Biomedical subjects

Karen L Goa

Publications and source records attributed to Karen L Goa.

At least 19 recordsLinked to original sources

PubMed2003

Nesiritide: a review of its use in acute decompensated heart failure.

UNLABELLED: Nesiritide (Natrecor) is a recombinant form of human B-type (brain) natriuretic peptide that has beneficial vasodilatory, natriuretic, diuretic and neurohormonal effects. The drug is administered intravenously for the management of patients with decompensated congestive heart failure (CHF). In the Vasodilation in the Management of Acute Congestive Heart Failure (VMAC) study, patients hospitalised with acute decompensated CHF who received nesiritide had significantly greater mean reductions from baseline in pulmonary capillary wedge pressure 3 hours after starting treatment than nitroglycerin or placebo recipients (-5.8 vs -3.8 and -2 mm Hg, respectively); all patients also received standard therapy (e.g. intravenous diuretics). Improvements in other haemodynamic parameters were also seen in nesiritide recipients. In addition, significantly more nesiritide than placebo recipients reported an improvement in dyspnoea after 3 hours' treatment in VMAC, whereas there was no significant difference between nitroglycerin and placebo recipients. Improvements in global clinical status, dyspnoea and fatigue were also seen with nesiritide in another active-comparator study and in a placebo-controlled study. In VMAC, there was no significant difference between nesiritide and nitroglycerin recipients in 6-month mortality. In the other active-comparator trial, 6-month mortality was significantly lower in recipients of nesiritide 0.015 micro g/kg/min than in dobutamine recipients (although mortality was not a prespecified endpoint and this result should be interpreted with caution). In this same study, the 21-day all-cause hospital readmission rate was significantly lower with nesiritide 0.015 micro g/kg/min than with dobutamine and the duration of active drug treatment was significantly shorter with nesiritide than with dobutamine. Nesiritide is generally well tolerated. In VMAC, significantly more adverse events occurred with nitroglycerin than with nesiritide. The most common adverse events reported during the first 24 hours of therapy in nesiritide and nitroglycerin recipients included general pain, abdominal pain, catheter-related pain, headache, nausea, asymptomatic and symptomatic hypotension, nonsustained ventricular tachycardia and angina pectoris. Most episodes of symptomatic hypotension resolved spontaneously or after an intravenous volume challenge of </=250 ml. In addition, nesiritide does not appear to be proarrhythmic. CONCLUSION: Short-term intravenous infusion of nesiritide is associated with haemodynamic and symptomatic improvements in patients with acutely decompensated CHF. Nesiritide may offer tolerability and practical advantages over currently used vasodilators, inodilators and inotropes in this condition; in particular, nesiritide does not appear to have proarrhythmic effects. Nesiritide also appears to be effective and well tolerated in patients receiving concomitant beta-blocker therapy and in patients with renal insufficiency. Thus, nesiritide is a suitable first-line option for the treatment of patients with acutely decompensated CHF and is a welcome addition in an area where intravenous agents are few.

Acute Disease↗

PubMed2003

Capecitabine: a review of its pharmacology and therapeutic efficacy in the management of advanced breast cancer.

Capecitabine is an orally administered prodrug of fluorouracil which is indicated in the US and Europe, in combination with docetaxel, for the treatment of patients with metastatic breast cancer failing anthracycline therapy, and as monotherapy for metastatic breast cancer resistant to paclitaxel and anthracycline therapy (US) or failing intensive chemotherapy (Europe). Capecitabine is also approved for use in metastatic colorectal cancer. Capecitabine is metabolically activated preferentially at the tumour site, and shows antineoplastic activity and synergy with other cytotoxic agents including cyclophosphamide or docetaxel in animal models. Bioavailability after oral administration is close to 100%. In patients with pretreated advanced breast cancer, capecitabine is effective as monotherapy and also in combination with other agents. Combination therapy with capecitabine 1,250 mg/m(2) twice daily for 2 weeks of every 3-week cycle plus intravenous docetaxel 75 mg/m(2) on day one of each cycle was superior to intravenous monotherapy with docetaxel 100 mg/m(2) on day one of each cycle. Capecitabine plus docetaxel significantly reduced the risks of disease progression and death by 35% (p = 0.0001) and 23% (p < 0.05), respectively, and significantly increased median survival (p < 0.05) and objective response rates (p < 0.01). Efficacy has also been demonstrated with capecitabine monotherapy and combination therapy in previously untreated patients in preliminary trials. The most common adverse effects occurring in patients receiving capecitabine monotherapy include lymphopenia, anaemia, diarrhoea, hand-and-foot syndrome, nausea, fatigue, hyperbilirubinaemia, dermatitis and vomiting (all >25% incidence). While gastrointestinal events and hand-and-foot syndrome occurred more often with capecitabine than with paclitaxel or a regimen of cyclophosphamide, methotrexate and fluorouracil (CMF), neutropenic fever, arthralgia, pyrexia and myalgia were more common with paclitaxel, and nausea, stomatitis, alopecia and asthenia were more common with CMF. The incidence of adverse effects and hospitalisation was similar in patients receiving capecitabine plus docetaxel and those receiving docetaxel monotherapy. In conclusion, capecitabine, an oral prodrug of fluorouracil which is activated preferentially at the tumour site, is an effective and convenient addition to the intravenous polychemotherapeutic treatment of advanced breast cancer in pretreated patients, and also has potential as a component of first-line combination regimens. Combined capecitabine plus docetaxel therapy resulted in similar rates of treatment-related adverse effects and hospitalisation to those seen with docetaxel monotherapy. Capecitabine is also effective as monotherapy in pretreated patients and phase II data for capecitabine as first-line monotherapy are also promising. While gastrointestinal effects and hand-and-foot syndrome occur often with capecitabine, the tolerability profile was comparatively favourable for other adverse effects (notably, neutropenia and alopecia).

Administration, Oral↗

PubMed2003

Losartan in diabetic nephropathy.

Losartan is an orally active, selective, nonpeptide, angiotensin II AT(1) receptor antagonist. Losartan 50 or 100 mg/day was significantly more effective than placebo in reducing the incidence of a doubling of serum creatinine, end-stage renal disease (ESRD) or death (43.5% vs 47.1%, p = 0.02) in a pivotal, well designed trial (Reduction of Endpoints in Non insulin dependent diabetes mellitus with the Angiotensin II Antagonist Losartan [RENAAL] study) in 1513 patients with type 2 diabetes mellitus and proteinuria. Losartan also significantly reduced the incidence of doubling of serum creatinine level (p = 0.006), ESRD (p = 0.002), ESRD or death (p = 0.01) and doubling of serum creatinine and ESRD (p = 0.01) compared with placebo in the RENAAL trial. There were similar incidences of overall mortality and morbidity and mortality from cardiovascular causes between treatment groups. In addition, data from several nonblind and double-blind studies indicates that losartan effectively reduces the mean albumin excretion rate. Two double-blind studies show that losartan has similar effects to enalapril on kidney function. Data from 4058 patients (3300 with essential hypertension) who have received losartan (10-150 mg/day) in clinical trials indicate it is well tolerated. In the RENAAL study 17.2% and 21.7% of losartan and placebo recipients discontinued treatment because of adverse events, but causality was not determined.

Angiotensin II↗

PubMed2003

Zoledronic acid: a review of its use in the management of bone metastases and hypercalcaemia of malignancy.

UNLABELLED: Zoledronic acid (Zometa) is an effective inhibitor of osteoclast-mediated bone resorption. Zoledronic acid demonstrated efficacy in the reduction of skeletalrelated events (SREs) in patients with multiple myeloma or bone metastases secondary to breast cancer, prostate cancer or other solid tumours, or hypercalcaemia of malignancy. Zoledronic acid was effective in patients with multiple myeloma or metastatic breast cancer with osteolytic or mixed bone lesions. The proportion of patients who experienced an SRE was similar during 12 months of treatment with zoledronic acid 4mg or pamidronic acid 90mg, but significantly fewer patients receiving zoledronic acid required radiotherapy to bone. Furthermore, in patients with breast cancer and osteolytic lesions, median time to a first SRE was more than 4 months longer with zoledronic acid than with pamidronic acid. In the multiple event analysis in a 12-month extension study (total study duration was 25 months) in patients with breast cancer, zoledronic acid was superior to pamidronic acid, with an 18% reduction in the risk of experiencing an SRE. Both drugs were associated with a slight reduction in pain. Zoledronic acid 4mg, compared with placebo, significantly reduced the proportion of patients with prostate cancer bone metastases experiencing an SRE, particularly pathological fractures after 15 months' treatment. The drug also significantly delayed the onset of skeletal complications compared with placebo in patients with prostate cancer and other solid tumours including non-small cell lung cancer. When administered as a single 15-minute intravenous infusion, zoledronic acid 4mg was significantly more effective than pamidronic acid administered as a 2-hour infusion in the treatment of severe hypercalcaemia of malignancy, as assessed by complete responses measuring normalised serum calcium concentrations at day 10 after a single dose. Furthermore, zoledronic acid normalised serum calcium concentrations significantly faster than pamidronic acid, and the duration of response and median time to relapse were approximately twice as long in zoledronic acid recipients than in pamidronic acid recipients. Zoledronic acid is well tolerated and has a similar tolerability profile to pamidronic acid. The most commonly reported adverse events included flu-like symptoms (fever, arthralgias, myalgias and bone pain), fatigue, gastrointestinal reactions, anaemia, weakness, dyspnoea and oedema. CONCLUSION: In conjunction with antitumour therapy, zoledronic acid should be considered for routine use to reduce skeletal complications in patients with advanced malignancies involving bone. In patients with hypercalcaemia of malignancy, zoledronic acid is expected to become the treatment of choice.

Antineoplastic Agents↗

PubMed2003

DTPa-HBV-IPV/Hib vaccine (Infanrix hexa).

Primary vaccination of infants with diphtheria-tetanus-acellular pertussis-hepatitis B recombinant (adsorbed)-inactivated poliomyelitis-adsorbed conjugated Haemophilus influenzae type b vaccine (DTPa-HBV-IPV/Hib; Infanrix hexa)-inactivated poliomyelitis-absorbed conjugated Haemophilus influenzae type b vaccine (DTPa-HBV-IPV/Hib) refers to Infanrix hexa trade mark.) provided high levels of seroprotection against diphtheria toxoid, tetanus toxoid, poliovirus 1, 2 and 3, pertussis antigens (pertussis toxoid, filamentous haemagglutinin and pertactin), hepatitis B virus surface antigen and H. influenzae polyribosyl-ribitol-phosphate (PRP) antigen. Most infants (97%) had anti-PRP levels >/=0.15 micro g/mL after a booster dose at 18 months. Primary vaccination with the DTPa-HBV-IPV/Hib vaccine produced a similar immune response to that with two different pentavalent plus monovalent vaccine combinations. Coadministration of DTPa-HBV-IPV/Hib vaccine and a heptavalent pneumonococcal conjugate vaccine resulted in a high level of seroprotection and was well tolerated. Primary or booster vaccination with DTPa- HBV-IPV/Hib vaccine was well tolerated. Commonly reported local adverse reactions included redness, pain and swelling. Systemic symptoms were usually mild to moderate, and included fussiness, fever, restlessness and sleepiness.

Antibody Formation↗

PubMed2003

Lovastatin extended release: a review of its use in the management of hypercholesterolaemia.

UNLABELLED: Lovastatin extended release (ER) provides a new form of delivery for lovastatin, an HMG-CoA reductase inhibitor. Lovastatin ER delivers the drug in a more sustained fashion, as shown by a smoother plasma concentration-time profile, a lower maximum plasma concentration and a prolonged half-life compared with that of lovastatin immediate release (IR). At dosages of 10-60 mg/day, lovastatin ER significantly reduced levels of total cholesterol, low density lipoprotein (LDL)-cholesterol and triglycerides, and increased levels of high density lipoprotein-cholesterol, in patients with primary hypercholesterolaemia in a randomised, double-blind study of 12 weeks' duration. These effects were maintained in a 6-month extension study in which patients received lovastatin 40 or 60 mg/day. In a randomised 4-week study in 24 patients with primary hypercholesterolaemia, the reduction in plasma LDL-cholesterol levels was significantly greater with lovastatin ER 40 mg/day than with the IR formulation administered at the same dosage. Lovastatin ER was well tolerated in all studies and adverse events were usually mild to moderate and transient. The tolerability profile of lovastatin ER was similar to that of lovastatin IR. There were no reports of clinically relevant elevations in liver transaminases or creatine phosphokinase attributed to the drug in recipients of lovastatin ER. CONCLUSION: The ER formulation of lovastatin provides smooth and sustained delivery of this established and well-tolerated agent over the dosage interval, significantly reducing LDL-cholesterol in patients with primary hypercholesterolaemia. If, as expected, the beneficial changes in lipid levels are maintained during long-term treatment and further clinical experience confirms the greater efficacy of the lovastatin ER formulation than the IR formulation, then lovastatin ER is likely to supplant lovastatin IR and provide a useful option in the management of patients with dyslipidaemia and prevention of coronary heart disease.

Absorption↗

PubMed2003

Lopinavir/ritonavir: a review of its use in the management of HIV infection.

Lopinavir is a novel protease inhibitor (PI) developed from ritonavir. Coadministration with low-dose ritonavir significantly improves the pharmacokinetic properties and hence the activity of lopinavir against HIV-1 protease. Coformulated lopinavir/ritonavir was developed for ease of administration and to ensure both drugs are taken together, as part of combination therapy with other antiretroviral agents. Coformulated lopinavir/ritonavir-based regimens provide adequate and durable suppression of viral load and sustained improvements in CD4+ cell counts, as demonstrated in randomised trials in antiretroviral therapy-naive and -experienced adults and children. To date, development of primary resistance to lopinavir/ritonavir has not been observed in 470 antiretroviral therapy-naive patients treated for >48 weeks. The lopinavir/ritonavir-based regimen was more effective than nelfinavir in antiretroviral therapy-naive HIV-1-infected patients in a phase III trial. The coformulation is also effective as 'salvage' therapy, as shown by low cross-resistance rates in patients who failed to respond to treatment with other PIs in phase II trials. Coformulated lopinavir/ritonavir was well tolerated in both antiretroviral therapy-naive and -experienced HIV-1-infected adults and children with low rates of study drug-related treatment discontinuations. The most common adverse event in adults associated with lopinavir/ritonavir was diarrhoea, followed by other gastrointestinal disturbances, asthenia, headache and skin rash. The incidence of moderate-to-severe adverse events in children was low, skin rash being the most common. Changes in body fat composition occurred with equal frequency in lopinavir/ritonavir- and nelfinavir-treated naive patients, through week 60 in a phase III study. Although laboratory abnormalities occurred with similar frequency in both treatment groups, triglycerides grade 3/4 elevations were significantly more frequent with lopinavir/ritonavir. Total cholesterol and triglycerides grade 3/4 elevations appear to occur more frequently in PI-experienced than in PI-naive lopinavir/ritonavir-treated patients. A number of clinically important drug interactions have been reported with lopinavir/ritonavir necessitating dosage adjustments of lopinavir/ritonavir and/or the interacting drugs, and several other drugs are contraindicated in patients receiving the coformulation. CONCLUSION: Coformulated lopinavir/ritonavir is a novel PI that, in combination with other antiretroviral agents, suppresses plasma viral load and enhances immunological status in therapy-naive and -experienced patients with HIV-1 infection. Lopinavir/ritonavir appears more effective than nelfinavir in 'naive' patients and is also suitable for 'salvage' therapy, because of its high barrier to development of resistance. Given its clinical efficacy, a tolerability profile in keeping with this class of drugs, favourable resistance profile and easy-to-adhere-to administration regimen, coformulated lopinavir/ritonavir should be regarded as a first-line option when including a PI in the management of HIV-1 infection. OVERVIEW OF PHARMACODYNAMIC PROPERTIES: Lopinavir/ritonavir is a coformulation of two structurally related protease inhibitor (PI) antiretroviral agents. Lopinavir is a highly potent and selective inhibitor of the HIV type 1 (HIV-1) protease, an essential enzyme for production of mature, infective virus. It acts by arresting maturation of HIV-1 thereby blocking its infectivity. Thus, the main antiviral action of lopinavir is to prevent subsequent infections of susceptible cells; it has no effect on cells with already integrated viral DNA. Lopinavir has an approximate, equals 10-fold higher in vitro activity against both wild-type and mutant HIV-1 proteases than ritonavir; however, its in vivo activity is greatly attenuated by a high first-pass hepatic metabolism. The low-dose ritonavir coadministered with lopinavir inhibits metabolic inactivation of lopinavir and acts only as its pharmacokinetic enhancer. Therefore, the antiretroviral activity of roviral activity of coformulated lopinavir/ritonavir 400/100mg twice daily is derived solely from lopinavir plasma concentrations. Combining lopinavir with low-dose ritonavir produces lopinavir concentrations far exceeding those needed to suppress 50% of in vitro and in vivo viral replication in CD4+ cells and monocyte/macrophages (main human reservoirs of HIV-1 infection). Thus far, no resistance to lopinavir has been detected in clinical trials in antiretroviral therapy-naive patients treated for up to 204 weeks and only 12% of HIV-1 strains from patients in whom prior treatment with multiple PIs have failed, have been observed to develop resistance to coformulated lopinavir/ritonavir. A strong negative correlation was found between the number of PI mutations at baseline and the viral response rates achieved with lopinavir/ritonavir-based regimens in PI-experienced patients, indicating that resistance to lopinavir increases with increasing number of PI mutations and that five PI mutations represent the clinically relevant genotypic breakpoint for lopinavir. OVERVIEW OF PHARMACOKINETIC PROPERTIES: The absolute bioavailability of lopinavir coformulated with ritonavir in humans has not yet been established. Multiple-dosage absorption pharmacokinetics of lopinavir/ritonavir 400/100mg twice daily (the mean peak [C(max)] and trough [C(trough)] plasma concentrations at steady-state and the 12-hour area under the plasma concentration-time curve [AUC(12)] of either drug) were stable in antiretroviral therapy-naive and single PI-experienced adult patients receiving therapy over a 24-week evaluation period. The C(trough) values of lopinavir, achieved with lopinavir/ritonavir 400/100mg twice daily, were median 84-fold higher than the protein binding-adjusted 50% effective concentration (EC(50)) of lopinavir against wild-type HIV-1 in antiretroviral therapy-naive HIV-1-infected patients in a phase II study. Bioavailability of lopinavir administered in either the capsule or the liquid lopinavir/ritonavir formulation can be increased substantially with concurrent ingestion of food with moderate-to-high fat content. At steady state, lopinavir is approximately 98-99% plasma protein bound and the percentage of its unbound (i.e. pharmacologically active) fraction is dependent on total drug plasma concentration. Both lopinavir and ritonavir penetrate poorly into the human genital tracts and the cerebrospinal fluid. Both agents undergo extensive and rapid first-pass metabolism by hepatic cytochrome P450 (CYP) 3A4 isoenzyme. However, ritonavir also potently inhibits this enzyme and acts as a pharmacokinetic enhancer of lopinavir. The elimination half-life and apparent oral clearance of lopinavir average approximately 4-6 hours and approximately 6-7 L/h, respectively, with lopinavir/ritonavir 400/100mg twice daily administration. Less than 3% and 20% of the lopinavir dose is excreted unchanged in the urine and faeces, respectively. Limited data show similar pharmacokinetics of lopinavir in children as in adults. DRUG INTERACTIONS: Coformulated lopinavir/ritonavir has the potential to interact with wide variety of drugs via several mechanisms, mostly involving the CYP enzymes. Coadministration of lopinavir/ritonavir is contraindicated with certain drugs (i.e. flecainide, propafenone, astemizole, terfenadine, ergot derivatives, cisapride, pimozide, midazolam and triazolam) that are highly dependent on CYP3A or CYP2D6 for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events. Coadministration with lopinavir/ritonavir is also not recommended for drugs or herbal products (i.e. rifampicin [rifampin] and St. John's wort [Hypericum perforatum]) that may substantially reduce lopinavir plasma concentrations, or drugs whose plasma concentrations elevated by the coformulation may lead to serious adverse reactions (i.e. simvastatin and lovastatin). However, a recent study in healthy volunteers suggests that adequate lopinavir concentrations may be achieved during rifampicin coadministration by increasing the twice-daily dosage of lopinavir/ritonavir in conjunction with therapeutic drug monitoring. The liquid (but not the capsule) formulation of lopinavir/ritonavir contains 42.4% ethanol (v/v) and should not be coadministered with drugs capable of producing disulfiram-like reactions (e.g. disulfiram, metronidazole). Coadministration with saquinavir or indinavir requires no dosage adjustment, whereas coadministration with amprenavir, nevirapine or efavirenz requires a dosage increase of the coformulation typically by 33%. As the oral bioavailability of both didanosine and lopinavir/ritonavir is significantly affected by concurrent food ingestion, didanosine should be administered 1 hour before or 2 hours after lopinavir/ritonavir has been taken with food. Interactions between lopinavir/ritonavir and other nucleoside reverse transcriptase inhibitors (NRTIs) are not expected. The coformulation is also likely to increase plasma concentrations of non-antiretroviral drugs metabolised through the CYP3A pathway. To reduce the risk of their toxicity when coadministered with lopinavir/ritonavir, the recommended actions include: (i) monitoring of the drug plasma concentration (antiarrhythmics and immunosuppressants) or the international normalised ratio (warfarin); (ii) the use of alternative treatment (atorvastatin) or birth control methods (ethinylestradiol); and (iii) dosage adjustment (clarithromycin [only in patients with renal failure], rifabutin, dihydropyridine calcium-channel blockers, atorvastatin, ketoconazole and itraconazole). (ABSTRACT TRUNCATED)

Clinical Trials as Topic↗

PubMed2003

Panipenem/betamipron.

Panipenem is a parenteral carbapenem antibacterial agent with a broad spectrum of in vitro activity covering a wide range of Gram-negative and Gram-positive aerobic and anaerobic bacteria, including Streptococcus pneumoniae and species producing beta-lactamases. Panipenem is coadministered with betamipron to inhibit panipenem uptake into the renal tubule and prevent nephrotoxicity. In large, randomised clinical trials, panipenem/betamipron demonstrated good clinical and bacteriological efficacy (similar to that of imipenem/cilastatin) in adults with respiratory tract or urinary tract infections. Panipenem/betamipron was also effective in adults with surgical or gynaecological infections, and in paediatric patients with respiratory tract and urinary tract infections in noncomparative trials. In small trials in elderly patients reported as abstracts, panipenem/betamipron demonstrated clinical efficacy similar to intravenous piperacillin and greater than oral ofloxacin in urinary tract infections. Elderly patients with respiratory tract infections also responded to therapy. Panipenem/betamipron is well tolerated with few adverse events reported in clinical trials, most commonly elevated serum levels of hepatic transaminases and eosinophils, rash and diarrhoea.

Adult↗

PubMed2003

Pranlukast: a review of its use in the management of asthma.

UNLABELLED: Pranlukast (Onon, Azlaire), is an orally administered, selective, competitive antagonist of the cysteinyl leukotrienes (LT) C(4), LTD(4) and LTE(4). It is indicated for the prophylactic treatment of chronic bronchial asthma in paediatric and adult patients. The efficacy of pranlukast 225mg twice daily in adults with mild to moderate asthma was demonstrated in double-blind, placebo- or azelastine-controlled studies of 4 or 8 weeks' duration. The drug at this dosage was superior to both comparators in improving mean attack scores and morning and/or evening peak expiratory flow rates, and decreasing the use of rescue bronchodilators (p < 0.05). In limited clinical studies, pranlukast 225mg twice daily appeared to be as effective as montelukast 10mg once daily and zafirlukast 40mg twice daily in adults with mild to moderate asthma. Tachyphylaxis was absent when the drug was administered for up to 4 years. In patients requiring high-dose inhaled corticosteroid therapy, pranlukast 225 mg twice daily plus a halved dosage of inhaled corticosteroid was as effective as the original dosage of inhaled corticosteroid. Pranlukast was also effective in patients with mild to severe asthma in a clinical practice setting. In a double-blind trial, greater improvements in most outcome measures were observed with pranlukast than with oxatomide in children and adolescents with asthma. In clinical trials, pranlukast was well tolerated in adult and paediatric patients with asthma, with an adverse event profile similar to that of placebo. Gastrointestinal events and hepatic function abnormalities were the most commonly reported adverse events. No clinically significant differences in adverse event profiles between pranlukast, zafirlukast or montelukast were shown in limited comparisons. Although Churg-Strauss syndrome has been noted in pranlukast recipients, a direct causal relationship is unlikely. CONCLUSIONS: Pranlukast is a well tolerated and effective preventative treatment in adult and paediatric patients with persistent asthma of all severities. In some patients, pranlukast may be beneficial when added to low-dose inhaled corticosteroids; it may also be a viable alternative to increasing inhaled corticosteroid dosages. The efficacy of pranlukast relative to placebo has been confirmed; its efficacy relative to other therapy awaits further investigation. Nonetheless, pranlukast is a useful therapeutic option (with as-required short-acting beta(2)-agonists), either as preventative monotherapy for the treatment of mild persistent asthma or in conjunction with inhaled corticosteroids in the management of moderate or severe persistent asthma.

Adolescent↗

PubMed2003

Darbepoetin alfa: in patients with chemotherapy-related anaemia.

Darbepoetin alfa, novel erythropoiesis stimulating protein closely related to human erythropoietin, has been developed for the treatment of chemotherapy-related anaemia in patients with non-myeloid malignancies. In three 12-week, phase II studies in patients with cancer and chemotherapy-related anaemia, subcutaneous darbepoetin alfa, administered in once-weekly or 2-, 3- or 4-weekly regimens, dose-dependently increased the mean haemoglobin levels. In a randomised, double-blind, phase III study in 320 patients with lung cancer and chemotherapy-related anaemia, recipients of subcutaneous darbepoetin alfa 2.25 micro g/kg once weekly, received red blood cell (RBC) transfusion approximate, equals 2-fold less frequently than placebo recipients (p < 0.001). In the same study, patients receiving darbepoetin alfa also received fewer standard units of RBC for transfusion and had greater haematopoietic response rate than placebo recipients (both p < 0.001). Subcutaneous darbepoetin alfa 2.25 micro g/kg once weekly also reduced patient-reported fatigue (assessed by a quality-of-life questionnaire) [p = 0.019 vs placebo]. black triangle Darbepoetin alfa was generally well tolerated in clinical trials. The most frequent darbepoetin alfa-related adverse events were: body oedema, arthralgia and skin rash.

Anemia↗

PubMed2003

Abciximab: an updated review of its therapeutic use in patients with ischaemic heart disease undergoing percutaneous coronary revascularisation.

UNLABELLED: Abciximab (Reopro) is an antibody fragment that dose-dependently inhibits platelet aggregation and leucocyte adhesion by binding to the glycoprotein (GP) IIb/IIIa, vitronectin and Mac-1 receptors. Abciximab (0.25 mg/kg bolus plus infusion of 0.125 micro g/kg/min for 12 hours) showed greater efficacy than tirofiban in reducing the 30-day composite endpoint of death, nonfatal myocardial infarction (MI) or urgent target-vessel revascularisation in the randomised, double-blind TARGET study in patients scheduled for stent placement. In addition, the beneficial effects of treatment with abciximab previously observed in the randomised, multicentre, placebo-controlled EPILOG and EPISTENT studies have been maintained to 1 year, with a significantly reduced incidence of ischaemic complications relative to placebo consistently observed across a range of subgroups including age, sex, bodyweight and indication for revascularisation. The incidence of the composite endpoint was reduced in patients presenting with acute MI of <48 hours' duration in comparison with either fibrinolytic therapy or stenting alone in the randomised STOPAMI and ADMIRAL trials, primarily because of a reduced requirement for urgent repeat revascularisation and reduced incidence of mortality. In the randomised, nonblind, multicentre CADILLAC trial in patients with acute myocardial infarction (MI), stenting alone was superior to percutaneous transluminal coronary angioplasty (PTCA) and stenting alone was not inferior to PTCA plus abciximab. Recent large randomised, multicentre studies (ASSENT-3 and GUSTO-V) have shown higher efficacy (on various ischaemic endpoints) of abciximab in combination with either a reduced dose of tenecteplase or reteplase compared with the fibrinolytic drug alone. TIMI grade 3 flow rates at 60 and 90 minutes in the TIMI-14 and SPEED trials were higher in patients who received abciximab in combination with either alteplase or reteplase than abciximab alone and were similar to that seen with the full-dose fibrinolytic alone. In the randomised, multicentre GUSTO IV-ACS study, no significant differences in any of the ischaemic endpoints at either 7 or 30 days in patients with acute coronary syndromes who were not scheduled to undergo early revascularisation (within 12 hours of end of infusion) were apparent between those who received abciximab (bolus and either 24- or 48-hour infusion) and those who received placebo in addition to aspirin and heparin. The most common adverse events associated with the use of abciximab are bleeding complications and thrombocytopenia, although the risk of major bleeding can be limited through adhering to current administration protocols. Treatment costs are generally higher in both stent plus abciximab and angioplasty plus abciximab groups than stent plus placebo, primarily because of the acquisition cost of abciximab. Abciximab appeared most cost beneficial in high-risk patients undergoing elective percutaneous coronary revascularisation; among lower risk patients, abciximab therapy has been associated with higher total in-hospital and 6-month medical costs than eptifibatide. CONCLUSION: The GP IIb/IIIa receptor antagonist abciximab, when used with aspirin and heparin, has demonstrated efficacy in reducing the short- and long-term risk of ischaemic complications in patients with ischaemic heart disease undergoing percutaneous coronary intervention, when used with aspirin and heparin. High-risk patients (including those with diabetes mellitus) derive particular benefits from abciximab treatment. Abciximab remains an important therapeutic option for the prevention of complications in patients with ischaemic heart disease.

Abciximab↗

PubMed2003

Reduced-antigen combined diphtheria-tetanus-acellular pertussis vaccine (Boostrix).

The reduced-antigen combined diphtheria-tetanus-acellular pertussis vaccine (dTpa) is intended for use as a booster dose in individuals aged > or =4 years. A single dose of dTpa elicited generally similar levels of antibodies against pertussis antigens (pertussis toxoid [PT], filamentous haemagglutinin [FHA] and pertactin [PRN]) as a similar monovalent pertussis booster vaccine (ap) in adolescents or adults, irrespective of their prevaccination serological status or vaccination history. Levels of antibodies directed against diphtheria toxoid were similar in recipients of dTpa or a licensed reduced-antigen combined diphtheria-tetanus booster vaccine (Td). However, levels of antitetanus antibodies were significantly higher in recipients of Td vaccines compared with those receiving dTpa. Similar serological response rates were observed for anti-PT, -FHA and -PRN between those receiving dTpa or ap and a similar high percentage of recipients of dTpa and the Td vaccines had seroprotective levels of antibodies against diphtheria and tetanus toxoid. The most frequently reported local adverse reactions following immunisation with dTpa included pain, redness and swelling; general symptoms included fatigue, headache and fever.

Clinical Trials as Topic↗

PubMed2003

Desloratadine: an update of its efficacy in the management of allergic disorders.

UNLABELLED: Desloratadine (Clarinex, Neoclarityn, Aerius, Azomyr, Opulis, Allex), the principal metabolite of loratadine, is itself an orally active, nonsedating, peripheral histamine H(1)-receptor antagonist. It is indicated in the US and Europe for the treatment of seasonal allergic rhinitis (SAR), perennial allergic rhinitis (PAR) and chronic idiopathic urticaria (CIU). It has a rapid onset of effect, efficacy throughout a 24-hour dosage interval, and sustained efficacy in these allergic conditions, as demonstrated in placebo-controlled trials of up to 6 weeks' duration in adult and adolescent patients. At present, there are no published direct comparisons of desloratadine and other H(1)-antihistamines; however, the principal, potential clinical advantages of desloratadine over late-generation H(1)-antihistamines are the drug's decongestant activity, which has been corroborated in several studies of patients with allergic rhinitis, and its anti-inflammatory effects. Indeed, the decongestant activity of desloratadine did not differ from that of pseudoephedrine in a trial in patients with SAR, and in patients with SAR and coexisting asthma, desloratadine reduced asthma symptoms and beta(2)-agonist use, and improved forced expiratory flow in 1 second. However, these issues warrant further study. Desloratadine is generally well tolerated. The overall incidence of adverse events in adults, adolescents and children was not significantly different to that with placebo, and similar proportions of desloratadine or placebo recipients reported events such as pharyngitis, dry mouth, myalgia, somnolence, dysmenorrhoea or fatigue. Desloratadine does not cause sedation or prolong the corrected QT (QTc) interval, can be administered without regard to concurrent intake of food and grapefruit juice, and appears to have negligible potential for drug interactions mediated by several metabolic systems. CONCLUSION: Although comparative studies with second-generation and other recently developed H(1)-antihistamines are needed to define the drug's clinical profile more clearly, desloratadine can be expected to claim a prominent place in the management of allergic disorders in general, and in the amelioration of specific symptoms of allergy (e.g. nasal congestion) in patients with such disorders.

Animals↗

PubMed2003

Measles, mumps, rubella vaccine (Priorix; GSK-MMR): a review of its use in the prevention of measles, mumps and rubella.

GSK-MMR (Priorix) is a trivalent live attenuated measles, mumps and rubella (MMR) vaccine which contains the Schwarz measles, the RIT 4385 mumps (derived from the Jeryl Lynn mumps strain) and the Wistar RA 27/3 rubella strains. GSK-MMR as a primary vaccination demonstrated high immunogenicity in clinical trials in >7500 infants aged 9-27 months, and was as immunogenic as Merck-MMR (MMR II). However, antimumps seroconversion rates and geometric mean titres (GMTs) were significantly higher in infants receiving GSK-MMR compared with Berna-MMR (Triviraten trade mark ) recipients. Coadministration of GSK-MMR with a varicella vaccine (Varilrix; GSK-MMR/V) did not significantly affect the immunogenicity of GSK-MMR. A persistent immune response to GSK-MMR has been demonstrated in follow-up data from several randomised trials. GMTs for measles, mumps and rubella antibodies remained high in GSK-MMR recipients 1-2 years post-vaccination and were similar to those in Merck-MMR recipients. The immunogenicity of GSK-MMR was high, and similar to that of Merck-MMR, when used as a second dose in children aged 4-6 or 11-12 years who had received a primary vaccination with Merck-MMR in their second year of life. Although there are no protective efficacy data concerning the GSK-MMR vaccine to date, the rubella Wistar RA 27/3 rubella and Schwarz measles strains have well established protective efficacy; the new RIT 4385 mumps strain is expected to afford similar protection from mumps to that achieved with mumps vaccines that contain the Jeryl Lynn mumps strain (e.g. Merck-MMR). GSK-MMR was well tolerated as a primary or secondary vaccination, and in most clinical studies comparing GSK-MMR with Merck-MMR as a primary vaccination in infants, GSK-MMR was associated with significantly fewer local adverse events (e.g. pain, swelling and redness). The incidence of local adverse events with GSK-MMR, GSK-MMR/V or Berna-MMR was similar. GSK-MMR and Merck-MMR were associated with similar rates of fever, rash and parotid gland swelling, but Berna-MMR was associated with a lower incidence of fever. In conclusion, GSK-MMR is a highly immunogenic MMR vaccine with good tolerability. In clinical trials, the immunogenicity of GSK-MMR was similar to that of Merck-MMR, and the mumps component was more effective at eliciting seroprotection than that of Berna-MMR. Furthermore, GSK-MMR causes fewer injection-site adverse events than Merck-MMR. As such, GSK-MMR is an attractive alternative for immunisation against measles, mumps and rubella.

Child↗

PubMed2003

Oxaliplatin: a review of its use in combination therapy for advanced metastatic colorectal cancer.

UNLABELLED: Oxaliplatin (Eloxatin) is the only platinum compound to show clinical activity in colorectal cancer. The efficacy of a combination of oxaliplatin with various schedules of fluorouracil (5-FU)/folinic acid (FA) as first- or second-line treatment for advanced metastatic colorectal cancer has been investigated in large phase III trials. FOLFOX4 (an oxaliplatin/5-FU/FA regimen) as first-line therapy (n = 795) was superior to irinotecan/5-FU/FA (IFL). Response rates were 45% vs 31%, and median progression-free survival duration was 8.7 vs 6.9 months. The survival advantage shown by FOLFOX4 over the irinotecan combination (median survival duration 19.5 vs 14.8 months) may be confounded by differences in post-study treatment but equivalent efficacy is supported by another phase III trial of oxaliplatin and irinotecan combinations. As first-line therapy, oxaliplatin added to various 5-FU/FA regimens more than doubled the response rates from 16-22.6% to 48.3-53% and the median duration of progression-free survival was significantly longer with oxaliplatin/5-FU/FA than 5-FU/FA alone (7.9-9 versus 5.3-6.2 months, respectively). In disease resistant to irinotecan-based therapies, the oxaliplatin (FOLFOX4) regimen had superior efficacy to 5-FU/FA alone in a pivotal phase III trial (n = 816). Response rates and median durations of progression-free survival were 9.6% vs 0.7% and 5.6 vs 2.6 months, respectively. An oxaliplatin-induced cumulative peripheral sensory neuropathy (evident when total dose reaches approximate, equals 800 mg/m(2)) is dose limiting. The most frequently occurring grade 3 or 4 toxicities in oxaliplatin/5-FU/FA-recipients were neutropenia (up to 48%) and neurological toxicities (up to 18%). Gastrointestinal effects (diarrhoea [ approximate, equals 12%], nausea, vomiting, or mucositis/stomatitis [up to 6%]) are manageable. Withdrawals from oxaliplatin treatment were due to neuropathy (up to 10%), diarrhoea and/or vomiting (1%) or cutaneous toxicity (1%). CONCLUSION: As first-line therapy for metastatic colorectal cancer, oxaliplatin with 5-FU/FA consistently improves response rates and progression-free survival compared with various regimens of 5-FU/FA alone. The significant survival advantage shown by oxaliplatin/5-FU/FA (FOLFOX4) compared with first-line therapy with irinotecan/5-FU/FA (IFL) is encouraging but may require further confirmation. Oxaliplatin/5-FU/FA produces a significantly higher response rate and longer progression-free survival than 5-FU/FA in patients failing irinotecan-based therapies, and as such is also a useful second-line treatment. Although cumulative neurotoxicity is dose limiting, oxaliplatin has a manageable tolerability profile. Oxaliplatin as first- or second-line therapy is a valuable addition to the limited, but expanding, armamentarium of cytotoxic agents useful in advanced metastatic colorectal cancer.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2003

Escitalopram : a review of its use in the management of major depressive and anxiety disorders.

UNLABELLED: Escitalopram is the therapeutically active S-enantiomer of RS-citalopram, a commonly prescribed SSRI. The R-enantiomer is essentially pharmacologically inactive. Escitalopram 10 or 20 mg/day produced significantly greater improvements in standard measurements of antidepressant effect (Montgomery-Asberg Depression Rating Scale [MADRS], Clinical Global Impressions Improvement and Severity scales [CGI-I and CGI-S] and Hamilton Rating Scale for Depression [HAM-D]) in patients with major depressive disorder (MDD) than placebo in several 8-week, placebo-controlled, randomised, double-blind, multicentre studies. Symptom improvement was rapid, with some parameters improving within 1-2 weeks of starting escitalopram treatment. In addition, escitalopram showed earlier and clearer separation from placebo than RS-citalopram, at one-quarter to half the dosage, in 8-week, placebo-controlled trials; had significantly better efficacy than RS-citalopram in a subgroup of patients with moderate MDD in a 24-week trial; and produced sustained response and remission significantly faster than venlafaxine extended release in patients with MDD. Escitalopram reduced relapse rate compared with placebo and increased the percentage of patients in remission in long-term trials (up to 52 weeks). Consistently significant improvements for all efficacy parameters were also observed in patients with generalised anxiety disorder, social anxiety disorder and panic disorder treated with escitalopram for 8-12 weeks in individual, randomised, placebo-controlled, double-blind investigations. The good tolerability profile of escitalopram is predictable and similar to that of RS-citalopram. Such adverse events as nausea, ejaculatory problems, diarrhoea and insomnia are expected but, with the exception of ejaculatory problems and nausea, which is mild and transient, these were generally no more frequent than with placebo in fully published clinical trials. No adverse events not previously seen in acute trials were reported with long-term use. CONCLUSIONS: Escitalopram, the S-enantiomer of RS-citalopram, is a highly selective inhibitor for the serotonin transporter, ameliorates depressive symptoms in patients with MDD at half the RS-citalopram dosage, has a rapid onset of symptom improvement and has a predictable tolerability profile of generally mild adverse events. Like RS-citalopram, escitalopram is expected to have a low propensity for drug interactions, a potential benefit in the management of patients with comorbidities. In combination, these properties place escitalopram, like other SSRIs, as first-line therapy in patients with MDD. Escitalopram is indicated for use in patients with panic disorder in Europe and, should further evidence confirm early findings that escitalopram reduces anxiety, the drug may well find an additional role in the management of anxiety disorders.

Animals↗

PubMed2003

Terbinafine: a review of its use in onychomycosis in adults.

UNLABELLED: Terbinafine, an orally and topically active antimycotic agent, inhibits the biosynthesis of the principal sterol in fungi, ergosterol, at the level of squalene epoxidase. Squalene epoxidase inhibition results in ergosterol-depleted fungal cell membranes (fungistatic effect) and the toxic accumulation of intracellular squalene (fungicidal effect). Terbinafine has demonstrated excellent fungicidal activity against the dermatophytes and variable activity against yeasts and non-dermatophyte molds in vitro. Following oral administration, terbinafine is rapidly absorbed and widely distributed to body tissues including the poorly perfused nail matrix. Nail terbinafine concentrations are detected within 1 week after starting therapy and persist for at least 30 weeks after the completion of treatment. Randomized, double-blind trials showed oral terbinafine 250 mg/day for 12 or 16 weeks was more efficacious than itraconazole, fluconazole and griseofulvin in dermatophyte onychomycosis of the toenails. In particular, at 72 weeks' follow-up, the multicenter, multinational, L.I.ON. (Lamisil vs Itraconazole in ONychomycosis) study found that mycologic cure rates (76 vs 38% of patients after 12 weeks' treatment; 81 vs 49% of recipients after 16 weeks' therapy) and complete cure rates were approximately twice as high after terbinafine treatment than after itraconazole (3 or 4 cycles of 400 mg/day for 1 week repeated every 4 weeks) in patients with toenail mycosis. Furthermore, the L.I.ON. Icelandic Extension study demonstrated that terbinafine was more clinically effective than intermittent itraconazole to a statistically significant extent at 5-year follow-up. Terbinafine produced a superior complete cure rate (35 vs 14%), mycologic cure rate (46 vs 13%) and clinical cure rate (42 vs 18%) to that of itraconazole. The mycologic and clinical relapse rates were 23% and 21% in the terbinafine group, respectively, compared with 53% and 48% in the itraconazole group. In comparative clinical trials, oral terbinafine had a better tolerability profile than griseofulvin and a comparable profile to that of itraconazole or fluconazole. Post marketing surveillance confirmed terbinafine's good tolerability profile. Adverse events were experienced by 10.5% of terbinafine recipients, with gastrointestinal complaints being the most common. Unlike the azoles, terbinafine has a low potential for drug-drug interactions. Most pharmacoeconomic evaluations have shown that the greater clinical effectiveness of oral terbinafine in dermatophyte onychomycosis translates into a cost-effectiveness ratio superior to that of itraconazole, fluconazole and griseofulvin. CONCLUSION: Oral terbinafine has demonstrated greater effectiveness than itraconazole, fluconazole and griseofulvin in randomized trials involving patients with onychomycosis caused by dermatophytes. The drug is generally well tolerated and has a low potential for drug interactions. Therefore, terbinafine is the treatment of choice for dermatophyte onychomycosis.

Antifungal Agents↗

PubMed2003

Linezolid: in infants and children with severe Gram-positive infections.

Linezolid is an oxazolidinone antibacterial agent that has inhibitory activity against a broad range of Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, and penicillin-resistant Streptococcus pneumoniae. The systemic clearance and, therefore, the area under the plasma concentration-time curve and elimination half-life of linezolid change with increasing age in pediatric patients. With the exception of pre-term neonates aged <1 week, systemic clearance is more rapid in pediatric patients aged 0-11 years than in adolescents. The pharmacokinetic profile of linezolid is similar in adolescents and adults. Linezolid was as effective as vancomycin in the treatment of pediatric patients with Gram-positive infections (clinical cure rate 89.3% vs 84.5%), and as effective as cefadroxil in the treatment of children and adolescents with Gram-positive uncomplicated skin and skin structure infections (91.0% vs 90.0%) in the clinically evaluable population of two randomized, comparator-controlled trials. The clinical cure rate with linezolid was 92.4% in a noncomparative trial in hospitalized pediatric patients with community-acquired pneumonia. All patients with proven pneumococcal pneumonia were considered cured. Linezolid is generally well tolerated. The most common drug-related adverse events in the comparator-controlled trials were diarrhea, nausea, and headache; most events were mild to moderate in severity.

Acetamides↗