Perospirone.

Perospirone is an atypical antipsychotic agent for the treatment of schizophrenia. Its primary mode of action is through antagonism of serotonin 5-HT2A and dopamine D2 receptors. An 8-week course of oral perospirone 8 to 48 mg/day displayed efficacy in up to 75% of patients with schizophrenia participating in phase II and phase III trials. The onset of action of the drug was about 2 weeks. Perospirone was effective against positive, negative and general symptoms in patients with schizophrenia, as assessed with standard rating scales (Brief Psychiatric Rating Scale, Positive and Negative Symptom Scale). Compared with haloperidol 2 to 12 mg/day, perospirone 8 to 48 mg/day was significantly more effective against negative symptoms and tended to be more effective against general symptoms and most positive symptoms in a trial in 145 patients with schizophrenia. Perospirone had efficacy similar to that of mosapramine 50 to 300 mg/day in a comparative phase III trial in 159 patients. Extrapyramidal symptoms (EPS) tended to occur less often and were generally milder with perospirone than with haloperidol or mosapramine.

Adjuvanted Lyme disease vaccine: a review of its use in the management of Lyme disease.

UNLABELLED: Lyme disease is a potentially serious infection which is caused by the spirochaete Borrelia burgdorferi and is endemic in certain areas of North America, Europe and Asia. Lyme disease vaccine (LYMErix) is an adjuvanted formulation of the outer surface protein A (OspA) of the causative spirochaete. It acts by inducing high titres of anti-OspA antibodies (anti-OspA), which must be present in vaccinated individuals before exposure to B. burgdorferi to provide protection against Lyme disease. Lyme disease vaccine efficacy against Lyme disease was 80% for definite and asymptomatic cases and 76% for definite cases at year 2 using the recommended dosage regimen [30 microg at months 0, 1 and 12 (0, 1, 12 schedule)] in a randomised, double-blind, multicentre trial in 10,936 enrolled adult volunteers who resided in areas of the US endemic for Lyme disease. On the basis of an anti-OspA correlate of protection, Lyme disease vaccine 30 microg was equally effective when administered by a shorter schedule (0, 1, 6 schedule); > or = 90% of adult volunteers developed protective anti-OspA titres with this or the 0, 1, 12 schedule. Although published data are fewer, a 0, 1, 2 schedule has also shown promise in adults. In addition, virtually all children (aged 2 to 15 years) given Lyme disease vaccine 30 microg developed protective anti-OspA titres, but published data are also limited and results of a large paediatric trial are awaited with interest. Long term protection against Lyme disease appears to be possible with Lyme disease vaccine. Although anti-OspA titres decline rapidly after completion of the recommended schedule, booster doses of 30 microg of the vaccine induced protective anti-OspA titres in > or = 96% of adult volunteers when administered 12 and/or 24 months later. Lyme disease vaccine 30 microg is well tolerated: most vaccination-related adverse events were transient and mild or moderate in severity in clinical trials. The most common spontaneously reported adverse event was pain at the injection site in 24% of vaccine recipients (vs 7.6% of the placebo group). The incidence of spontaneously reported, early nonspecific systemic adverse events was <4% but was higher with the vaccine than with placebo for some events (e.g. myalgias, fever and chills but not arthralgia). There appeared to be no association between the vaccine and the incidence of arthritis or any late systemic adverse events. The tolerability profile of Lyme disease vaccine did not appear to vary with the schedule of administration, nor to differ between adults and children. CONCLUSIONS: Lyme disease vaccine, an adjuvanted formulation of OspA, protects most adults against Lyme disease when administered by the recommended 0, 1, 12 schedule before disease exposure, and is well tolerated. The optimal schedule(s) of administration, duration of protection against Lyme disease, long term tolerability in adults and potential role in children are not fully defined for this vaccine. Lyme disease vaccine is indicated in North America for active immunisation of adults at moderate to high risk of contracting Lyme disease.

Rapacuronium bromide: a review of its use in anaesthetic practice.

UNLABELLED: Rapacuronium bromide (rapacuronium) is an aminosteroid, nondepolarising neuromuscular blocking agent (NMBA). At the recommended dose for endotracheal intubation (1.5 mg/kg), an intravenous bolus of rapacuronium has a rapid onset (approximately 1.2 to 1.8 minutes) and short duration of action (10.2 to 16.5 minutes) in adults undergoing elective surgery. Rapacuronium 1.5 mg/kg produced clinically acceptable intubating conditions in 68 to 89% of these patients at about 1 minute after administration. The onset, extent and duration of action and clinical efficacy of an intubating dose of rapacuronium appeared to be similar in the general adult population, adult patients with renal or hepatic dysfunction, patients undergoing Caesarean section, and elderly, paediatric or obese adult patients. Onset time with rapacuronium 1.3 to 2.5 mg/kg (0.9 to 1.8 minutes) was similar to or slower than that with a 1 mg/kg dose of the depolarising NMBA suxamethonium chloride (0.8 to 1.2 minutes). Intubating conditions were clinically acceptable about I minute after administration in 86 to 100% of patients with rapacuronium 1.3 to 2.5 mg/kg compared with in 88 to 97% of patients with suxamethonium chloride 1 or 1.5 mg/kg. Spontaneous recovery was slower with rapacuronium than with suxamethonium chloride, but neostigmine 0.04 or 0.05 mg/kg administered 2 or 5 minutes after rapacuronium 1.3 or 1.5 mg/kg accelerated recovery. In the few available comparative clinical trials, rapacuronium 1.5 mg/kg appeared to have a more rapid onset of action than the nondepolarising NMBAs mivacurium chloride 0.25 mg/kg, rocuronium bromide 0.45 or 0.6 mg/kg or vecuronium bromide 0.07 mg/kg, and a shorter duration of action than rocuronium bromide 0.45 or 0.6 mg/kg or vecuronium bromide 0.07 mg/kg. Additional boluses (< or =3) of rapacuronium 0.5 or 0.55 mg/kg after an intubating bolus of 1.5 mg/kg provided continued skeletal muscle relaxation during short surgical procedures in adult patients. However, these patients may recover more slowly than those who receive a single bolus of the drug. Bronchospasm was the most common treatment-related adverse event with rapacuronium 0.3 to 3 mg/kg (3.4% of adult patients). Tachycardia, injection site reaction and hypotension were also reported in small proportions of patients (1.6, 1.1 and 0.9%). The overall incidence of drug-related adverse events was similar with rapacuronium 1.5 or 2.5 mg/kg or suxamethonium chloride 1 mg/kg (8 vs. 6%) but bronchospasm, tachycardia and injection site reaction tended to occur more often with rapacuronium. CONCLUSIONS: At the recommended dose of 1.5 mg/kg, the nondepolarising NMBA rapacuronium has a rapid onset and short duration of action. It may provide a nondepolarising alternative to suxamethonium chloride for endotracheal intubation. Rapacuronium may be preferred over rocuronium bromide, vecuronium bromide or mivacurium chloride in this indication.

Epirubicin: a review of its intravesical use in superficial bladder cancer.

UNLABELLED: The anthracycline epirubicin has been investigated for intravesical use in patients with superficial bladder cancer. In multicentre, randomised trials, prophylaxis with intravesical epirubicin 30 to 80 mg after transurethral resection (TUR) was more effective than no prophylaxis in the prevention of disease recurrence. Intravesical prophylaxis with epirubicin was as effective as that with equivalent dosages of doxorubicin after TUR. Data are conflicting concerning the relative efficacy of intravesical epirubicin and bacillus Calmette-Guerin (BCG) in patients at intermediate risk of recurrence after TUR, but epirubicin was less effective than BCG in those at high risk. The efficacy and tolerability of prophylaxis with epirubicin relative to that with mitomycin is not yet established. The efficacy of epirubicin as prophylaxis after TUR in combination with BCG or interferon-alpha-2b, or as treatment in patients with superficial bladder cancer has been evaluated in small, noncomparative trials, but requires clarification. Adverse events associated with intravesical epirubicin were generally mild and transient. The most common adverse events were localised to the bladder (cystitis, haematuria and urinary tract infection). Systemic adverse events (cardiac, haematological or related to hypersensitivity) were not reported in many trials of intravesical epirubicin, and when reported generally occurred in < or =5% of patients who received the drug. Intravesical epirubicin was generally tolerated as well as intravesical doxorubicin and was associated with a lower incidence of mild chemical cystitis in 1 clinical trial. The incidence of adverse events associated with intravesical epirubicin was markedly lower than that associated with intravesical BCG. CONCLUSIONS: Intravesical epirubicin has shown efficacy in preventing disease recurrence after TUR of superficial bladder cancer. In comparison with equivalent dosages of doxorubicin, the efficacy of epirubicin for this indication is generally similar, and the tolerability profile may be more favourable. Epirubicin is less effective than BCG as intravesical prophylaxis in patients at high risk of recurrence after TUR; the relative efficacy of epirubicin and BCG after TUR in patients at intermediate risk is not yet clear. Intravesical epirubicin is generally tolerated better than BCG. Intravesical epirubicin may be used as prophylaxis after TUR in patients who are at low or intermediate risk of recurrence of superficial bladder cancer.

Rituximab.

Rituximab is a chimaeric monoclonal antibody which specifically binds to the CD20 antigen on normal and malignant B lymphocytes. It produces antibody-dependent cell- and complement-mediated cytotoxicity in these cells. Rituximab reduced peripheral B lymphocyte counts by approximately 90% within 3 days in patients with relapsed indolent lymphoma. Counts remained depleted for 6 months and recovered by months 9 to 12 after 4 doses of rituximab 375 mg/m2 once weekly. Clinical response rates were 46 and 48% in 2 non-comparative trials in patients with relapsed indolent lymphoma. The rate of response to rituximab appeared to be markedly higher in patients with follicular lymphoma than in those with small lymphocytic disease (56 or 60% versus 13 or 15%). 85 to 94% of patients reported adverse events during clinical trials of rituximab; 90% of events were mild or moderate. The most common adverse event, a transient set of flu-like symptoms during the first infusion in approximately 50 to 87% of patients, generally resolved completely in < 3 hours. Diphenhydramine and/or paracetamol was administered to some patients. In 10% of patients, the flu-like symptoms during the first infusion were accompanied by bronchospasm and/or hypotension or severe cytokine release syndrome. Patients were generally able to complete treatment after these symptoms revolved.

Valrubicin.

Valrubicin (AD-32) is an N-trifluoroacetyl, 14-valerate derivative of the anthracycline doxorubicin. It has antineoplastic activity which probably results from interference with nucleic acid metabolism by the drug. Valrubicin entered individual cells more rapidly than doxorubicin in vitro. When valrubicin was administered intravesically to patients with bladder cancer, cytotoxic concentrations of the drug penetrated the superficial muscle layer of the bladder. Complete response rates were 18 and 29% in patients with carcinoma in situ of the bladder which was refractory to intravesical BCG in 2 non-comparative trials of prophylactic intravesical valrubicin. In patients with recurrent superficial papillary tumours, the complete response rate was 46%. Adverse events were generally transient in patients who received intravesical valrubicin. Bladder irritation occurred in 88% of patients. Systemic absorption of intravesically administered valrubicin was minimal. Accordingly, systemic adverse events generally occurred in < or =5% of patients. Valrubicin was less toxic to chick embryos and haematopoietic stem cells in vitro and produced a lower incidence of cardiotoxicity in rabbits, compared with doxorubicin.

Basiliximab.

The chimaeric monoclonal antibody basiliximab specifically binds the alpha subunit of the interleukin-2 (IL-2) receptor on activated T lymphocytes. Through competitive antagonism of IL-2, basiliximab supplements standard immunosuppressive therapy after renal transplantation. < or =24 Hours after a single intravenous dose of basiliximab 2.5 to 25 mg, approximately 90% of available IL-2 receptors on T lymphocytes were complexed with the drug. This level of basiliximab binding was maintained for 4 to 6 weeks when renal transplant patients received basiliximab 20 mg 2 hours before and then 4 days after transplantation surgery. In 2 large, well-designed trials, the percentage of patients with biopsy-confirmed acute rejection episodes after renal transplantation was significantly lower with basiliximab 20 mg (administered 2 hours before and then 4 days after transplantation surgery; 30 or 33%, respectively) than placebo (44 or 46%) at 6 months after surgery. Basiliximab was well tolerated during clinical trials. The incidence of infections (including active cytomegalovirus infection) and post-transplant lymphoproliferative disorders was similar with basiliximab and placebo. Cytokine release syndrome was not observed in patients who received basiliximab.

Calfactant: a review of its use in neonatal respiratory distress syndrome.

UNLABELLED: Calfactant (Infasurt) is a natural bovine surfactant which has been evaluated for intratracheal use in the prevention and rescue treatment of respiratory distress syndrome (RDS) in preterm infants. In 2 randomised, double-blind, multicentre clinical trials of prophylactic use, calfactant 100 or 105 mg phospholipid per kg bodyweight (mg/kg) reduced RDS incidence, RDS severity and mortality rates to a greater extent than colfosceril palmitate (Exosurf Neonatal) 67.5 mg/kg and was generally similar to beractant (Survanta) 100 mg/kg. Although the rate of mortality before discharge from hospital was significantly higher in infants with birthweights <600 g who received calfactant than in those who received beractant, this may not be a typical result. As rescue treatment, calfactant 100 or 105 mg/kg reduced RDS severity, but not mortality rates, significantly more than colfosceril palmitate 67.5 mg/kg or beractant 100 mg/kg in 2 randomised, double-blind, multicentre clinical trials. In addition, the duration of effect of calfactant as prophylaxis or rescue treatment appeared to be longer than that of beractant. In other randomised trials, prophylaxis was more effective than rescue treatment with calfactant, particularly in infants of < or =29 weeks gestational age. The incidence of pulmonary air leak events was lower with calfactant than with colfosceril palmitate (12 vs 22%) but was identical with calfactant and beractant (15% with either agent). The incidence of other complications associated with RDS was usually similar with all 3 agents in clinical trials in preterm infants. The incidence of intraventricular haemorrhage was significantly higher in 1 clinical trial, and that of septicaemia was significantly lower in another, with calfactant versus colfosceril palmitate, but the combined incidences of these complications was similar with the 2 agents when results from different trials were pooled. The incidence of acute adverse events (i.e. those which occurred during administration of the drug) with calfactant was similar to that with beractant and higher than that with colfosceril palmitate; the difference may been related to reduced RDS severity in calfactant versus colfosceril palmitate recipients. Acute adverse events were usually transient and not severe. CONCLUSIONS: Calfactant is a well tolerated natural bovine surfactant which is effective in the prevention and treatment of RDS in preterm infants. Further investigation is needed to more clearly determine the efficacy and tolerability of calfactant relative to that of other surfactant preparations. When more data are available, it is likely that calfactant will be useful as an alternative to beractant (at least in infants of birthweights >600 g), and calfactant may be preferred over colfosceril palmitate in both the prophylaxis and treatment of RDS.

Ofloxacin. A reappraisal of its use in the management of genitourinary tract infections.

UNLABELLED: Ofloxacin is an established fluoroquinolone agent which achieves good concentrations in genitourinary tract tissues and fluids. It has good in vitro activity against most Enterobacteriaceae, Staphylococcus saprophyticus, methicillin-susceptible S. aureus, Neisseria gonorrhoeae, Chlamydia trachomatis and Haemophilus ducreyi, intermediate activity against Ureaplasma urealyticum and most enterococci, but limited or no in vitro activity against enterococci, Serratia marcescens, Pseudomonas aeruginosa and many anaerobes. However, high concentrations achieved in the urine ensure its activity against most urinary tract pathogens. Ofloxacin demonstrates consistent efficacy in a broad range of urinary tract infections, achieving bacteriological response rates in excess of 80% in uncomplicated and 70% in complicated infections. The efficacy of ofloxacin was similar to that of all comparators tested including other fluoroquinolones, cephalosporins and cotrimoxazole (trimethoprim/sulfamethoxazole). Ofloxacin is also effective as a single-dose regimen in the treatment of uncomplicated gonorrhoea, as a 7-day regimen in uncomplicated C. trachomatis infections, and as monotherapy in uncomplicated pelvic inflammatory disease (PID). Again, ofloxacin demonstrated similar efficacy to alternative treatments in each type of infection. The availability of an intravenous formulation and near-complete oral bioavailability allow ofloxacin to be administered as a sequential regimen without loss of activity. The tolerability and drug interaction profile of ofloxacin is consistent with that of other fluoroquinolones. The most commonly reported adverse events with ofloxacin are gastrointestinal, neurological and dermatological. It was associated with a lower incidence of photosensitivity and tendinitis and higher incidence of some neurological events than some other fluoroquinolones. Ofloxacin seems to have a lower propensity to interact with xanthines than other fluoroquinolones. CONCLUSION: ofloxacin has established efficacy in the treatment of a wide variety of urinary tract infections, although, like other fluoroquinolones, it should be used rationally to preserve its activity. Currently, ofloxacin also holds an important place among fluoroquinolones in the treatment of C. trachomatis infections and uncomplicated PID, although its acceptance as monotherapy in PID is likely to depend on clarification of the causative role of anaerobic pathogens in this infection.

Mometasone furoate. A review of its intranasal use in allergic rhinitis.

UNLABELLED: Mometasone furoate is a synthetic corticosteroid which has been evaluated for intranasal use in the treatment of adults and children with allergic rhinitis. In several large, well-controlled clinical trials, mometasone furoate 200 micrograms administered once daily as an aqueous intranasal spray was significantly more effective than placebo in controlling the symptoms associated with moderate to severe seasonal or perennial allergic rhinitis. Mometasone furoate was as effective as twice-daily beclomethasone dipropionate or once-daily fluticasone propionate in the treatment of perennial allergic rhinitis, and was as effective as twice-daily beclomethasone dipropionate and slightly more effective than once-daily oral loratadine in the treatment of seasonal allergic rhinitis. Mometasone furoate was also as effective as twice-daily beclomethasone dipropionate or once-daily budesonide, and significantly more effective than placebo in the prophylaxis of seasonal allergic rhinitis. The onset of action of mometasone furoate was approximately 7 hours in patients with seasonal allergic rhinitis. Mometasone furoate was as well tolerated as beclomethasone dipropionate, fluticasone propionate and budesonide in clinical trials, with an overall incidence of adverse events similar to placebo. Adverse events were generally mild to moderate and of limited duration. The most common adverse events associated with mometasone furoate therapy were nasal irritation and/or burning, headache, epistaxis and pharyngitis. Intranasal or oral mometasone furoate had no detectable effect on hypothalamic-pituitary-adrenal axis function in studies of < or = 1 year in duration. CONCLUSIONS: Mometasone furoate is a well tolerated intranasal corticosteroid with minimal systemic activity and an onset of action of < or = 7 hours. It is effective in the prophylaxis and treatment of seasonal allergic rhinitis and the treatment of perennial allergic rhinitis in patients with moderate to severe symptoms.

Infliximab: a review of its use in Crohn's disease and rheumatoid arthritis.

UNLABELLED: Infliximab is a chimaeric monoclonal antibody which binds to and inhibits the activity of tumour necrosis factor-alpha (TNFalpha), a cytokine which is involved in the development of both Crohn's disease and rheumatoid arthritis. In patients with treatment-resistant Crohn's disease, infliximab was significantly more effective than placebo in the relief of symptoms. 50 to 89% of patients responded to infliximab and most of them also achieved remission. Patients showed signs of relapse 8 to 12 weeks after a single infusion but responded to additional infusions of the drug. Infliximab was also effective in closing the fistulae in 68% of patients with fistulising Crohn's disease; the response rate with placebo was 26%. Infliximab achieved a clinical response in 44 to 81% of patients with refractory rheumatoid arthritis. Following a single infusion, symptom recurrence was evident after 6 to 12 weeks, but subsequent infusions re-established a clinical response. Concurrent methotrexate appeared to prolong the effects of infliximab in this patient group. Anti-infliximab and anti-double-stranded DNA antibodies developed in some patients, particularly those who received multiple infusions of infliximab. Acute adverse events consistent with hypersensitivity occurred in some patients who received multiple infusions of infliximab. Infection occurred slightly more frequently with infliximab than with placebo. CONCLUSIONS: Infliximab appears to be an effective therapy for patients with treatment-resistant or fistulising Crohn's disease or refractory rheumatoid arthritis. The tolerability, long term efficacy and optimal dosage regimen need to be further defined in comparative trials before the full potential of infliximab is realised in these patients.

Modulation of L-selectin ligand expression during an immune response accompanying tumorigenesis in transgenic mice.

Immune surveillance depends on lymphocyte access to tissue. Lymphocytes emigrate from blood when adhesion receptors such as L-selectin and the alpha 4 beta 7 integrin on these cells bind to ligands expressed on venular endothelium. Among transgenic mouse lines expressing an oncoprotein (Tag) in islet beta cells, some recognize Tag as nonself. In these mice, Tag expression elicits both beta cell hyperplasia with subsequent progression to tumors and lymphocytic infiltration. Endothelial ligands for L-selectin and alpha 4 beta 7 were upregulated in infiltrated islets in these transgenic mice. These ligands were not expressed in tumors, which were devoid of lymphocytic infiltration. In contrast, the adhesion molecules PECAM-1, ICAM-1, and VCAM-1 were expressed on endothelium in both noninfiltrated tumors and infiltrated islets. Thus, upregulation of expression of endothelial ligands for L-selectin and alpha 4 beta 7 may contribute to autoimmune infiltration. Repression of expression of these same ligands may be involved in the failure of tumor immunity.