John Waugh

Pioglitazone : A review of its use in type 2 diabetes mellitus

Pioglitazone is an antihyperglycaemic agent that, in the presence of insulin resistance, increases hepatic and peripheral insulin sensitivity, thereby inhibiting hepatic gluconeogenesis and increasing peripheral and splanchnic glucose uptake. Pioglitazone is generally well tolerated, weight gain and oedema are the most common emergent adverse events, and there are no known drug interactions between pioglitazone and other drugs. In clinical trials in patients with type 2 diabetes mellitus, pioglitazone as monotherapy, or in combination with metformin, repaglinide, insulin or a sulphonylurea, induced both long- and short-term improvements in glycaemic control and serum lipid profiles. Pioglitazone was also effective in reducing some measures of cardiovascular risk and arteriosclerosis. Pioglitazone thus offers an effective treatment option for the management of patients with type 2 diabetes.

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

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

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

Topiramate: As monotherapy in newly diagnosed epilepsy

Topiramate is an antiepileptic drug that has a broad spectrum of antiseizure effects, which appear to be the result of several neurostabilising pharmacological mechanisms. These include blockade of ion channels, potentiation of GABA neuroinhibition and glutamate receptor antagonism at non-NMDA receptors, as well as mild inhibition of carbonic anhydrase. Topiramate monotherapy dose dependently reduced the number of patients who met seizure related exit criteria in children (aged > or =6 years) and adults with epilepsy. This effect was also observed in patients who had previously experienced partial onset seizures and for those who had experienced generalised tonic clonic seizures. Six-month and 1-year seizure-free rates were dose-dependently reduced. In epilepsy, topiramate monotherapy 100 or 200 mg/day was as effective as carbamazepine 600 mg/day or valproate 1250 mg/day as measured by time to study exit for any reason, time to first seizure and percentage of patients seizure-free in the final 6 months of treatment (mean treatment duration 244 days). Adverse events associated with topiramate monotherapy that were dosage related included paraesthesia, weight loss and diarrhoea. Renal calculi were also reported in both fully published trials.

Adapalene: a review of its use in the treatment of acne vulgaris.

Adapalene (Differin) is a retinoid agent indicated for the topical treatment of acne vulgaris. In clinical trials, 0.1% adapalene gel has proved to be effective in this indication and was as effective as 0.025% tretinoin gel, 0.1% tretinoin microsphere gel, 0.05% tretinoin cream and 0.1% tazarotene gel once every two days; however, the drug was less effective than once-daily 0.1% tazarotene gel. It can be used alone in mild acne or in combination with antimicrobials in inflammatory acne and has proved efficacious as maintenance treatment. Adapalene has a rapid onset of action and a particularly favourable tolerability profile compared with other retinoids. These attributes can potentially promote patient compliance, an important factor in treatment success. Adapalene is, therefore, assured of a role in the first-line treatment of acne vulgaris.

The Paclitaxel (TAXUS™)-Eluting Stent

SummaryAbstractThe TAXUS™/Express2™ stent contains paclitaxel 1 μg/mm2. On deployment, paclitaxel is slowly released into the intimal tissue of the coronary artery to prevent cell proliferation and neointimal hyperplasia. When deployed in patients with previously untreated coronary artery lesions, the paclitaxel-eluting stent (PES) effectively reduces the need for revascularization without increasing the risk of in-stent thrombosis. While long-term outcomes data and comparative efficacy and cost-benefit trials versus other drug-eluting stents are required, the PES appears to be an attractive alternative for the management of de novo coronary artery lesions.Pharmacoloaic PropertiesThe PES comprises a stainless steel stent coated with a non-erodible biocompatible polyolefin matrix containing paclitaxel 1 μg/mm2. Paclitaxel dose dependently inhibits vascular smooth muscle cell proliferation at therapeutic concentrations as a result of binding to and stabilizing cellular microtubules. This prevents the cascade of events associated with obstructive in-stent neointimal hyperplasia.Paclitaxelwas released in a controlled manner from the stent coating in in vitro studies. The higher release rate in the first 2 days after implantation (to reduce response to implantation injury) slows over the next 8–10 days. The drug is rapidly taken up by intimal cells with minimal dispersion in the plasma; it was not detected systemically after stent deployment in clinical trials. Paclitaxel is extensively bound to proteins (88–98%), and is principally metabolized in the liver, undergoing biliary clearance after systemic administration.Therapeutic EfficacyThe efficacy of the PES was compared with that of a bare-metal stent (BMS) in a number of randomized, double-blind, multicenter trials in patients with de novo coronary artery lesions. The TAXUS I and II trials used the NIR® stent, while the pivotal TAXUS IV trial used the Express™ stent.The primary endpoints of the well designed TAXUS II and IV trials indicated superiority for the PES over the BMS. Twice as many patients receiving the BMS required target vessel revascularization at 9 months postprocedure and, 6 months following the procedure, the in-stent neointimal volume in the PES system was only one-third of that in the BMS. The incidence of cumulative major adverse cardiac events (MACE; cardiac death, myocardial infarction [MI], or target vessel revascularization [TVR]) was also significantly lower in PES than BMS recipients at 9 and 12 months postprocedure. The incidence of cardiac death and MI was low and similar between treatment groups; however, TVR was significantly reduced by the PES versus the BMS. Other secondary endpoints, such as target lesion revascularization, luminal diameter stenosis, minimal luminal diameter, and serial intravascular ultrasound measurements from one or both trials supported these results.Preliminary analysis of the subgroup of patients with diabetes mellitus in the TAXUS IV trial suggested that the PES was also effective in diabetic patients who receive oral medications. The group receiving insulin was too small to draw meaningful conclusions.TolerabilityBecause of the small paclitaxel dosages and the mainly local uptake, systemic adverse events associated with the PES are considered unlikely. The incidences of cardiac death and MI were very low and similar in both groups.Local events such as in-stent aneurysms, incomplete stent apposition, or in-stent thrombosis occurred at a similar rate in PES and BMS recipients. There has been no evidence of late thrombosis in PES recipients followed for 2 years. The rate of late luminal loss in the 5mm of vessel proximal and distal to the stent edges was significantly lower in PES than BMS systems.Pharmacoeconomic ConsiderationsInitial deployment costs associated with the PES are likely to be offset by savings in repeat procedures, according to a cost-effectiveness analysis in the UK.

Conserved primers for DNA barcoding historical and modern samples from New Zealand and Antarctic birds

Our ability to DNA barcode the birds of the world is based on the effective amplification and sequencing of a 648 base pair (bp) region of the mitochondrial cytochrome c oxidase (COI or cox1) gene. For many geographic regions the large numbers of vouchered specimens necessary for the construction of a DNA barcoding database have already been collected and are available in museums and other institutions. However, many of these specimens are old (>20 years) and are stored as either fixed study skins or dried skeletons. DNA extracted from such historical samples is typically degraded and, generally, only short DNA fragments can be recovered from such specimens making the recovery of the barcoding region as a single fragment difficult. We report two sets of conserved primers that allow the amplification of the entire DNA barcoding region in either three or five overlapping fragments. These primer sets allow the recovery of DNA barcodes from valuable historical specimens that in many cases are unique in that they are unable or unlikely to be collected again. We also report three new primers that in combination allow the effective amplification from modern samples of the entire DNA barcoding region as a single DNA fragment for 17 orders of Southern Hemisphere birds.

Birdstrikes and barcoding: can DNA methods help make the airways safer?

While flying remains one of the safest means of travel, reported birdstrikes on aircraft have risen. This is a result of increased aircraft flight movements, changes in agricultural methods and greater environmental awareness contributing to growing populations of hazardous bird species, as well as more diligent reporting of incidents. Measures to mitigate this hazard require accurate data about the species involved; however, the remains of birds from these incidents are often not easy to identify. Reported birdstrikes include a substantial number where the species cannot be determined from morphology alone. DNA barcoding offers a reliable method of identifying species from very small amounts of organic material such as blood, muscle and feathers. We compare species identification based on morphological criteria and identifications based on mitochondrial cytochrome c oxidase subunit I DNA barcoding methods for New Zealand species. Our data suggest that DNA‐based identification can substantially add to the accuracy of species identifications, and these methods represent an important addition to existing procedures to improve air safety. In addition, we outline simple and effective protocols for the recovery and processing of samples for DNA barcoding.

Ciprofloxacin extended release: In the treatment of urinary tract infections and uncomplicated pyelonephritis

Abstract▲ Ciprofloxacin extended release (XR) is a new oral formulation of a fluoroquinolone that allows once-daily administration while maintaining therapeutic serum levels of the drug.▲ The maximum plasma concentrations (Cmax) of once-daily ciprofloxacin XR 500mg was higher than that of twice-daily ciprofloxacin immediate release 250mg and the Cmax of once-daily ciproflocaxin XR 1000mg was higher than that of twice-daily ciprofloxacin 500mg. No accumulation of ciprofloxacin XR at steady state was observed in healthy men and all other pharmacokinetic parameters were similar to those of the immediate-release formulation.▲ In patients with uncomplicated urinary tract infection (UTI), bacteriological eradication rates were similar in recipients of ciprofloxacin XR and immediate-release ciprofloxacin at the test-of-cure (TOC) visit, as were rates of persistence or new infection. Clinical cure rates were also similar in the two treatment groups.▲ Bacteriological eradication occurred in 89% of ciprofloxacin XR and 85% of immediate-release ciprofloxacin recipients with complicated UTIs or acute uncomplicated pyelonephritis at the TOC visit. Clinical cure rates were also similar in the two treatment groups.▲ Ciprofloxacin XR was generally well tolerated in patients with uncomplicated or complicated UTIs or acute uncomplicated pyelonephritis and showed similar tolerability to that of the immediate-release formulation.

Spotlight on Adapalene in Acne Vulgaris

Adapalene (Differin®) is a retinoid agent indicated for the topical treatment of acne vulgaris. In clinical trials, 0.1% adapalene gel has proved to be effective in this indication and was as effective as 0.025% tretinoin gel, 0.1% tretinoin microsphere gel, 0.05% tretinoin cream and 0.1% tazarotene gel once every two days; however, the drug was less effective than once-daily 0.1% tazarotene gel. It can be used alone in mild acne or in combination with antimicrobials in inflammatory acne and has proved efficacious as maintenance treatment. Adapalene has a rapid onset of action and a particularly favorable tolerability profile compared with other retinoids. These attributes can potentially promote patient compliance, an important factor in treatment success. Adapalene is, therefore, assured of a role in the first-line treatment of acne vulgaris.