Susan M. Cheer

Pantoprazole: an update of its pharmacological properties and therapeutic use in the management of acid-related disorders.

Pantoprazole (Protonix) is an irreversible proton pump inhibitor (PPI) that reduces gastric acid secretion. In combination with two antimicrobial agents (most commonly metronidazole, clarithromycin or amoxicillin) for 6-14 days, pantoprazole 40 mg twice daily produced Helicobacter pylori eradication rates of 71-93.8% (intent-to-treat [ITT] or modified ITT analysis) in patients without known antibacterial resistance. Pantoprazole-containing triple therapy was at least as effective as omeprazole- and similar in efficacy to lansoprazole-containing triple therapy in large trials. In the treatment of moderate to severe gastro-oesophageal reflux disease (GORD), oral pantoprazole 40 mg/day was as effective as other PPIs (omeprazole, omeprazole multiple unit pellet system, lansoprazole and esomeprazole) and significantly more effective than histamine H(2)-antagonists. Pantoprazole 20 mg/day provided effective mucosal healing in patients with GORD and mild oesophagitis. Intravenous pantoprazole 40 mg/day can be used in patients who are unable to take oral medication. Oral pantoprazole 20-40 mg/day for up to 24 months prevented relapse in most patients with healed GORD. According to preliminary data, oral pantoprazole 20 or 40 mg/day was effective at healing and preventing non-steroidal anti-inflammatory drug (NSAID)-related ulcers, and intravenous pantoprazole was at least as effective as intravenous ranitidine in preventing ulcer rebleeding after endoscopic haemostasis. Oral or intravenous pantoprazole up to 240 mg/day maintained target acid output levels in most patients with hypersecretory conditions, including Zollinger-Ellison syndrome. Oral and intravenous pantoprazole appear to be well tolerated in patients with acid-related disorders in short- and long-term trials. Tolerability with oral pantoprazole was similar to that with other PPIs or histamine H(2)-antagonists in short-term trials. Formal drug interaction studies have not revealed any clinically significant interactions between pantoprazole and other agents. In conclusion, pantoprazole is an effective agent in the management of acid-related disorders. As a component of triple therapy for H. pylori eradication and as monotherapy for the healing of oesophagitis and maintenance of GORD, pantoprazole has shown similar efficacy to other PPIs and greater efficacy than histamine H(2)-antagonists. Limited data suggest that it is also effective in Zollinger-Ellison syndrome and in preventing ulcer rebleeding. Pantoprazole is well tolerated with minimal potential for drug interactions. The availability of pantoprazole as both oral and intravenous formulations provides flexibility when the oral route of administration is not appropriate. Thus, pantoprazole is a valuable alternative to other PPIs in the treatment of acid-related disorders.

Inhaled tobramycin (TOBI): a review of its use in the management of Pseudomonas aeruginosa infections in patients with cystic fibrosis.

SummaryAbstractSpecifically formulated for nebulisation using the PARI LC PLUS™ reusable nebuliser, tobramycin solution for inhalation (TSI) [TOBI®] provides a high dose of tobramycin (an aminoglycoside antibacterial with good activity against Pseudomonas aeruginosa) to the lungs of patients with cystic fibrosis, while maintaining low serum concentrations of the drug, thus reducing the risk of systemic toxicity.Intermittent (28-day on/28-day off) treatment with TSI 300mg twice daily significantly (p < 0.001) improved lung function and sputum P. aeruginosa density compared with placebo (randomised double-blind trials), and was significantly (p = 0.008) more effective than colistin for improvement in forced expiratory volume in 1 second (small nonblind trial) in patients aged ≥6 years with cystic fibrosis and chronic P. aeruginosa infection. Improvements in lung function were most marked in adolescent patients (aged 13–17 years) in placebo-controlled trials. Improvements were maintained for up to 96 weeks in patients in an open-label extension study. Fewer TSI than placebo recipients required parenteral antipseudomonal agents or hospitalisation. In addition, TSI 300mg twice daily for 28 days reduced P. aeruginosa density in the lower airways of patients aged <6 years with early colonisation and cystic fibrosis, although TSI is not currently indicated in this patient group.A decrease in tobramycin susceptibility of P. aeruginosa isolates and an increase in fungal organisms (Candida albicans and Aspergillus species) during prolonged intermittent treatment with TSI 300mg twice daily was not associated with adverse clinical outcome. There was no evidence of selection for the most resistant isolates.TSI is generally well tolerated, with no renal toxicity or hearing loss in clinical trials, although transient mild or moderate tinnitus occurred more frequently in TSI than placebo recipients. Bronchospasm after administration of TSI was transient and occurred with a similar incidence to that with placebo; TSI is preservative free and specifically formulated for the lung in terms of osmolality and pH.In conclusion, TSI provides an effective means of delivering tobramycin to the lungs of patients with cystic fibrosis with chronic P. aeruginosa infection, improving lung function and sputum P. aeruginosa density in these patients without the nephrotoxicity or ototoxicity of parenteral aminoglycosides. Further data on the potential for and clinical significance of increased tobramycin resistance and fungal colonisation during TSI treatment would be beneficial, as would longer-term data. In the meantime, TSI represents a valuable option for suppressive antipseudomonal therapy in patients with cystic fibrosis.Antibacterial ActivityTobramycin, an aminoglycoside antibacterial, had good in vitro activity against Pseudomonas aeruginosa in sputum isolates from patients with cystic fibrosis; the minimum concentrations required to inhibit the growth of 90% (MIC90) of strains was 8 μg/mL in the largest study (involving 1240 isolates) [MIC90 = 8–64 μg/mL in smaller studies]. According to breakpoint values for systemic antibacterials issued by the US National Committee for Clinical Laboratory Standards (NCCLS) [MIC ≤4 μg/mL susceptible, MIC 8 μg/mL intermediate, MIC ≥16 μg/mL resistant], 89% of 1240 P. aeruginosa isolates from 508 patients with cystic fibrosis were susceptible to tobramycin and 5.4% were resistant; the range of resistance for other antibacterial agents was 11–21%. Increased resistance of non-mucoid compared with mucoid strains was evident with tobramycin in one study (although statistical analysis was not performed) but not in another study. Tobramycin was active against most (65–84%) nonaminoglycoside single- or multiple-drug resistant isolates. About one- to two-thirds of isolates resistant to tobramycin were susceptible to other agents. Resistance to tobramycin results mostly from impermeability of isolates.In phase III placebo-controlled trials in patients aged ≥6 years with cystic fibrosis, there was a significant decrease in the tobramycin susceptibility of P. aeruginosa isolates (characterised by an increase in MIC90 from 8 [baseline] to 16 μg/mL [weeks 20 and 24]) and an increase in fungal organisms (Candida albicans and Aspergillus species) during intermittent treatment with tobramycin solution for inhalation (TSI) 300mg twice daily. However, clinical outcome was not adversely affected. Furthermore there was no evidence of selection for the most resistant isolates.Similarly, improvement in lung function was not affected by tobramycin MIC after 96 weeks of alternating treatment (i.e. 28 days on/28 days off) with TSI 300mg twice daily in patients with cystic fibrosis, despite reduced susceptibility of P. aeruginosa to tobramycin. In a subgroup of adolescent patients, increases were observed in the percentage of resistant isolates (5% [baseline] to 19% [study end]) and MIC90 (from 8 to 32 μg/mL).Pharmacokinetic PropertiesTSI achieved lung concentrations of tobramycin sufficient for an antibacterial effect against P. aeruginosa in most patients aged ≥6 with moderate-to-severe cystic fibrosis, while maintaining minimal systemic exposure. Ten minutes after single-dose TSI 300mg, sputum concentrations of tobramycin were 35–7417 μg/g (mean 1237 μg/g; median 959 μg/g), demonstrating wide interindividual variability. At 60 minutes after TSI, serum tobramycin concentrations remained low (≤3.62 μg/mL, mean 0.95 μg/mL, median 0.91 μg/mL). There was no accumulation of tobramycin in sputum or serum after multiple-dose administration (measured at week 20). The median ratio of serum-to-sputum tobramycin concentrations was 0.01 after TSI administration, demonstrating an improved therapeutic ratio compared with parenteral aminoglycosides.The estimated bioavailability of tobramycin following administration of TSI 300mg was 11.7% in a population pharmacokinetic analysis using systemic clearance of 5.79 L/h and an apparent clearance of 49.6 L/h.In children aged <6 years with cystic fibrosis, peak serum drug concentrations (0.6 μg/mL [range <0.2–1.2 μg/mL]) were reached 1 hour after administration of TSI 300mg, and were lower than the maximum accepted trough concentrations (2 μg/mL) for parenteral administration of tobramycin. Lower respiratory tract drug concentrations were within the bactericidal range for P. aeruginosa, with lung epithelial lining fluid concetrations being 16–204 μg/mL (mean 90 μg/mL) and above the target of 20 μg/mL (i.e. 10 times the MIC90 for P. aeruginosa) in 11 of 12 patients.After inhalation, systemically absorbed tobramycin is assumed to be eliminated primarily by glomerular filtration, and unabsorbed tobramycin residing in the endobronchial space is probably eliminated primarily in expectorated sputum.Therapeutic EfficacyIn Patients aged ≥6 years with cystic fibrosis and chronic P. aeruginosa respiratory infection, TSI 300mg twice daily significantly improved lung function and sputum P. aeruginosa density versus placebo or baseline in well designed trials. In addition, TSI 300mg twice daily was significantly more effective than colistin for improvement in forced expiratory volume in 1 second (FEV1) in a nonblind trial of short duration (involving only the antibacterial phase of one 28-day on/28-day off cycle of TSI) in 100 patients with cystic fibrosis and chronic P. aeruginosa infection.In two identically designed, randomised, double-blind, placebo-controlled trials (pooled analysis, n = 520), marked improvements in lung function (≈12% increase from baseline in FEV1) occurred within 2 weeks of treatment initiation and were maintained throughout the treatment period (three 28-day on/28-day off cycles). At treatment end, the total treatment effect (absolute difference between TSI and placebo) was ≈12%. Mean FEV1 was maintained above pretreatment (baseline) for up to 96 weeks in an open-label extension phase. Patients aged 13–17 years were more responsive to treatment than other patient age-groups. There were no observed differences according to gender, disease severity or dornase alfa use. These results can be contextualised when one considers the progressive decline in lung function of ≈2% per year generally observed in patients with cystic fibrosis.Mean sputum P. aeruginosa density showed marked reductions from baseline during the first two active TSI-treatment periods and tended back towards baseline during the non-treatment phases in these placebo-controlled trials. The effect of TSI on sputum P. aeruginosa density was significantly (p = 0.01) reduced with increasing age.Fewer TSI than placebo recipients required hospitalisation or intravenous antibacterial treatment, and the mean duration of both was shorter with TSI than placebo, during the controlled phase of clinical trials. Similar trends for hospitalisation rate and duration of stay were recorded during the 96-week open-label extension phase. Reductions in hospitalisation rates and the use of intravenous antibacterials produced cost savings that partially off-set the acquisition cost of TSI in a small UK observational economic evaluation in patients with cystic fibrosis and P. aeruginosa infection. Global ratings for health-related quality of life were significantly (p ≤ 0.03) better for TSI than placebo recipients during each treatment cycle in a retrospective analysis using a nonvalidated single-item questionnaire.In 21 patients aged <6 years with cystic fibrosis and early P. aeruginosa colonisation in a randomised, double-blind, placebo-controlled trial, TSI 300mg twice daily was more effective than placebo for change in bronchoalveolar lavage (BAL) P. aeruginosa density (primary endpoint; between group difference 5.36 log10 colony forming units/mL, p < 0.0001) and eradication rate at 28 days (p < 0.0001), with all eight patients in the TSI group having a negative BAL culture.TolerabilityChildren and adults generally tolerated TSI treatment we

Parecoxib (Parecoxib Sodium)

Abstract▴ Parecoxib (parecoxib sodium) is an injectable prodrug of valdecoxib, which is a potent and selective inhibitor of cyclo-oxygenase-2.▴ Intravenous (TV) or intramuscular (IM) parecoxib ≥20mg has analgesic activity superior to that of placebo and similar to that of IV or IM ketorolac 30 or 60mg in well controlled trials in patients with postoperative dental pain (n = 304 to 457).▴ In a well controlled trial (n = 202), IV parecoxib 20 or 40mg showed analgesic activity greater than that of placebo and IV morphine 4mg and similar to that of IV ketorolac 30mg following gynaecological surgery.▴ Following orthopaedic surgery, the analgesic activity of IV parecoxib 20 or 40mg was similar to that of IV ketorolac 30mg and superior to that of IV morphine 4mg or placebo in well controlled trials (n = 175 and 208).▴ IV parecoxib (40mg twice daily for 7 days) produced significantly fewer gastrointestinal erosions and/or ulcers than ketorolac (15mg 4 times a day for 5 days) in healthy volunteers in a well controlled trial; effects on upper gastrointestinal mucosa were similar for parecoxib and placebo.▴ Parecoxib is well tolerated after dental, gynaecological or orthopaedic surgery. The most common adverse events irrespective of treatment (parecoxib, ketorolac or placebo) after dental surgery were nausea, alveolar osteitis, dizziness and headache.▴ Nausea, abdominal pain, headache, abdominal fullness, dizziness, back pain, fever, hypoactive bowel sounds, vomiting, tachycardia, somnolence, abnormal breath sounds and pruritus occurred in ≥10% of parecoxib recipients after gynaecological surgery. Similar results were seen in placebo recipients.

Quetiapine: A review of its use in the management of schizophrenia

Quetiapine (Seroquel), a dibenzothiazepine derivative, is an atypical antipsychotic with demonstrated efficacy in acute schizophrenia. In short-term, randomised, double-blind trials, it was usually more effective than placebo, and was generally effective against both positive and negative symptoms. Overall, quetiapine (up to 750 mg/day) was at least as effective as chlorpromazine (up to 750 mg/day) and had similar efficacy to haloperidol (up to 16 mg/day) in patients with acute schizophrenia in randomised, double-blind trials; it was at least as effective as haloperidol 20 mg/day in patients with schizophrenia unresponsive or partially responsive to previous antipsychotic treatment. Improvements in overall psychopathology and positive and negative symptoms with quetiapine (up to 800 mg/day) were similar to those with risperidone (up to 8 mg/day) or olanzapine (15 mg/day) [interim analysis]. Efficacy was maintained for at least 52 weeks in open-label follow-up studies in adult and elderly patients. Quetiapine improved cognitive function versus haloperidol, and depressive symptoms and hostility/aggression versus placebo. Quetiapine is well tolerated. It is associated with placebo-level incidence of extrapyramidal symptoms (EPS) across its entire dose range, appears to have a low risk for EPS in vulnerable patient groups (e.g. the elderly, adolescents or patients with organic brain disorders) and has a more favourable EPS profile than risperidone. Irrespective of dose, quetiapine, unlike risperidone and amisulpride, does not elevate plasma prolactin levels compared with placebo, and previously elevated levels may even normalise. Quetiapine appears to have minimal short-term effects on bodyweight and a favourable long-term bodyweight profile. Preliminary studies indicate that there is a high level of patient acceptability and satisfaction with quetiapine. In conclusion, quetiapine has shown efficacy against both positive and negative symptoms of schizophrenia, and has benefits in improving cognitive deficits, affective symptoms and aggression/hostility. The beneficial effects of quetiapine have been maintained for at least 52 weeks. Quetiapine was effective and well tolerated in hard-to-treat patients, and may be of particular use in these individuals. It is at least as effective as standard antipsychotics and appears to have similar efficacy to risperidone and olanzapine. The relative risk/benefit profile of quetiapine compared with other atypical antipsychotics requires further research in head-to-head trials, although quetiapines relatively benign tolerability profile distinguishes it from other commonly used atypical agents, particularly with respect to bodyweight, EPS and plasma prolactin levels. Overall, quetiapine has an excellent risk/benefit profile and is a suitable first-line option for the treatment of schizophrenia.

Fluoxetine: a review of its therapeutic potential in the treatment of depression associated with physical illness.

UNLABELLED Fluoxetine is a potent and selective inhibitor of neuronal serotonin (5-hydroxytryptamine) reuptake. Fluoxetine reduces food, energy and carbohydrate intake and increases resting energy expenditure, which may account for the moderate and transient bodyweight loss observed with its use. Glucose tolerance and/or hypoglycaemia in patients with type 2 diabetes mellitus improve with fluoxetine therapy. The ability of fluoxetine to inhibit cytochrome P450 (CYP) isoenzymes (CYP2D6, CYP2C and CYP3A4), is potentially important for patients with physical illness who may be taking multiple concomitant medications. Fluoxetine was more effective than placebo in 2 double-blind, randomised trials, and according to limited data appears to be equally effective compared with other SSRIs and tricyclic antidepressants (TCAs), in the treatment of depression in patients with HIV/AIDS. The efficacy of fluoxetine is also superior to that of placebo in the treatment of depression in patients with diabetes mellitus and stroke as shown in double-blind randomised trials, although its efficacy relative to that of nortriptyline in stroke is uncertain. Fluoxetine had similar efficacy to that of desipramine in patients with cancer, with improved Hamilton Depression Rating Scale and quality-of-life scores from baseline; however, the drug was not more effective than placebo in a double-blind randomised trial. Medically healthy individuals tolerate fluoxetine well. Like other SSRIs, fluoxetine lacks the anticholinergic, cardiovascular, sedative and weight-increasing properties of TCAs, and is safer in overdose than TCAs and monoamine oxidase inhibitors. Rates of sexual dysfunction and suicidal ideation with fluoxetine appear similar to those seen with other SSRIs. CONCLUSION Fluoxetine has shown superior efficacy compared with placebo in the treatment of depression in patients with HIV/AIDS, diabetes mellitus or stroke; however, it has not significantly improved depressive symptoms versus placebo in patients with cancer. The efficacy of fluoxetine appears similar to that of desipramine in patients with stroke, cancer or HIV, and is similar to that of sertraline or paroxetine in patients with HIV/AIDS; comparisons with nortriptyline give equivocal results. The potential for drug interactions with fluoxetine use should be carefully considered because most patients with comorbid physical illness will be receiving multiple comedications. Although fluoxetine has proved effective as an antidepressant in this population in several clinical trials, its drug interaction profile and long half-life are a potential limitation, and these properties should be carefully considered in relation to the status of each patient.

Octreotide long-acting release (LAR): a review of its use in the management of acromegaly.

SummaryAbstractOctreotide long-acting release (LAR) is a somatostatin analogue designed for once monthly intramuscular injection. As with endogenous somatostatin, octreotide LAR inhibits secretion of growth hormone (GH) as well as various other peptide hormones.In the treatment of acromegaly, octreotide LAR effectively controlled the secretion of GH and insulin-like growth factor-1 (IGF-1) in about 55–70% of patients (n > 100) who had previously been treated with somatostatin analogues, a similar degree of control to that observed with subcutaneous octreotide and lanreotide slow release (SR). Progressive control of serum levels of GH and IGF-1 was achieved with octreotide LAR in clinical studies of up to 4 years’ duration. In addition, primary therapy with octreotide LAR provided effective control of GH and IGF-1 secretion, particularly in patients with a pretreatment GH level <20 µg/ L.The percentage of patients achieving a target serum GH level of <2–2.5 µg/L or normal IGF-1 levels was significantly greater with octreotide LAR 10, 20 or 30mg every 28 days than with lanreotide SR 30mg every 7–14 days in a large (n = 125) sequential, 6-month study, but was not significantly different between treatment groups in a small, randomised, nonblind, parallel group study of previously untreated patients. The volume of pituitary tumour shrinkage achieved with octreotide LAR or lanreotide SR was also similar (≈33% after 24 months). Acromegaly symptoms, such as headache, increased perspiration, paraesthesia, fatigue and osteoarthralgia were improved during treatment with octreotide LAR or lanreotide SR.Overall, octreotide LAR is generally well tolerated by most patients. The incidence of gastrointestinal symptoms is about 30% but, in most cases, events are transient and mild to moderate. Gallbladder abnormalities (sediment, sludge, microlithiasis and gallstones) can occur, but only 1% have become symptomatic to date. The prevalence of biliary abnormalities did not change after switching from subcutaneous octreotide, or from lanreotide SR, to octreotide LAR. Glucose metabolism can be affected by octreotide LAR in some patients; about 15% become hyperglycaemic, usually mild in severity.In summary, octreotide LAR controls GH and IGF-1 secretion in about 55–70% of patients with acromegaly. Octreotide LAR is administered intramuscularly every 28 days, offering improved patient compliance and convenience over three-times-daily subcutaneous octreotide. Long-term therapy provides progressive control of serum GH and IGF-1 levels, and is generally well tolerated by most patients. Thus, for the medical management of acromegaly, octreotide LAR is an effective, well tolerated and convenient treatment option.Pharmacodynamic PropertiesOctreotide long-acting release (LAR) is an octapeptide somatostatin analogue, with pharmacodynamic properties that are qualitatively similar to those of the subcutaneously administered formulation. A reduction in growth hormone (GH) levels from >5 µg/L, to <2 and <5 µg/L, respectively, was achieved in ≈29–61% and 87–100% of patients receiving a single intramuscular injection of octreotide LAR 20 or 30mg. The extent of GH suppression with octreotide LAR 20mg was similar to that with the 30mg dose, although the effect tended to persist for shorter periods. Octreotide LAR 10mg was generally not as effective as the higher doses. Marked reductions were also seen in insulin-like growth factor-1 (IGF-1) levels. Treatment with octreotide LAR for up to 1 year was not associated with receptor down-regulation, and antibody formation with octreotide LAR is rare.Subcutaneous octreotide inhibits the secretion of various endocrine hormones (e.g. insulin, glucagon, gastric inhibitory peptide, secretin, gastrin, neurotensin and motilin) and decreases intestinal motility, blood flow to the gut, and carbohydrate, electrolyte and water absorption. With the exception of one small, crossover study in which glucose levels were significantly increased with octreotide LAR compared with baseline and lanreotide slow release (SR), glucose tolerance was not markedly impaired in patients receiving octreotide LAR. The increased incidence of biliary tract dysfunction and gallstones in patients with acromegaly receiving long-term octreotide LAR treatment appears largely related to suppression of cholecystokinin release and reduced gall-bladder emptying.Octreotide LAR may arrest the progression of cardiomyopathy (as evidenced by decreased left ventricular mass index and increased left ventricular ejection fraction response at peak exercise) and improve atherosclerotic risk factors (as evidenced by a significant reduction in the intima media thickness of carotid arteries) in acromegaly by controlling the underlying disease, particularly in patients with an early diagnosis.Pharmacokinetic PropertiesOctreotide LAR comprises a biodegradable polymer matrix, from which octreotide is released in a biphasic manner. In patients with acromegaly, an initial peak in serum octreotide concentrations occurred within 1 hour of a single intramuscular dose of octreotide LAR 10–30mg, presumably from drug adsorbed to the carrier microspheres; this coincided with an 8- to 12-hour period of GH suppression (level not specified). Serum octreotide concentrations declined within 12 hours of drug administration, remaining subtherapeutic until day 7 before increasing in a dose-dependent manner to plateau at about day 14. The plateau concentration remained stable until day 35–60 and then steadily declined. Peak serum concentrations were dose dependent and were reached in 28–34 days. Octreotide concentrations reached steady state after three intramuscular injections of octreotide LAR at 4-week intervals.Therapeutic drug concentrations (usually 1000–3000 ng/L) were maintained throughout the plateau phase in patients receiving octreotide LAR 20 or 30mg; suppression of GH secretion was maximal (levels reached 2–5 µg/L) during this period. Bioavailability after 20 or 30mg doses is 39% or 50% relative to the subcutaneous formulation.Distributed mainly to the plasma, octreotide is 41–65% protein bound. In patients with acromegaly, the volume of distribution is 18–30L (after an intravenous dose of 25–200µg). Hepatic extraction is believed to be extensive (30–40%), and ≈11–32% of the administered drug is eliminated unchanged in the urine. The elimination half-life of octreotide is 1.7 hours. Total body clearance is ≈10 L/h in healthy volunteers, 18 L/h in patients with acromegaly and 4.5 L/h in patients with chronic renal failure.Clinical EfficacyIn patients not previously medically treated, octreotide LAR 10, 20 or 30mg every 28 days for 2 years was associated with GH levels <2.5 µg/L in 50–76% of patients and normal IGF-1 levels in 50–71%. In patients who had previously shown sensitivity to therapy with subcutaneous octreotide and subsequently received octreotide LAR for 6–36 months, GH levels ≤2.5 µg/L were achieved in 50–79%, and normal IGF-1 levels in 53–88%. Compared with patients who underwent prior surgery, patients receiving primary therapy with octreotide LAR had similar levels of GH and IGF-1 at 24 months. Patients with a pretreatment GH level <20 µg/L were more likely to attain target GH levels during primary therapy with octreotide than those with higher baseline values.Octreotide LAR 10, 20 or 30mg per month for 3 months further improved control of GH and IGF-1 levels over those achieved during prior therapy with lanreotide SR 30mg every 7–14 days for at least 3 months in a large, nonblind, sequential study (n = 107; no washout period between treatments). In a small 24-month, randomised, nonblind, parallel-design study of previously untreated patients (n = 20), the efficacy of intramuscular octreotide LAR 10, 20 or 30mg every 28 days or intramuscular lanreotide SR 30mg every 7–10 days was similar, as demonstrated by the lack of a significant difference in the percentage of patients with GH levels <2 µg/L (50% vs 58%) and normal IGF-1 levels (50% vs 67%). Tumour shrinkage after 24 months was similar in both treatment groups: 34.8% versus 30.0%. Symptoms of acromegaly, such as headache, increased perspiration, paraesthesia, fatigue and osteoarthralgia, were generally improved during both treatment regimens and the incidence did not change following a switch from lanreotide SR to octreotide LAR.Octreotide LAR decreased serum levels of growth hormone and IGF-1 after the first injection and levels continued to decline throughout the entire treatment period in studies of up to 4 years’ duration. Symptoms of acromegaly showed further improvement after patients (n = 128) were switched from subcutaneous octreotide to octreotide LAR.TolerabilityOctreotide LAR is generally well tolerated by most patients. The most common adverse events are gastrointestinal disturbances and injection site reactions, both of which are usually transient and mild to moderate in severity. About a third of patients receiving octreotide LAR experience diarrhoea, abdominal pain and/or flatulence. Injection site pain is dose-related and has been reported in about 9% of patients receiving octreotide LAR 20mg per month. Withdrawal of medication as a result of gastrointestinal or injection site events is rare.Biliary abnormalities, including gallstones, microlithiasis, sediment, and sludge are associated with octreotide LAR therapy; however, to date, only 1% of patients have become symptomatic and require a cholycystectomy. The prevalence of biliary abnormalities did not change after switching from subcutaneous octreotide, or from lanreotide SR, to octreotide LAR.Approximately 2% of patients with acromegaly treated with octreotide (subcutaneous or long-acting intramuscular) develop hypoglycaemia, and about 15% develop hyperglycaemia. In most cases, the hypo- or hyperglycaemia is mild. Although most clinical studies reported no change in vital signs during therapy with octreotide LAR, two trials report

Spotlight on paroxetine in psychiatric disorders in adults

Paroxetine is a selective serotonin reuptake inhibitor (SSRI), with antidepres-sant and anxiolytic activity.In 6- to 24-week well designed trials, oral paroxetine 10 to 50 mg/day was significantly more effective than placebo, at least as effective as tricyclic anti-depressants (TCAs) and as effective as other SSRIs and other antidepressants in the treatment of major depressive disorder. Relapse or recurrence over 1 year after the initial response was significantly lower with paroxetine 10 to 50 mg/day than with placebo and similar to that with imipramine 50 to 275 mg/day.The efficacy of paroxetine 10 to 40 mg/day was similar to that of TCAs and fluoxetine 20 to 60 mg/day in 6- to 12-week trials in patients aged ≥60 years with major depression. Paroxetine 10 to 40 mg/day improved depressive symptoms to an extent similar to that of TCAs in patients with comorbid illness, and was more effective than placebo in the treatment of dysthymia and minor depression.Paroxetine 20 to 60 mg/day was more effective than placebo after 8 to 12 weeks’ treatment of obsessive-compulsive disorder (OCD), panic disorder, social anxiety disorder (social phobia), generalised anxiety disorder (GAD) and post-traumatic stress disorder (PTSD). Improvement was maintained or relapse was prevented for 24 weeks to 1 year in patients with OCD, panic disorder, social anxiety disorder or GAD. The efficacy of paroxetine was similar to that of other SSRIs in patients with OCD and panic disorder and similar to that of imipramine but greater than that of 2′chlordesmethyldiazepam in patients with GAD.Paroxetine is generally well tolerated in adults, elderly individuals and patients with comorbid illness, with a tolerability profile similar to that of other SSRIs. The most common adverse events with paroxetine were nausea, sexual dysfunction, somnolence, asthenia, headache, constipation, dizziness, sweating, tremor and decreased appetite.In conclusion, paroxetine, in common with other SSRIs, is generally better tolerated than TCAs and is a first-line treatment option for major depressive disorder, dysthymia or minor depression. Like other SSRIs, paroxetine is also an appropriate first-line therapy for OCD, panic disorder, social anxiety disorder, GAD and PTSD. Notably, paroxetine is the only SSRI currently approved for the treatment of social anxiety disorder and GAD, which makes it the only drug of its class indicated for all five anxiety disorders in addition to major depressive disorder. Thus, given the high degree of psychiatric comorbidity of depression and anxiety, paroxetine is an important first-line option for the treatment of major depressive disorder, OCD, panic disorder, social anxiety disorder, GAD and PTSD.

Epoetin Beta: a review of its clinical use in the treatment of anaemia in patients with cancer.

SummaryAbstractEpoetin beta (NeoRecormon®) is a recombinant form of erythropoietin. It increases reticulocyte counts, haemoglobin (Hb) levels and haematocrit.Epoetin beta administered subcutaneously once weekly corrected anaemia and had equivalent efficacy to that of epoetin beta administered three times weekly in patients with haematological malignancies. Subcutaneous epoetin beta reduced transfusion requirements and increased Hb levels versus no treatment in patients with solid tumours and chemotherapy-induced anaemia in nonblind, randomised trials. Anaemia and quality of life were also improved, and blood transfusion requirements were reduced to a significantly greater extent than placebo or no treatment (with supportive blood transfusion) in patients with haematological malignancies. Most patients were receiving chemotherapy.Subcutaneous epoetin beta was well tolerated by patients with cancer; adverse events with the drug occurred with a similar incidence to those with placebo or no treatment (with supportive blood transfusion). Hypertension was relatively uncommon with epoetin beta in clinical trials.Patients with haematological malignancies and a baseline platelet count ≥100 × 109/L, Hb levels of >-9 g/dL or lower erythropoietin levels have demonstrated better responses to epoetin beta than other patients in clinical trials. However, neither baseline erythropoietin level nor the observed to predicted ratio of erythropoietin levels correlated with the response to epoetin beta in patients with solid tumours and chemotherapy-induced anaemia. A decrease of <1 g/dL or an increase in Hb with epoetin beta during the first chemotherapy cycle indicated a low transfusion need in subsequent cycles in patients with ovarian carcinoma.In general, the efficacy of epoetin beta is not limited by tumour type. Response to the drug occurred irrespective of the nature (platinum- or nonplatinum-based) or presence of chemotherapy treatment in randomised trials. Conclusion: Epoetin beta has shown efficacy in the management of cancer-related anaemia in patients with haematological malignancies and of chemotherapy-induced anaemia in patients with solid tumours. Once-weekly administration provides added convenience for patients and may be cost saving, although additional research into the potential pharmacoeconomic benefits of this regimen are required. The drug is well tolerated in patients with cancer and is associated with little injection-site pain when administered subcutaneously. Epoetin beta is an important option in the prevention of chemotherapy-induced anaemia, and a valid and valuable alternative to blood transfusion therapy for the treatment of cancer-related or chemotherapy-induced anaemia.Pharmacodynamic ProfileEpoetin beta produces dose-proportional increases in reticulocyte counts and haematocrit and haemoglobin (Hb) levels. The increases in Hb levels with recommended dosages of epoetin beta were significantly greater than those with no treatment (with supportive blood transfusion) or placebo in randomised trials in patients with anaemia and cancer.The correction of anaemia with epoetin beta is associated with beneficial changes in cardiovascular parameters in patients with chronic renal failure (CRF) undergoing haemodialysis (HD); these include reduced left ventricular hypertrophy, and increased exercise capacity and maximum oxygen consumption. These effects have not been evaluated in patients with cancer. Increases in blood pressure (BP) are relatively uncommon (≤10%) in clinical trials in patients with cancer, although BP monitoring is recommended in the manufacturer’s prescribing information. Epoetin beta is associated with little injection-site pain.Pharmacokinetic ProfileThe mean maximum plasma concentration (Cmax) was lower and maintained for longer periods with subcutaneous than with intravenous administration of epoetin beta. After single-dose subcutaneous epoetin beta 40–120 IU/kg, Cmax was 40.5–176 IU/L in adults with CRF undergoing HD or continuous ambulatory peritoneal dialysis (CAPD) [n = 8–12]; the time to reach Cmax was 12–18 hours. Values for area under the concentration-time curve were 1372–9610 IU · h/L, and the absolute bioavailability was 21.5–46.4%. Absorption kinetics were not significantly altered after up to 17 months’ administration of subcutaneous epoetin beta (40 IU/kg three times weekly or a median dose of 78.5 IU/kg/week) in this patient group.After an initial distribution phase, the mean elimination half-life (t1/2β) of subcutaneous epoetin beta 40 IU/kg was 16.1 or 11.2 hours in patients with CRF undergoing HD or CAPD; this was longer than that after intravenous administration (6.7 or 8.8 hours). There were no significant changes in t1/2β after prolonged treatment with subcutaneous epoetin beta 40 IU/kg three times weekly for 6 weeks. The precise route of elimination of epoetin beta is unknown, but nonrenal mechanisms appear to predominate. Reduced hepatic function does not appear to affect the metabolism and elimination of the drug administered intravenously.The site of subcutaneous injection may affect the pharmacokinetics of epoetin beta, although results have not been consistent.Therapeutic EfficacyEpoetin beta 30 000IU administered subcutaneously once weekly corrected anaemia in most patients and had equivalent efficacy (assessed across multiple endpoints, including time-adjusted Hb area under the curve for weeks 5–16) to epoetin beta 10 000IU administered three times weekly in a randomised, nonblind, noninferiority study in 241 patients with haematological malignancies.Subcutaneous epoetin beta (initial dosage 450 IU/kg/week or 2000–10 000 IU/ day) improved anaemia (increased Hb levels) and reduced transfusion requirements in randomised double-blind or nonblind trials of 12–24 weeks’ duration involving 121–343 evaluable patients with malignant disease (solid tumours or haematological malignancies); most patients were receiving chemotherapy.The observed response rates (≥2.5-fold) and the reduction in transfusion requirements (by 18–46%) with epoetin beta 14 000–70 000 IU/week were significantly greater than those with placebo or no treatment in patients with anaemia associated with haematological malignancies. Response was defined as a ≥2 g/dL increase in Hb level from baseline with no transfusion requirement during a given period.In addition, epoetin beta reduced the need for blood transfusions and maintained Hb levels in patients with relapsed aggressive lymphoma receiving aggressive sequential chemotherapy.Subcutaneous epoetin beta was effective in the treatment of chemotherapy-induced anaemia in patients with solid tumours; the drug (5000 IU/day, or 450 or 900 IU/kg/week) reduced transfusion requirements by 37–90% compared with no treatment and 3000–30 000 IU/week increased Hb levels from baseline by 0.89–2.7 g/dL in randomised, nonblind trials of 8 to ≈24 weeks’ duration in 34–189 evaluable patients.Epoetin beta was effective in the treatment of anaemia in all tumour types. In trials involving patients with haematological malignancies, response with epoetin beta occurred irrespective of the nature or presence of chemotherapy; however, in patients with solid tumours treated with chemotherapy, response with the drug is more pronounced in patients receiving platinum-based regimens.Patients with haematological malignancies and a baseline platelet count ≥100 × 109/L, Hb levels of ≥9 g/dL or lower erythropoietin levels have demonstrated better responses to epoetin beta than other patients in clinical trials. An observed to predicted ratio of erythropoietin levels (O/P ratio) of ≤0.8 was associated with an Hb response to epoetin beta in a trial in patients with ovarian carcinoma, and a decrease of ≤1 g/dL or an increase in Hb during the first cycle of chemotherapy indicated low transfusion requirements during subsequent cycles. Nevertheless, in two other trials in patients with solid tumours and chemotherapy-induced anaemia, there was no correlation between serum erythropoietin levels or O/P ratios and a response.Subcutaneous epoetin beta (450 IU/week) significantly improved quality of life (across multiple assessment scales) over 12–16 weeks in patients with solid tumours or haematological malignancies compared with control (with supportive blood transfusion) or placebo. Improvements were significantly greater in responders to epoetin beta treatment than in nonresponders, and were correlated with changes in Hb levels.TolerabilitySubcutaneous epoetin beta was well tolerated in clinical trials in patients (n = 144–343) with cancer-related or chemotherapy-induced anaemia; most adverse events in these trials were considered unrelated to treatment with the study drug. Injection-site adverse events, which were transient in nature, were relatively uncommon in clinical trials.The incidence of adverse events with subcutaneous epoetin beta (initial dosage 450 IU/kg/week) was similar to that with placebo or control (with supportive blood transfusion) in patients with cancer-related anaemia; 33% and 42% of patients treated with epoetin beta experienced serious adverse events compared with 32% of those receiving placebo and 33% of untreated patients (receiving supportive blood transfusion therapy). Tolerability with epoetin beta administered once weekly was similar to that with the drug administered three times weekly.Hypertensive events occur in approximately 10% of patients with cancer after subcutaneous epoetin beta. Hypertension was slightly more common in epoetin beta recipients than in patients treated with placebo or in those receiving no treatment in two randomised trials, although there were no reported statistically significant differences between treatment groups in any trial in patients with cancer.The incidences of death, which occurred during the treatment phase or follow-up period, or withdrawal from the study because of adverse events, were similar with epoetin beta to those

Zanamivir: an update of its use in influenza.

UNLABELLED Zanamivir is a potent competitive inhibitor of the neuraminidase glycoprotein, which is essential in the infective cycle of influenza A and B viruses. Zanamivir (10mg by inhalation via the Diskhaler twice daily, or 10mg inhaled plus 6.4mg intranasally two or four times daily, for 5 days) reduced the median time to alleviation of major influenza symptoms by up to 2.5 days compared with placebo. Significant reductions of 1 to 2.5 days versus placebo were observed with inhaled zanamivir in phase III trials involving otherwise healthy adults, high-risk patients or children aged 5 to 12 years. Accelerated return to normal activities, and reduced interference with sleep, consumption of relief medication and incidence of complications leading to antibacterial use were also observed with zanamivir. When used for prophylaxis, inhaled zanamivir 10 to 20 mg/day for 10 days to 4 weeks (plus 6.4 mg/day intranasally in one trial) prevented influenza A in 67% of recipients in a university community, significantly reduced the number of families with new cases of influenza compared with placebo or prevented new cases of influenza in long-term care facilities. The tolerability of inhaled or intranasal zanamivir was similar to that of placebo in otherwise healthy adults, high-risk and elderly patients, and children. Recommended dosages of zanamivir did not adversely affect pulmonary function in patients with respiratory disorders in a well-controlled trial, although there have been rare reports of bronchospasm and/or a decline in respiratory function. CONCLUSION Zanamivir (used within 48 hours of symptom development) reduces the duration of symptomatic illness, causes accelerated return to normal activities or reduces complications requiring antibacterial use in adults, high-risk individuals and children with influenza. Vaccination remains the intervention of choice for prophylaxis in selected populations. However, the efficacy, good tolerability profile and lack of resistance with zanamivir make it a useful option, particularly in those not covered or inadequately protected by vaccination, who are able to use the inhalation device. The use of zanamivir in patients with respiratory disorders remains unclear because of concerns regarding its potential for bronchospasm. Prospective cost-effectiveness analyses and investigations of efficacy in preventing serious complications of influenza, particularly in high-risk patients, are required. Zanamivir shows potential for prophylaxis in persons for whom vaccination is contraindicated or ineffective, in elderly or high-risk patients in long-term care facilities and in households.

Tinzaparin sodium: a review of its pharmacology and clinical use in the prophylaxis and treatment of thromboembolic disease.

SummaryAbstractTinzaparin sodium (tinzaparin; innohep®) is a low molecular weight heparin (LMWH) formed by the enzymatic degradation of porcine unfractionated heparin (UFH).In clinical trials, once-daily subcutaneous (SC) tinzaparin was effective and generally well tolerated in the prophylaxis and treatment of thromboembolic disease. SC tinzaparin 75 anti-Xa IU/kg/day showed similar thromboprophylactic efficacy to adjusted-dosage oral warfarin in patients undergoing total hip arthroplasty; in patients undergoing knee replacement, the incidence of deep vein thrombosis (DVT) was significantly lower with tinzaparin. The drug had similar efficacy to equivalent-dosage SC enoxaparin sodium in orthopaedic surgery. In patients undergoing general surgery, SC tinzaparin 3500 anti-Xa IU/day was of equivalent thromboprophylactic efficacy to SC UFH 5000IU twice daily. Encouraging preliminary results have been obtained with tinzaparin in the prevention of DVT in patients with complete motor paralysis. In the initial treatment of acute proximal DVT and pulmonary embolism, SC tinzaparin 175 anti-Xa IU/kg/day was at least as effective as adjusted-dosage intravenous (IV) UFH. In the outpatient treatment of venous thromboembolism, tinzaparin has demonstrated similar efficacy to dalteparin sodium (dalteparin) and warfarin. Tinzaparin was effective in preventing clotting in haemodialysis circuits; the anticoagulant efficacy of tinzaparin in patients undergoing haemodialysis was similar to that of SC dalteparin and similar to or less than (although in this case the tinzaparin dose was too low for sufficient anticoagulant efficacy) that of IV UFH.Advantages of tinzaparin over UFH and warfarin include ease of administration and lack of need for laboratory monitoring. Tinzaparin is more cost effective than UFH in the treatment of established thromboembolic disease, and homebased treatment with tinzaparin may offer greater cost benefits than hospitalbased therapy. Tinzaparin is well tolerated, including in elderly patients and those with renal impairment receiving long-term treatment. Incidences of major bleeding complications were low and reports of heparin-induced thrombocytopenia were infrequent in clinical studies. In conclusion, tinzaparin is a valuable LMWH in the prophylaxis and management of thromboembolic disease.Pharmacological PropertiesSubcutaneous (SC) tinzaparin sodium (tinzaparin) increases anti-factor Xa and anti-factor IIa activities in plasma in a dose-related fashion. Tinzaparin stimulates the release of tissue factor pathway inhibitor, which contributes to the anticoagulant, and possibly the anti-tumour activities, of tinzaparin. Plasma antithrombin levels and platelet counts are not affected to a clinically significant extent by tinzaparin.The absorption half-life of single-dose SC tinzaparin in terms of anti-factor Xa activity was 200–248 minutes in healthy volunteers, and the bioavailability of the drug is 87–90%. However, the pharmacokinetics of tinzaparin are subject to wide interindividual variability. Elimination is predominately by renal filtration. Clearance of tinzaparin may be reduced in patients with severe renal impairment. The pharmacokinetics of tinzaparin are not affected by bodyweight or body mass index when the drug is administered at 75 or 175 anti-Xa IU/kg.Therapeutic EfficacyUse in Thromboprophylaxis: Prophylactic dosages of SC tinzaparin were superior to placebo and intravenous (IV) dextran in the prevention of deep vein thrombosis (DVT) in patients undergoing total hip replacement. Efficacy tended to be greater with higher dosages of tinzaparin (approximately 75 anti-Xa IU/kg) than with lower dosages (approximately 50 anti-Xa IU/kg).In a study of 1207 patients, SC tinzaparin 75 anti-Xa IU/kg once daily was of similar thromboprophylactic efficacy to adjusted-dosage oral warfarin when given for 14 days to patients undergoing total hip arthroplasty, but the incidence of DVT was significantly lower with tinzaparin than with warfarin in patients receiving knee replacement. Tinzaparin 4500 anti-Xa IU/day was of equivalent antithrombotic efficacy to enoxaparin sodium (enoxaparin) 40 mg/day; both low molecular weight heparins (LMWHs) were given as single daily SC injections in 440 patients undergoing total hip replacement.Seven to ten days prophylaxis with SC tinzaparin 3500 anti-Xa IU once daily or SC unfractionated heparin (UFH) 5000IU twice daily was of equivalent efficacy and superior to tinzaparin 2500 anti-Xa IU once daily in a double-blind study in 1290 patients undergoing general surgery. Prolonged thromboprophylaxis with tinzaparin for up to an additional 28 days maintains, and may even improve on, short-term efficacy in terms of DVT reduction. The thromboprophylactic efficacy of tinzaparin has been further demonstrated in small studies in patients with motor paralysis. Treatment of Established Venous Thromboembolic Disease: SC tinzaparin 175 anti-Xa IU/kg/day for approximately 5–7 days was at least as effective as adjusted-dosage IV UFH in the initial management of 432 patients with acute proximal DVT in one study, and in 812 patients with pulmonary embolism in two other studies. Preliminary data indicate that tinzaparin (175 anti-Xa IU/kg/day or dosage not stated) is as effective as SC dalteparin sodium (200 anti-Xa IU/kg/day) or long-term oral warfarin in the outpatient treatment of venous thromboembolism, and suggests that home treatment with an LMWH is well accepted by patients. Analyses of hospital costs from the perspective of healthcare or third party payers have indicated cost advantages with SC tinzaparin relative to IV adjusted-dosage UFH in the treatment of established thromboembolic disease. Costs may be further reduced with outpatient treatment with tinzaparin in this patient group. Use in Haemodialysis: Tinzaparin was effective in the maintenance of patency of haemodialysis circuits, with additional benefits compared with UFH in terms of improvements in patients’ lipid metabolism, especially over the long term. Tinzaparin 3000–4500 anti-Xa IU was less effective than, or had similar efficacy to, IV adjusted-dose UFH in terms of clot formation in small crossover studies, although, in one study, the initial tinzaparin dose (3500 anti-Xa IU) was considered too low for sufficient anticoagulant effect. The anticoagulant efficacy of tinzaparin (mean 5024 anti-Xa IU/session) was similar to that of dalteparin (mean 5546 anti-Xa IU/session) in a randomised single-blind trial in 149 evaluable patients.TolerabilityMajor bleeding complications with SC tinzaparin are infrequent in clinical studies. There were no significant differences in incidence of postoperative bleeding between SC tinzaparin 2500 or 3500 anti-Xa IU daily or SC UFH 5000IU twice daily for thromboprophylaxis in 1290 patients (mean age 61 years) undergoing general surgery. In 1207 patients (mean age 66 years) undergoing orthopaedic surgery, rates of major bleeding over 14 days were 2.8% with SC tinzaparin 75 anti-Xa IU/kg/day and 1.2% with adjusted-dosage oral warfarin (p = 0.04). Incidences of major bleeding with SC tinzaparin 175 anti-Xa IU/kg once daily were either similar to or significantly lower (0.5% vs 5%; p = 0.006) than those with IV activated partial thromboplastin time-adjusted UFH in patients with established VTE, including elderly individuals. Tinzaparin was well tolerated in patients undergoing haemodialysis; during long-term maintenance, the incidence of major or minor bleeding was similar with tinzaparin (mean 5024 anti-Xa IU) to that with dalteparin (mean 5546 anti-Xa IU). In patients with renal insufficiency relative to those with normal renal function, the incidence of bleeding events with tinzaparin appeared lower than that with UFH. The incidence of major bleeding (1.5%) in 200 very elderly patients (mean age 85.2 years) receiving tinzaparin (initial dosage 175 anti-Xa IU/kg) in an observational study was similar to that reported in clinical trials in younger patients.Heparin-induced thrombocytopenia was rarely reported in clinical studies of tinzaparin (incidence approximately 1%). The drug appears well tolerated, with no evidence of placental transfer, in pregnant women. Effects of tinzaparin on liver function tests are transient and do not normally require cessation of therapy.