Spotlight on VSL#3 probiotic mixture in chronic inflammatory bowel diseases.

VSL#3 (VSL#3) is a high-concentration probiotic preparation of eight live freeze-dried bacterial species that are normal components of the human gastrointestinal microflora, including four strains of lactobacilli (Lactobacillus casei, L. plantarum, L. acidophilus, and L. delbrueckii subsp. bulgaricus), three strains of bifidobacteria (Bifidobacterium longum, B. breve, and B. infantis), and Streptococcus salivarius subsp. thermophilus. Data from noncomparative trials suggest that VSL#3 has clinical potential in the treatment of active mild to moderate ulcerative colitis and as maintenance therapy for patients with ulcerative colitis in remission. In addition, a randomized, open-label, multicenter trial showed that VSL#3 in combination with low-dose balsalazide (a prodrug of mesalazine [mesalamine; 5-aminosalicylic acid]) was more effective than standard doses of basalazide or mesalazine monotherapy in the treatment of acute mild to moderate ulcerative colitis. Randomized, double-blind, placebo-controlled studies have shown VSL#3 is effective in preventing the onset of acute pouchitis in patients with newly formed surgical pouches, and in maintaining remission following antibacterial treatment of acute pouchitis in patients with a history of refractory or recurrent pouchitis. Treatment guidelines from the US and the UK include VSL#3 as a therapeutic option for the prevention of pouchitis relapse in patients with chronic pouchitis. In general, VSL#3 was well tolerated in clinical trials. Large, well designed, controlled confirmatory clinical trials will further determine the place of VSL#3 in the treatment of ulcerative colitis.

VSL#3 probiotic mixture: a review of its use in chronic inflammatory bowel diseases.

VSL#3 (VSL#3) is a high-concentration probiotic preparation of eight live freeze-dried bacterial species that are normal components of the human gastrointestinal microflora, including four strains of lactobacilli (Lactobacillus casei, L. plantarum, L. acidophilus and L. delbrueckii subsp. bulgaricus), three strains of bifidobacteria (Bifidobacterium longum, B. breve and B. infantis) and Streptococcus salivarius subsp. thermophilus. Data from noncomparative trials suggest that VSL#3 has clinical potential in the treatment of active mild to moderate ulcerative colitis and as maintenance therapy for patients with ulcerative colitis in remission. In addition, a randomised, open-label, multicentre trial showed that VSL#3 in combination with low-dose balsalazide (a prodrug of mesalazine [mesalamine; 5-aminosalicylic acid]) was more effective than standard doses of basalazide or mesalazine monotherapy in the treatment of acute mild to moderate ulcerative colitis. Randomised, double-blind, placebo-controlled studies have shown VSL#3 is effective in preventing the onset of acute pouchitis in patients with newly formed surgical pouches, and in maintaining remission following antibacterial treatment of acute pouchitis in patients with a history of refractory or recurrent pouchitis. Treatment guidelines from the US and the UK include VSL#3 as a therapeutic option for the prevention of pouchitis relapse in patients with chronic pouchitis. In general, VSL#3 was well tolerated in clinical trials. Large, well designed, controlled confirmatory clinical trials will further determine the place of VSL#3 in the treatment of ulcerative colitis.

Oxaliplatin: in operable colorectal cancer.

Oxaliplatin is available in numerous countries for the treatment of metastatic colorectal cancer (in conjunction with fluoropyrimidine therapy). The activity of oxaliplatin in advanced disease has led to investigation of its potential in operable disease. The addition of oxaliplatin to adjuvant therapy with fluorouracil and folinic acid (FOLFOX4 regimen) is associated with a significantly greater disease-free survival at 3 years (78% vs 73%; p = 0.002), according to results of the MOSAIC (Multicenter International Study of Oxaliplatin/5FU/Leucovorin [folinic acid] in the Adjuvant Treatment of Colon Cancer) trial, a study in 2246 patients with stage II or III colon cancer. In addition, a 23% reduction in the risk of disease recurrence after surgery was seen with FOLFOX4 compared with fluorouracil/folinic acid in the MOSAIC trial. Results from several phase I/II studies suggest that the addition of oxaliplatin to preoperative radiochemotherapy may be of benefit in patients with locally advanced lower rectal cancer in terms of disease downstaging and sphincter preservation. Oxaliplatin was generally well tolerated in the MOSAIC trial and neuro- and myelotoxicity with FOLFOX4 were manageable.

Pregabalin: as adjunctive treatment of partial seizures.

Pregabalin, the pharmacologically active S-enantiomer of 3-aminomethyl-5-methylhexanoic acid, possesses anticonvulsant activity. Pregabalin binds with high affinity and specificity to voltage-gated calcium channel alpha(2)-delta proteins. The putative mechanism of action of the drug is reduced excitatory neurotransmitter release caused by binding to the alpha(2)-delta protein, resulting in allosteric modulation of P/Q-type voltage-gated calcium channels. In three well designed trials, oral pregabalin as adjunctive therapy in patients with refractory partial seizures was significantly (p < or = 0.0007) more effective than placebo in reducing seizure frequency when administered at dosages of 150-600 mg/day (as two or three divided doses). Adjunctive pregabalin produced an overall mean 41.3% improvement from baseline in 28-day seizure-free rate in four long-term (maximum exposure 1764 days), open-label studies in 1480 patients. CNS-related effects (e.g. dizziness and somnolence) were the most frequent dose-related treatment-emergent adverse events associated with adjunctive pregabalin therapy.

Acamprosate: a review of its use in the maintenance of abstinence in patients with alcohol dependence.

Acamprosate (Campral delayed-release tablet), a synthetic compound with a similar structure to that of the neurotransmitter GABA and the neuromodulator taurine, facilitates the maintenance of abstinence in detoxified alcohol-dependent patients. Although the precise mechanism(s) of action of the drug remains to be fully elucidated, it appears that it most likely involves beneficial modulation of the glutamatergic neurotransmitter system, including antagonism of the mGLu5 metabotropic glutamate receptor, to counteract the imbalance between the glutamatergic and GABAergic systems associated with chronic alcohol exposure and alcohol withdrawal. In several double-blind, placebo-controlled trials of up to 12 months' duration, acamprosate effectively maintained complete abstinence in detoxified alcohol-dependent patients, irrespective of disease severity or the type of psychosocial support. The drug showed better efficacy than placebo and was very well tolerated. Limited data from a relatively well designed trial indicate that the drug has similar efficacy to that of naltrexone and that combination therapy with these two agents provides better efficacy than acamprosate monotherapy, although multicentre direct head-to-head investigations are required to fully establish the potential of this combination. The drug may be particularly useful in those with hepatic impairment and/or liver disease. Thus, in combination with psychosocial and behavioural management programmes, acamprosate is a promising option for the maintenance of abstinence in alcohol-dependent patients after alcohol withdrawal.

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

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

Bicalutamide: in early-stage prostate cancer.

Bicalutamide is an oral, once-daily nonsteroidal antiandrogen. Its efficacy in localised or locally advanced prostate cancer is currently being investigated as part of the Early Prostate Cancer (EPC) programme. In the EPC programme, bicalutamide 150 mg/day, as an adjunct to radiotherapy, radical prostatectomy or watchful waiting, significantly reduced the risk of objective disease progression, the incidence of bone metastases and the risk of prostate specific antigen progression compared with placebo (p < 0.0001 for all three parameters) after a median follow-up of 3 years. Survival data are currently immature, with an overall mortality rate of 6% in both treatment arms. On two nonblind, randomised trials, bicalutamide 150 mg/day monotherapy was as effective as medical or surgical castration in terms of overall survival in patients with locally advanced nonmetastatic prostate cancer. After a median follow-up of 6.3 years, median survival was 63.5 and 69.9 months for bicalutamide and castration, respectively; time to disease progression was also similar between treatment groups. Bicalutamide recipients reported a significantly smaller loss in sexual interest and a better physical capacity than recipients of castration (p

Combined two-dose hepatitis A and B vaccine (AmBirix).

One month after the last dose (i.e. at month 7), geometric mean titres (GMTs) of antibodies directed against hepatitis A virus (anti-HAV) were generally greater in participants (aged 12-15 years) receiving combined two-dose (0 and 6 months) hepatitis A and B vaccine (AmBirix) compared with the three-dose (containing one half the dose of the two active components per dose, given at 0, 1 and 6 months; Twinrix Paediatric) schedule. Moreover, at month 7 all patients had seroconverted to anti-HAV. GMTs of antibodies directed against hepatitis B surface antigen greatly exceeded the threshold for seroprotection (>/=10 mIU/mL) 1 month after the last dose of vaccine. Seroprotection rates against hepatitis B virus (HBV) were similar 1 month after completion of either a two- (97.9%) or three-dose (100%) vaccination schedule. At 24 months' follow-up, all patients tested remained positive for anti-HAV, and 93.3% and 96.2% of those treated with the two- and three-dose schedules, respectively, remained above the threshold for seroprotection against HBV. Administering the second dose in the two-dose series at 12 months rather than at 6 months did not compromise the immune response to the combined vaccine in adolescents aged 12-15 years in a randomised, multicentre trial. Local adverse events reported in the 4 days following administration of combined two-dose hepatitis A and B vaccine include pain or soreness, redness and swelling; systemic symptoms included headache, fatigue, gastrointestinal events and fever.

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

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

Oral fludarabine.

Fludarabine is an antimetabolite antineoplastic agent used in the treatment of various haematological malignancies, particularly B-cell chronic lymphocytic leukaemia (CLL). An oral formulation of fludarabine has recently become available in the majority of European countries for the treatment of patients with relapsed or refractory B-cell CLL after initial treatment with an alkylating agent-based regimen. It is the first oral formulation of a purine analogue available for clinical use in B-cell CLL. Pharmacokinetic studies evaluating the bioavailability of oral fludarabine indicate that an oral dose of 40 mg/m2/day would provide similar systemic drug exposure to the standard intravenous dose of 25 mg/m2/day. A phase II study evaluated the clinical efficacy of six to eight cycles of oral fludarabine 40 mg/m2/day for 5 days of each 28-day cycle in 78 patients with previously treated B-cell CLL. Depending on the criteria used, the overall response rate was 46.2% (20.5% complete response [CR], 25.6% partial response [PR]) or 51.3% (17.9% CR, 33.3% PR). These results were similar to the 48% overall response rate reported in a similar historical control group treated with intravenous fludarabine. Myelosuppression (WHO grade 3 or 4) was the most frequently reported adverse effect with oral fludarabine therapy. Other common adverse effects included infection and gastrointestinal disturbances, although these were usually of mild to moderate severity (WHO grade 1 or 2). Overall, the tolerability profile of oral fludarabine is similar to that of the intravenous formulation.

Intravenous esomeprazole.

The proton pump inhibitor esomeprazole comprises the S-isomer of omeprazole. An intravenous formulation of the drug has been developed for use in patients not able to take oral drugs. The level of gastric acid control was similar with intravenous and oral esomeprazole in two studies in healthy volunteers receiving 20 or 40 mg once daily for 5 days. In addition, a similar level of gastric acid control occurred with intravenous esomeprazole 40 mg administered by infusion or injection once daily for 10 days. In healthy volunteers, intravenous esomeprazole provided faster and more effective gastric acid control than intravenous pantoprazole (40 mg once daily for 5 days). In addition, control of basal and pentagastrin-stimulated gastric acid secretion was better with intravenous esomeprazole 40 mg than with intravenous omeprazole 40 mg (single-dose study). Healing rates at 4 weeks were approximate, equals 80% in a well designed study in patients with erosive oesophagitis (n = 246) who received esomeprazole 40 mg once daily intravenously (by injection or infusion) or orally. Intravenous therapy was administered for the first week, after which all patients received oral esomeprazole. Intravenous esomeprazole was generally well tolerated in patients with erosive oesophagitis, with a tolerability profile similar to that of the oral formulation.

Zoledronic acid: a review of its use in patients with advanced cancer.

Zoledronic acid (Zometa), a parenteral bisphosphonate, is an inhibitor of osteoclast-mediated bone resorption and is used in the management of patients with cancer. Zoledronic acid 4 mg is administered as an intravenous infusion over 15 minutes. In the treatment of bone metastases, zoledronic acid is the first and only bisphosphonate to demonstrate efficacy in patients with a broad range of tumour types and in multiple myeloma. In well-designed trials, a single 4 mg dose of zoledronic acid showed good efficacy in the treatment of patients with hypercalcaemia of malignancy. Zoledronic acid 4 mg was superior to pamidronic acid 90 mg, administered as a 2-hour infusion, as assessed by normalised serum calcium concentrations 10 days after administration. In conjunction with antineoplastic therapy, zoledronic acid was an effective long-term (up to 25 months) treatment for skeletal-related events in patients with bone metastases associated with multiple myeloma or solid tumours. In patients with bone metastases secondary to breast cancer or bone lesions from myeloma, zoledronic acid was at least as effective as pamidronic acid, based on assessments of skeletal-related events 25 months after the start of treatment. In addition, compared with pamidronic acid, the overall risk of developing skeletal complications, including hypercalcaemia of malignancy, was significantly reduced in recipients of zoledronic acid. Compared with pamidronic acid, zoledronic acid reduced the risk of patients with breast cancer developing a skeletal-related event by an additional 20%. Zoledronic acid was significantly more effective than placebo on most efficacy measures in patients with bone metastases secondary to other solid tumours (e.g. lung, prostate) and showed sustained efficacy for up to 15 months. Preliminary data indicate that its efficacy in these patients is sustained for up to 24 months. Estimates of the cost effectiveness of zoledronic acid in the treatment of prostate cancer were consistent with those of other bisphosphonates, and cost-effectiveness ratios were within limits considered acceptable economic value. Zoledronic acid was generally well tolerated, with a tolerability profile similar to that of pamidronic acid and placebo. As with other bisphosphonates, deterioration of renal function has occasionally been reported in patients receiving zoledronic acid and monitoring of serum creatinine is recommended during treatment. The efficacy of zoledronic acid is therefore well established in patients with hypercalcaemia of malignancy and, for up to 25 months, in the treatment of complications arising from metastatic bone disease in patients with multiple myeloma or solid tumours. The clinical profile of zoledronic acid compares favourably with that of pamidronic acid in patients with cancer and zoledronic acid has a more convenient administration schedule with the potential for better compliance. Thus, zoledronic acid is an effective bisphosphonate and is positioned to play an important role in the management of advanced cancer patients with bone metastases.

Botulinum toxin B: a review of its therapeutic potential in the management of cervical dystonia.

UNLABELLED: Botulinum toxins are well known as the causative agents of human botulism food poisoning. However, in the past two decades they have become an important therapeutic mainstay in the treatment of dystonias including cervical dystonia, a neurological disorder characterised by involuntary contractions of the cervical and/or shoulder muscles. The toxins inhibit acetylcholine release from neuromuscular junctions, producing muscle weakness when injected into dystonic muscles. Data from three double-blind, randomised, placebo-controlled trials demonstrate that botulinum toxin B effectively reduces the severity, disability and pain of cervical dystonia. In two of the trials, mean Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS)-Total score at week 4 (primary efficacy measure) after botulinum toxin B 10 000U was reduced by 11.7 (25%) or 11 (21%) compared with baseline. These changes were significantly greater than those obtained with placebo [4.3 (10%) or 2 (4%)] and were generally similar in patients who were responsive or resistant to botulinum toxin A. Statistically significant benefits compared with placebo were also evident for a range of other efficacy parameters including TWSTRS-Severity, -Pain and -Disability subscales, patient- assessed pain and patient-/physician-assessed global improvement ratings. In another trial, the percentage of patients with botulinum toxin A-resistant or -responsive cervical dystonia who had a > or =20% improvement in the TWSTRS-Total score between baseline and week 4 was significantly higher with botulinum toxin B 2500 to 10 000U (58 to 77%) than with placebo (27%). Overall, botulinum toxin B was generally well tolerated. The most frequently reported treatment-related adverse events were dry mouth and dysphagia. Most adverse events in patients receiving botulinum toxin B were mild or moderate; no serious adverse events or laboratory abnormalities were associated with the use of botulinum toxin B and, where reported, no patients discontinued from any of the clinical trials as a result of adverse events. CONCLUSIONS: Botulinum toxin B has shown clinical efficacy in patients with cervical dystonia at doses up to 10 000U and is generally well tolerated. Its efficacy extends to patients who are resistant to botulinum toxin A. Although the potential for secondary resistance to botulinum toxin B remains unclear, it may occur less than with botulinum toxin A because methods for manufacturing commercially available botulinum toxin B do not include lyophilisation and the product does not require reconstitution before use. As injection with botulinum toxin is generally considered the treatment of choice for patients with cervical dystonia, botulinum toxin B should be considered a potential treatment option in this setting.

Tipranavir.

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

Dexmethylphenidate.

Dexmethylphenidate comprises only the d-enantiomer (the pharmacologically effective isomer) of racemic methylphenidate and is indicated for the treatment of patients aged > or =6 years with attention deficit hyperactivity disorder (ADHD). In a 4-week, double-blind trial in 132 children with ADHD, significantly greater improvements from baseline in teacher-rated Swanson, Nolan and Pelham (SNAP)-ADHD scores were seen in dexmethylphenidate and methylphenidate recipients, compared with placebo recipients. In addition, significantly more dexmethylphenidate and methylphenidate recipients, compared with placebo recipients, were much improved or very much improved according to Clinical Global Impression-Improvement of Illness scale scores. In the same study, parent-rated SNAP-ADHD scores had decreased by a significantly greater extent in dexmethylphenidate recipients at 3pm and 6pm and in methylphenidate recipients at 3pm, compared with placebo recipients. Significantly fewer dexmethylphenidate than placebo recipients failed treatment in a double-blind, treatment-withdrawal trial in 75 children with ADHD (17.1 vs 61.5%). In a noncomparative study in 22 children with ADHD, symptoms of ADHD, as assessed by teachers and parents, were controlled during the entire school day in 68 and 86% of dexmethylphenidate recipients, respectively, with a median duration of effect of 6.3 and 7.5 hours, respectively. Dexmethylphenidate was generally well tolerated in children with ADHD; adverse events were consistent with those known to be associated with agents containing methylphenidate.

Combined hepatitis A and B vaccines: a review of their immunogenicity and tolerability.

UNLABELLED: Three combined hepatitis A and B vaccine preparations are commercially available in various countries: a two-dose paediatric formulation (Ambirix) [administered at months 0 and 6-12]; and a three-dose adult (Twinrix Adult) or paediatric (Twinrix Paediatric) formulation (administered at months 0, 1 and 6). The adult vaccine provides consistent, marked immunogenicity which is at least similar to that of its constituent vaccines used together and with a tolerability profile that is possibly improved. An accelerated, day-0, -7 and -21 regimen has also shown immunogenicity similar to that of the monovalent vaccines given concurrently, and now has an emerging role in adults likely to travel to hepatitis A virus (HAV) and/or hepatitis B virus (HBV) endemic regions within 1 month. The adult vaccine appears effective and generally well tolerated when given concurrently with monovalent typhoid vaccine (Typherix). Immunogenicity of the two-dose paediatric vaccine is high and appears to be similar whether administered as a month-0, -6 or month-0, -12 schedule and when compared to that of the three-dose paediatric vaccine (months 0, 1, 6), both of which provide a similar degree of protection to the adult vaccine. Although both preparations also provide high end-of-schedule seroprotection against hepatitis B surface antigen, protection between the first and second doses of the two-dose regimen appears lower than with the three-dose schedule. Therefore, the three-dose paediatric vaccine is a practical option in individuals at risk of immediate exposure to HBV, while the two-dose regimen may have an important function in immunisation programmes in regions where such risk is low. Combined hepatitis A and B vaccines are generally well tolerated. The most frequently reported adverse events in clinical trials were injection-site pain and redness, and general fatigue and headache; most events were mild and transient. Pharmacoeconomic models suggest the combined vaccine is cost effective compared with no vaccine (in children/adolescents) or monovalent hepatitis B vaccine (in children/adolescents and prison inmates). CONCLUSION: The three commercially available combined hepatitis A and B adult and paediatric vaccines are highly immunogenic and generally well tolerated; the adult vaccine demonstrates immunogenicity at least as marked as that of monovalent hepatitis A and B vaccines. While further research is required to confirm potential advantages such as improved cost effectiveness, the combined vaccines have established a key role in the prevention of hepatitis A and B in defined risk groups, and have an expanding role in population-based vaccination programmes with younger age groups.

Micafungin.

Micafungin, an echinocandin antifungal agent with a novel mechanism of action, inhibits beta-(1,3)-D-glucan synthase interfering with fungal cell wall synthesis. It shows excellent antifungal activity against a broad range of Candida spp., including azole-resistant strains, and Aspergillus spp. in in vitro and animal studies. In HIV-positive patients, intravenous micafungin 50-150 mg/day dose-dependently eradicated endoscopically confirmed oesophageal candidiasis, with micafungin 100 and 150 mg/day being more effective than micafungin 50 mg/day and as effective as fluconazole 200 mg/day in a double-blind trial. In nonblind trials, micafungin (monotherapy or combination therapy) was effective against invasive aspergillosis, candidiasis and candidaemia in paediatric and adult patients with newly diagnosed or refractory infections. Micafungin 50 mg/day provided significantly better antifungal prophylaxis than fluconazole 400 mg/day in 882 haematopoietic stem cell transplant recipients in a randomised, double-blind trial. Respective overall success rates were 80% and 73.5%. Micafungin is generally well tolerated. Adverse events were not dose- or infusion-related with micafungin 12.5-900 mg/day; no histamine-like reactions occurred. Micafungin was as well tolerated as fluconazole, with numerically fewer micafungin recipients discontinuing treatment (4.2% vs 7.2%).

Brivudin (bromovinyl deoxyuridine).

Brivudin is an oral thymidine analogue indicated for the early treatment of acute herpes zoster in immunocompetent adults. It has high, selective activity against varicella zoster virus (VZV), inhibiting VZV replication, possibly through competitive inhibition of viral DNA polymerase, or by acting as an alternative substrate to deoxythymidine triphosphate, causing viral DNA strand breakage. In a large, 7-day, phase III trial in immunocompetent patients with herpes zoster, once-daily brivudin 125mg was significantly more effective than oral acyclovir 800mg five times daily in reducing the mean time from start of treatment to last vesicular eruption, and was as effective as acyclovir at healing lesions and alleviating acute zoster-related pain. The likelihood of developing post-herpetic neuralgia (PHN) in immunocompetent patients aged > or =50 years was significantly lower with brivudin than with acyclovir. Brivudin was as effective as oral famciclovir 250mg three times daily in terms of the prevalence of PHN, the time to last vesicular eruption and lesion healing in another large, 7-day, phase III study in immunocompetent patients with herpes zoster. Oral brivudin is generally well tolerated, with a similar tolerability profile to those of oral acyclovir or famciclovir. Nausea was the most commonly reported adverse event.

Ceftriaxone: an update of its use in the management of community-acquired and nosocomial infections.

UNLABELLED: Ceftriaxone is a parenteral third-generation cephalosporin with a long elimination half-life which permits once-daily administration. It has good activity against Streptococcus pneumoniae, methicillin-susceptible staphylococci, Haemophilus influenzae, Moraxella catarrhalis and Neisseria spp. Although active against Enterobacteriaceae, the recent spread of derepressed mutants which hyperproduce chromosomal beta-lactamases and extended-spectrum beta-lactamases has diminished the activity of all third-generation cephalosporins against these pathogens necessitating careful attention to sensitivity studies. Extensive data from randomised clinical trials confirm the efficacy of ceftriaxone in serious and difficult-to-treat community-acquired infections including meningitis, pneumonia and nonresponsive acute otitis media. Ceftriaxone also has efficacy in other community-acquired infections including uncomplicated gonorrhoea, acute pyelonephritis and various infections in children. In the nosocomial setting, extensive data also confirm the efficacy of ceftriaxone with or without an aminoglycoside in serious Gram-negative infections, pneumonia, spontaneous bacterial peritonitis and as surgical prophylaxis. Outpatient use of ceftriaxone, either as part of a step-down regimen or parenterally, is a distinguishing feature of the data gathered on the agent over the last decade. The review focuses on new applications of the drug and its use in infections in which the causative pathogens or their resistance patterns have changed over the past decade. Ceftriaxone has a good tolerability profile, the most common events being diarrhoea, nausea, vomiting, candidiasis and rash. Ceftriaxone may cause reversible biliary pseudolithiasis, notably at higher dosages of the drug (>/=2 g/day); however, the incidence of true lithiasis is <0.1%. Injection site discomfort or phlebitis can occur after intramuscular or intravenous administration. CONCLUSIONS: As a result of its strong activity against S. pneumoniae, ceftriaxone holds an important place, either alone or as part of a combination regimen, in the treatment of invasive pneumococcal infections, including those with reduced beta-lactam susceptibility. Its once-daily administration schedule allows simplification of otherwise complex regimens in a hospital setting and has also contributed to its popularity as a parenteral agent in an ambulatory setting. These properties, together with a well characterised tolerability profile, mean that ceftriaxone is likely to retain its place as an important third-generation cephalosporin in the treatment of serious community-acquired and nosocomial infections.

Levofloxacin: an updated review of its use in the treatment of bacterial infections.

UNLABELLED: Levofloxacin is the L-form of the fluoroquinolone antibacterial agent, ofloxacin. In in vitro studies, levofloxacin demonstrated a broad range of activity against Gram-positive and -negative organisms and anaerobes. The drug is more active against Gram-positive organisms than ciprofloxacin, but less active than newer fluoroquinolones such as gatifloxacin. Its activity against Streptococcus pneumoniae is unaffected by the presence of penicillin resistance. In several randomised controlled trails, 5 to 14 days' treatment with intravenous and/or oral levofloxacin proved an effective therapy for upper and lower respiratory tract infections. In patients with mild to severe community-acquired pneumonia (CAP), intravenous and/or oral levofloxacin 500mg once or twice daily was as effective as intravenous and/or oral gatifloxacin, clarithromycin, azithromycin or amoxicillin/clavulanic acid. Overall, clinical response rates with levofloxacin ranged from 86 to 95% versus 88 to 96% with comparator agents; bacteriological response rates were 88 to 95% and 86 to 98%, respectively. Sequential (intravenous +/- oral switch) therapy with levofloxacin 750mg once daily was as effective as intravenous imipenem/cilastatin (+/- oral switch to ciprofloxacin) in patients with severe nosocomial pneumonia. Generally, oral levofloxacin 250 or 500mg once daily was at least as effective as oral cefaclor, cefuroxime axetil, clarithromycin or moxifloxacin in patients with acute exacerbations of chronic bronchitis as assessed by either clinical or bacteriological response rates. This approach also provided similar efficacy to amoxicillin/ clavulanic acid or clarithromycin in patients with acute sinusitis. Sequential therapy with levofloxacin 500mg twice daily for 7 to 14 days' was as effective as intravenous imipenem/cilastatin in patients with suspected bacteraemia. Oral levofloxacin 500mg once daily for 7 to 10 days was also an effective treatment in patients with uncomplicated skin and skin structure infections, and in those with complicated urinary tract infections. A higher dosage of sequential levofloxacin 750mg once daily proved as effective as intravenous ticarcillin/clavulanic acid (+/- oral switch to amoxicillin/clavulanic acid) in the treatment of complicated skin and skin structure infections. Pharmacoeconomic studies suggest that levofloxacin may be cost-saving in comparison to conventional therapies. CONCLUSIONS: Levofloxacin continues to demonstrate good clinical efficacy in the treatment of a range of infections, including those in which S. pneumoniae is a potential pathogen. Importantly, it has efficacy in CAP similar to that of gatifloxacin and at least as good as that of the third generation cephalosporins. Extensive clinical data confirm the good tolerability profile of this agent without the phototoxicity, hepatic and cardiac events evident with some of the other newer fluoroquinolone agents. Levofloxacin therefore offers a unique combination of documented efficacy and tolerability, and provides an important option for the treatment of bacterial infections.