated symptoms of migraine, normalising functional ability and improving patient quality of life, and showed that rizatriptan provides faster freedom from pain and reduces nausea to a greater extent than oral sumatriptan. More recently, rizatriptan 10mg was shown to be more effective than zolmitriptan 2.5mg or naratriptan 2.5mg at producing a pain-free state 2 hours postdose. Furthermore, compared with naratriptan, significantly more patients who received rizatriptan were pain free or had pain relief from 1 hour onwards. The number of patients with normal functional ability at 2 hours was significantly higher after rizatriptan than after naratriptan or zolmitriptan. Rizatriptan was also generally more effective than zolmitriptan or naratriptan at relieving migraine-associated symptoms. Rizatriptan is generally well tolerated and adverse events are usually mild and transient. The most common adverse events associated with rizatriptan in recent randomised trials were asthenia/fatigue, dizziness, somnolence and nausea. There was a trend towards a lower incidence of adverse events with rizatriptan compared with zolmitriptan (31.2 vs 38.8%). However, rizatriptan was associated with a significantly higher incidence of adverse events than naratriptan (39 vs 29%). The incidence of chest pain was similar after the administration of rizatriptan, zolmitriptan or naratriptan (2 to 4%). CONCLUSION: Rizatriptan is an effective drug for the acute treatment of moderate or severe migraine. Oral rizatriptan 5 and 10mg have shown greater efficacy than placebo in providing pain relief, an absence of pain, relief from associated symptoms, normal functional ability and an improvement in patient quality of life. Earlier results showed that rizatriptan provides faster freedom from pain and reduces nausea to a greater extent than oral sumatriptan. More recent studies have shown that rizatriptan 10mg provides faster pain relief and a higher percentage of patients with an absence of pain and normal functional ability at 2 hours than naratriptan 2.5mg or zolmitriptan 2.5mg. The efficacy of rizatriptan is retained when used in the long term and the drug is generally well tolerated. Although well designed studies comparing rizatriptan with almotriptan, eletriptan and frovatriptan would further define the position of rizatriptan, current data suggest rizatriptan should be considered as a first-line treatment option in the management of migraine.

Administration, Oral↗

PubMed2002

Rosuvastatin.

Rosuvastatin is a hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor used in the treatment of patients with dyslipidaemia. Rosuvastatin is not extensively metabolised and has a low propensity for drug interactions. In well designed trials of between 6 and 52 weeks' duration, rosuvastatin was superior to atorvastatin, simvastatin and pravastatin in improving the lipid profile of patients with hypercholesterolaemia. In a 1-year dose-titration study, rosuvastatin 13.4mg daily (mean dose) allowed more patients to achieve US National Cholesterol Education Program (Adult Treatment panel II)[NCEP] target low-density lipoprotein (LDL)-cholesterol levels than atorvastatin 20.8mg daily (98 vs 87%) with the difference most marked in high-risk patients (97 vs 61%). Similarly, when compared with pravastatin and simvastatin 20 mg/day in a further 1-year trial, 88% of rosuvastatin recipients [9.5 and 13.8 mg/day (mean doses)] achieved NCEP target serum LDL-cholesterol levels compared with 60 and 73% of pravastatin and simvastatin recipients, respectively, with the difference more marked in high-risk patients. In further clinical trials, rosuvastatin improved the lipid profile of patients with heterozygous or homozygous familial hypercholesterolaemia, hypertriglyceridaemia or mixed dyslipidaemias. Rosuvastatin was well tolerated in clinical trials of up to 1 years' duration.

Clinical Trials as Topic↗

PubMed2002

Mycophenolate mofetil: a pharmacoeconomic review of its use in solid organ transplantation.

UNLABELLED: Most pharmacoeconomic studies of mycophenolate mofetil have focused on its use as part of maintenance immunosuppression for renal transplantation, involving short-term (3 to 12 months) time frames. In general, mycophenolate mofetil reduced the treatment costs for rejection episodes and graft failure which offset its higher drug acquisition cost compared with azathioprine. Several cost analyses have been modelled on the large multicentre trials of adult renal transplant recipients. The use of mycophenolate mofetil was associated with either cost savings or no additional costs after 6 or 12 months in French, US and Canadian analyses of triple or quadruple immunosuppressant therapy. A further cost analysis utilising a registry database of renal transplant recipients in the US found mycophenolate mofetil to be cost saving compared with azathioprine after 6.4 years when evaluating costs due to graft loss only. Of the limited cost-effectiveness analyses with the drug, one US study modelled the 1- and 10-year cost effectiveness of mycophenolate mofetil and various other immunosuppressants used in combined regimens. Long-term use of mycophenolate mofetil was less cost effective than other regimens, but the use of long-term mycophenolate mofetil in high-risk patients was shown to be a relatively cost-effective strategy. In another US analysis comparing mycophenolate mofetil with azathioprine as part of quadruple therapy, mycophenolate mofetil was associated with slightly lower costs during the first year after renal transplantation as well as improved clinical outcomes. CONCLUSION: Pharmacoeconomic studies support the use of mycophenolate mofetil as part of immunosuppressant therapy in renal transplantation, at least in the short term. Although the cost effectiveness of mycophenolate mofetil in the long term is less clear, limited pharmacoeconomic data available appear promising. Among issues to be examined in future economic analyses in renal transplantation are the calcineurin-sparing potential of mycophenolate mofetil and the feasibility of using more efficient mycophenolate mofetil dosage regimens when using the drug on a long-term basis. Additional pharmacoeconomic analyses of mycophenolate mofetil are also needed in other types of solid organ transplantation.

Cost-Benefit Analysis↗

PubMed2002

Galantamine: a pharmacoeconomic review of its use in Alzheimer's disease.

Galantamine is one of several orally administered cholinesterase inhibitors that improve cognition in patients with mild to moderate Alzheimer's disease. Compared with placebo, galantamine 16 or 24 mg/day improved cognition and activities of daily living, delayed emergence of behavioural symptoms and reduced caregiver burden in three pivotal randomised studies of 5 or 6 months' duration. Galantamine may reduce the considerable economic burden of Alzheimer's disease by delaying the need for full-time care (FTC) in patients with mild to moderate Alzheimer's disease. In pharmacoeconomic analyses with a time horizon of 10 years conducted in Canada, Sweden, The Netherlands and the US, data from the pivotal trials were incorporated into a model to examine economic implications associated with galantamine treatment. FTC was defined in the model as the consistent requirement for caregiving and supervision for the greater part of each day regardless of the location of care and the identity of caregiver. When the effect of galantamine 16 or 24 mg/day was analysed from the perspective of a comprehensive healthcare payer, treatment was associated with cost savings (inclusive of drug costs) relative to no treatment, regardless of country for which the model was customised. Cost savings resulted from the delay in the time until FTC was required in patients with mild to moderate disease. In sensitivity analyses, cost savings were most sensitive to the cost of institutional care. In the analyses that considered the effect of galantamine 24 mg/day solely on cognition, galantamine was predicted to reduce the time FTC was required by approximately 10% in patients with mild to moderate Alzheimer's disease compared with no pharmacological treatment. Greater reductions in the time that FTC was required were predicted when the effects of galantamine 16 or 24 mg/day on behavioural symptoms in addition to cognition were considered in the US analysis or in sensitivity analyses in studies in other countries. In conclusion, pharmacoeconomic analyses, which were based on modelling of data from pivotal clinical trials with galantamine and included drug costs, indicate that galantamine treatment may result in cost savings from a healthcare payer perspective. The effects of galantamine on cognition and behavioural symptoms in patients with mild to moderate Alzheimer's disease are predicted to delay the need for FTC, which may result in cost savings. From a societal perspective, the caregiver burden of caring for a patient with Alzheimer's disease in the community may be decreased and the time that patients have without severe disease may be prolonged.

Alzheimer Disease↗