Gabapentin. A review of its pharmacological properties and clinical potential in epilepsy.

Gabapentin is an antiepileptic drug with an unknown mechanism of action apparently dissimilar to that of other antiepileptic agents, and possessing some desirable pharmacokinetic traits. The drug is not protein bound, is not metabolised and does not induce liver enzymes, diminishing the likelihood of drug interactions with other antiepileptic agents and drugs such as oral contraceptives. Although gabapentin is a structural analogue of the neurotransmitter gamma-aminobutyric acid (GABA), which does not cross the blood-brain barrier, gabapentin penetrates into the CNS and its activity is seemingly distinct from GABA-related effects. Present clinical evaluation is largely restricted to proof of efficacy trials of gabapentin as add-on therapy in patients with partial epilepsy resistant to conventional treatment. Gabapentin (usually 600 to 1800 mg/day) provides notable benefit, reducing seizure frequency by > or = 50% in 18 to 28% of patients with refractory partial seizures, as shown in 3 double-blind, placebo-controlled trials. Overall, seizure frequency decreased by 18 to 32% during 3-month treatment periods. Patients with complex partial seizures, and partial seizures secondarily generalised, are particularly likely to respond to gabapentin. Current experience with the drug in other seizure types, and as monotherapy, is limited. Mild adverse events, commonly somnolence, fatigue, ataxia and dizziness, have been reported in about 75% of gabapentin recipients. While the drug has been well tolerated when administered to a few patients for periods of up to 5 years, its long term tolerability profile has yet to be fully expounded. Thus, with its favourable pharmacokinetic profile, and efficacy in some refractory patients, gabapentin is poised to fill a niche as an adjunct to the treatment of partial epilepsy. Promising results obtained thus far warrant further work to clarify its long term tolerability, its possible efficacy in other seizure types, its position relative to other agents and its use as monotherapy. In the meantime, gabapentin is likely to provide a much-needed option in a therapeutic area requiring complex management.

Propiram. A review of its pharmacodynamic and pharmacokinetic properties, and clinical use as an analgesic.

Propiram is an orally administered opioid analgesic with partial morphine-like agonist and weak antagonist properties. Analgesic efficacy of propiram, usually 50 or 100mg, appears comparable to that of standard dosages of other oral opioid drugs [i.e. pentazocine, pethidine (meperidine)] in patients with acute pain of moderate to severe intensity arising from various gynaecological and surgical procedures, and may be superior to codeine in gynaecological and postoperative dental pain. Some evidence of a more rapid onset of action for propiram than for these opioid agents, and a longer duration of action for propiram than for codeine, is encouraging but remains to be substantiated in more extensive clinical use. The tolerability profile of propiram resembles those of others in its class, with drowsiness, nausea and vomiting, and dizziness experienced most frequently in controlled trials. The apparently low propensity of propiram for development of physical dependence and psychotomimetic effects requires confirmation with wider clinical experience. Available data thus indicate that propiram is an effective, orally administered opioid analgesic suitable for providing relief of acute moderate to severe pain arising from various surgical or gynaecological procedures, and that the drug is likely to become a useful alternative in such conditions where opioid analgesia is appropriate.

Miglustat.

Miglustat is an orally administered ceramide glucosyltransferase inhibitor which prevents the lysosomal accumulation of glucocerebroside that occurs in patients with Gaucher's disease. In noncomparative trials in patients with type 1 Gaucher's disease, miglustat (50 or 100mg three times daily) for 6-12 months significantly reduced baseline liver and spleen volumes. At both 6 and 12 months, the reductions in organ volumes were greater with the higher dosage. Miglustat 50 or 100mg three times daily for 6-12 months had no significant effect on haemoglobin concentrations. Baseline platelet counts were not significantly improved by either dosage at 6 months, although the higher dosage significantly increased platelet counts at 12 months. In an open extension phase, patients continued to show further reductions in organ volume as well as significant improvements in haematological parameters at 24 and 36 months. black triangle In a 6-month randomised study in patients with type 1 Gaucher's disease who had previously received long-term enzyme replacement therapy (ERT), liver volume reduction was greater with miglustat plus ERT than with ERT alone. Diarrhoea and weight loss were the most frequent adverse events associated with miglustat therapy. Fine tremor has been reported in approximately 30% of miglustat-treated patients.

Levofloxacin: a review of its use in the treatment of bacterial infections in the United States.

UNLABELLED: Levofloxacin (Levaquin) is a fluoroquinolone antibacterial agent with a broad spectrum of activity against Gram-positive and Gram-negative bacteria and atypical respiratory pathogens. It is active against both penicillin-susceptible and penicillin-resistant Streptococcus pneumoniae. The prevalence of S. pneumoniae resistance to levofloxacin is <1% overall in the US.A number of randomised comparative trials in the US have demonstrated the efficacy of levofloxacin in the treatment of infections of the respiratory tract, genitourinary tract, skin and skin structures. Sequential intravenous to oral levofloxacin 750mg once daily for 7-14 days was as effective in the treatment of nosocomial pneumonia as intravenous imipenem/cilastatin 500-1000mg every 6-8 hours followed by oral ciprofloxacin 750mg twice daily in one study. In patients with mild to severe community-acquired pneumonia (CAP), intravenous and/or oral levofloxacin 500mg once daily for 7-14 days achieved clinical and bacteriological response rates similar to those with comparator agents, including amoxicillin/clavulanic acid, clarithromycin, azithromycin, ceftriaxone and/or cefuroxime axetil and gatifloxacin. A recent study indicates that intravenous or oral levofloxacin 750mg once daily for 5 days is as effective as 500mg once daily for 10 days, in the treatment of mild to severe CAP. Exacerbations of chronic bronchitis and acute maxillary sinusitis respond well to treatment with oral levofloxacin 500mg once daily for 7 and 10-14 days, respectively. Oral levofloxacin was as effective as ofloxacin in uncomplicated urinary tract infections and ciprofloxacin or lomefloxacin in complicated urinary tract infections. In men with chronic bacterial prostatitis treated for 28 days, oral levofloxacin 500mg once daily achieved similar clinical and bacteriological response rates to oral ciprofloxacin 500mg twice daily. Uncomplicated skin infections responded well to oral levofloxacin 500mg once daily for 7-10 days, while in complicated skin infections intravenous and/or oral levofloxacin 750mg for 7-14 days was at least as effective as intravenous ticarcillin/clavulanic acid (+/- switch to oral amoxicillin/clavulanic acid) administered for the same duration. Levofloxacin is generally well tolerated, with the most frequently reported adverse events being nausea and diarrhoea; in comparison with some other quinolones it has a low photosensitising potential and clinically significant cardiac and hepatic adverse events are rare. CONCLUSION: Levofloxacin is a broad-spectrum antibacterial agent with activity against a range of Gram-positive and Gram-negative bacteria and atypical organisms. It provides clinical and bacteriological efficacy in a range of infections, including those caused by both penicillin-susceptible and -resistant strains of S. pneumoniae. Levofloxacin is well tolerated, and is associated with few of the phototoxic, cardiac or hepatic adverse events seen with some other quinolones. It also has a pharmacokinetic profile that is compatible with once-daily administration and allows for sequential intravenous to oral therapy. The recent approvals in the US for use in the treatment of nosocomial pneumonia and chronic bacterial prostatitis, and the introduction of a short-course, high-dose regimen for use in CAP, further extend the role of levofloxacin in treating bacterial infections.

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.

Beraprost: a review of its pharmacology and therapeutic efficacy in the treatment of peripheral arterial disease and pulmonary arterial hypertension.

UNLABELLED: Beraprost sodium (beraprost) is a stable, orally active prostacyclin analogue with vasodilatory, antiplatelet and cytoprotective effects. Beraprost acts by binding to prostacyclin membrane receptors ultimately inhibiting the release of Ca2+ from intracellular storage sites. This reduction in the influx of Ca2+ has been postulated to cause relaxation of the smooth muscle cells and vasodilation. Data from a large, randomised, double-blind, multicentre study indicated that beraprost was as efficacious as ticlopidine in the treatment of patients with peripheral arterial disease (Buerger's disease and arteriosclerosis obliterans). Most patients receiving beraprost exhibited reduction of ulcer size, reported improvement of granulation appearance of the tissue and showed improvement of pain at rest and sensation of cold in the extremities. In a large pivotal clinical trial in patients with intermittent claudication, beraprost treatment was associated with statistically significant increases in pain-free and absolute walking distances compared with those in patients receiving placebo. Statistically significant differences in the incidence of critical cardiovascular events among both treatment groups were not observed but patients receiving beraprost were more likely to be satisfied with changes in their quality of life. However, while preliminary unpublished data from a large, phase III, placebo-controlled study in the US suggested a trend toward fewer critical cardiovascular events (no specific data presented), this study did not confirm the positive results from the European phase III trial and statistical significance was not achieved in the study's endpoints relating to exercise. A series of small, noncomparative clinical trials of patients with the rare condition of pulmonary arterial hypertension (PAH) demonstrated that substantial reductions of pulmonary arterial pressure and resistance, increase of cardiac output, and increase of exercise capacity appeared to be associated with beraprost therapy; however, these data are very limited and in most instances are not fully published. Beraprost is a well tolerated agent. Overall, the main adverse events include headache, hot flushes, diarrhoea and nausea. However, patients with PAH showed higher incidence of adverse events than those with peripheral arterial disease. CONCLUSION: Beraprost, an orally administered PGI2 analogue, is generally well tolerated and appears to be an effective agent in the treatment of patients with Buerger's disease and arteriosclerosis obliterans. Comparative data from a large randomised trial indicated that the drug appears as effective as ticlopidine in patients with these conditions. In patients with intermittent claudication, significant benefits of beraprost compared with placebo were reported in a randomised clinical trial; however, the use of beraprost in these patients is not supported by recent preliminary unpublished data from a large, phase III, placebo-controlled study. Limited data suggest some efficacy with long-term beraprost treatment of patients with PAH, where options are few and where oral administration of the drug could be a considerable advantage over intravenous prostacyclin (PGI2) therapy. Additional well-designed and, where possible, large trials with active comparators are necessary to define more precisely the place of beraprost in the treatment of patients with PAH, Buerger's disease and arteriosclerosis obliterans.

Fondaparinux sodium.

black triangle Fondaparinux sodium, a selective factor Xa inhibitor, is the first in a new class of antithrombotics. It binds selectively with high affinity to antithrombin III and specifically catalyses the inactivation of factor Xa. The elimination half-life of fondaparinux sodium permits once daily treatment. black triangle A randomised, double-blind, parallel-group, dose-ranging, multicentre phase IIb study in 933 eligible patients established that a subcutaneous dose of between 1.5 and 3mg of fondaparinux sodium has the optimum efficacy and safety profile for prophylaxis of venous thromboembolism in patients undergoing major orthopaedic surgery. black triangle Fondaparinux sodium, given to more than 3600 patients undergoing major orthopaedic surgery who participated in prospective, randomised, double-blind, multicentre phase III clinical trials, significantly reduced the incidence of venous thromboembolism, with an overall risk reduction of 55.2% compared with enoxaparin. black triangle Fondaparinux sodium was well tolerated by patients undergoing major orthopaedic surgery, and at the recommended clinical dose of 2.5mg has a similar tolerability profile, including bleeding events, to standard enoxaparin regimens. Fondaparinux sodium has not been reported to cause antibody-induced thrombocytopenia.

Enoxaparin: an update of its clinical use in the management of acute coronary syndromes.

UNLABELLED: Enoxaparin (enoxaparin sodium) is a low molecular weight heparin (LMWH) indicated for use in the treatment of ischaemic complications of unstable angina and non-Q wave myocardial infarction (MI). Unfractionated heparin (UFH) has for many years represented the standard in anticoagulant therapy for patients with acute coronary syndromes; however, recent studies suggest that enoxaparin is also a viable option for anticoagulant therapy in these patients. The ESSENCE (Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q wave Coronary Events) and the TIMI 11B (Thrombolysis in Myocardial Infarction) studies reported that twice daily enoxaparin was significantly more effective than a continuous infusion of UFH in reducing the composite triple endpoint of death, MI, or recurrent angina or urgent revascularisation. Follow-up of both patient populations showed continued benefit associated with enoxaparin. Enoxaparin has been compared with tinzaparin in the treatment of unstable coronary artery disease using a nonblind study design. There was no difference between treatment groups in the therapeutic endpoints. Three nonblind studies have also compared the effects of enoxaparin and UFH in patients receiving thrombolytic therapy following acute MI. The HART II (Heparin and Aspirin Reperfusion Therapy), the ASSENT 3 (Assessment of the Safety and Efficacy of a New Thrombolytic Regimen) and the ENTIRE-TIMI 23 (Enoxaparin and Tenecteplase with or without glycoprotein IIb/IIIa Inhibitor as Reperfusion strategy in ST Elevation MI - Thrombolysis in Myocardial Infarction) studies have revealed that enoxaparin in combination with alteplase or tenecteplase is at least equivalent (HART II and ENTIRE-TIMI 23), and possibly superior (ASSENT 3) to UFH. Enoxaparin is administered as a twice-daily subcutaneous injection. In contrast, UFH is administered as an intravenous infusion which requires routine monitoring of the activated partial thromboplastin time to ensure adequate levels of anticoagulation are maintained. During the acute phase of the the ESSENCE and TIMI 11B studies, the incidence of major bleeding was similar in patients receiving enoxaparin to that in patients receiving UFH. In contrast, the rates of minor bleeding were higher in patients receiving enoxaparin than in those receiving UFH throughout these studies. CONCLUSIONS: Data from the ESSENCE, TIMI 11B and ASSENT 3 studies have prompted calls for those LMWHs which have been shown to be superior to UFH, to be considered as first choice treatment for anticoagulation in unstable coronary syndromes. To date, these suggestions are not reflected in current guidelines which consider UFH and LMWHs equally. Irrespective, the clinical data reported in this review support the use of enoxaparin in the treatment of acute coronary syndromes. These data suggest that enoxaparin shows certain clinical and practical advantages over standard treatment with UFH and represents an important development in the treatment of acute coronary syndromes.

Tiotropium bromide.

Tiotropium bromide is an anticholinergic bronchodilator that antagonises muscarinic M(1), M(2) and M(3) receptors. It dissociates more slowly from M(1) receptors and, importantly, from M(3) receptors (which are located in bronchial smooth muscle) than from M(2) receptors and subsequently has a long duration of action permitting once-daily administration. In patients with chronic obstructive pulmonary disease (COPD), tiotropium 18microg once daily significantly improved lung function compared with placebo and ipratropium 40microg four times daily in 1-year trials or salmeterol 50microg twice daily in a 6-month study. The incidence of COPD exacerbations decreased and use of rescue medication was lower with tiotropium compared with placebo or ipratropium. There was no evidence of tachyphylaxis during 1-year treatment with tiotropium. Compared with placebo, salmeterol and ipratropium, tiotropium produced significant improvements in patients' perception of dyspnoea and health-related quality of life. Tiotropium is generally well tolerated; dry mouth is the most common drug-related adverse event, occurring in about 10 to 16% of patients in clinical trials.

Pegfilgrastim.

Pegfilgrastim is a covalent conjugant of filgrastim (a recombinant human granulocyte colony-stimulating factor) and monomethoxypolyethylene glycol. It is administered as a single dose per myelosuppressive chemotherapy cycle to decrease the incidence of infection, as manifest by febrile neutropenia, in patients with nonmyeloid cancer. Pegfilgrastim increases the terminal elimination half-life and decreases the apparent serum clearance of the drug in patients with nonmyeloid cancer. Serum concentrations of pegfilgrastim remain elevated during neutropenia but decline when the neutrophil count increases. In phase III trials in patients with breast cancer and in a phase II trial in patients with non-Hodgkin's lymphoma or Hodgkin's disease, the mean duration of grade 4 neutropenia and the time to absolute neutrophil recovery during cycle 1 of chemotherapy was similar in recipients of single-dose pegfilgrastim or daily filgrastim. In the larger of two phase III trials in patients with breast cancer, the incidence of febrile neutropenia over four cycles of chemotherapy was significantly lower in recipients of single-dose pegfilgrastim than that in recipients of daily injections of filgrastim. Moreover, the mean duration of grade 4 neutropenia in cycles 2 to 4 of chemotherapy was significantly lower in recipients of pegfilgrastim than that in recipients of daily filgrastim. In comparative trials, there were no differences in the incidence and severity of adverse events, including skeletal pain, between single-dose pegfilgrastim and daily filgrastim in patients with nonmyeloid cancer receiving myelosuppressive chemotherapy.

Stavudine once daily.

Stavudine administered once daily is a nucleoside analogue reverse transcriptase inhibitor. The efficacy (reduction in viral load and increase in CD4+ lymphocyte counts from baseline) of stavudine once daily-containing triple therapy was similar to that of stavudine immediate release (IR)-containing triple therapy in the treatment of antiretroviral-naive patients with HIV infection in two 48-week, randomised, double-blind trials. In the largest trial (n = 783), 80% of patients receiving stavudine 75 or 100mg once daily in combination with lamivudine 150mg twice daily and efavirenz 600mg once daily, and 75% of patients receiving stavudine IR 30 or 40mg twice daily-containing combination therapy, had HIV RNA levels reduced to below the limit of quantification at 48 weeks (<400 copies/ml; intent-to-treat analysis). These findings are supported by those from the smaller trial in 150 patients. Stavudine once daily triple therapy was well tolerated, with the incidence of adverse events being similar to that with stavudine IR. Grades 2-4 treatment related adverse events occurring in > or =3% of patients in either group were dizziness, rash, abnormal dream, headache, insomnia, fatigue and peripheral neurological symptoms. Peripheral neurological symptoms occurred in 3% of patients receiving long-term treatment with stavudine once daily and 6% of patients receiving stavudine IR in a combined analysis.

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

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.

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.

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)

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.

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.

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.

Bemiparin: a review of its use in the prevention of venous thromboembolism and treatment of deep vein thrombosis.

UNLABELLED: Bemiparin (bemiparin sodium; Hibor, Ivor, Zibor, Badyket) is a low molecular weight heparin (LMWH) with a lower mean molecular weight (3600 D) and a higher anti-Xa/IIa ratio (8:1) than other LMWHs. Bemiparin was effective as thromboprophylaxis in surgical patients in well controlled clinical trials. No cases of venous thromboembolism (VTE) were reported in low- to moderate-risk patients receiving prophylaxis with bemiparin 2500 anti-Xa IU/day for 7 days or unfractionated heparin (UFH) 5000 anti-Xa IU twice daily for 7 days. In high-risk patients, bemiparin 3500 anti-Xa IU/day for > or =8 days was more effective than UFH 5000 anti-Xa IU twice daily for > or =8 days in the prevention of VTE in patients undergoing total hip replacement. Postoperative bemiparin 3500 anti-Xa IU/day for 10 days was as effective as enoxaparin 4000 anti-Xa IU/day for 10 days commenced 12 hours before surgery in high-risk patients undergoing total knee replacement. As a short-term treatment for acute established deep vein thrombosis (DVT), bemiparin 5000-10 000 anti-Xa IU/day (dependent on bodyweight) for 7 or 10 days was more effective than intravenous UFH (5000 anti-Xa IU bolus followed by 30,000 or 40,000 anti-Xa IU/day for 7 days) in reducing thrombus size from baseline. Bemiparin 3500 anti-Xa IU/day was also as effective as oral warfarin (10 mg/day for the first 3 days, then adjusted to achieve an international normalised ratio between 2 and 3) for the long-term (12 weeks) treatment of DVT, although data are limited. Subcutaneous bemiparin was generally well tolerated. The most commonly reported adverse events in clinical trials were postoperative bleeding complications (similar incidence to that with UFH or enoxaparin in high-risk patients, lower incidence in low- to moderate-risk patients). CONCLUSIONS: Bemiparin is a new LMWH which has shown efficacy in a small number of well controlled trials in the prevention of postoperative VTE in low- to moderate- and high-risk patients and in the treatment of established DVT. It can be initiated pre- or post-operatively, whereas recommendations for other LMWHs in Europe primarily involve preoperative initiation. Additional comparative studies would be beneficial in determining the overall place of bemiparin, particularly with respect to the relative incidence of bleeding complications. In the meantime, available data suggest that bemiparin is an effective and useful addition to the available range of LMWHs for the prevention of VTE and treatment of DVT.

Budesonide (Entocort EC Capsules): a review of its therapeutic use in the management of active Crohn's disease in adults.

UNLABELLED: Budesonide (Entocort EC Capsules) is an oral corticosteroid with a high degree of topical activity and low systemic bioavailability (approximately 11%). This action is achieved by a high affinity for the glucocorticoid receptor and an extensive first-pass hepatic metabolism. The budesonide capsule has been formulated to dissolve in a pH dependent manner, delivering most of the drug to the ileum and ascending colon, areas of the intestine most commonly affected by Crohn's disease. In large (n > or = 176), well designed clinical trials of 10 to 12 weeks' duration in patients with active, mild to moderate Crohn's disease, budesonide (9 mg/day) was significantly more effective in inducing remission than placebo or mesalazine (mesalamine) slow release, and demonstrated similar efficacy to recommended dosages of prednisolone. Results of health-related quality-of-life assessments support clinical data, showing a significantly greater improvement among patients treated with budesonide than with placebo or mesalazine slow release. Oral budesonide was well tolerated in clinical trials of up to 16 weeks' duration. In these studies, the incidence of adverse events associated with budesonide (9 mg/day) was similar to that seen with placebo and mesalazine slow release. The rate of glucocorticoid-related adverse effects observed with budesonide was significantly less than that reported with prednisolone. CONCLUSION: Oral budesonide 9 mg/day offers efficacy that is superior to mesalazine slow release and placebo, and similar to prednisolone in the treatment of patients with active mild to moderate Crohn's disease involving the ileum and/or ascending colon. Budesonide is generally well tolerated and the incidence of adverse events is similar to that seen with placebo or mesalazine slow release. Glucocorticoid-related adverse effects are significantly less frequent during short-term therapy with budesonide than with prednisolone. Thus, for the medical management of patients with active mild to moderate Crohn's disease, oral budesonide has superior efficacy to mesalazine slow release and a more favourable tolerability profile than prednisolone.