Continuous infusion of ticarcillin-clavulanate for home treatment of serious infections : clinical efficacy, safety, pharmacokinetics and pharmacodynamics

Continuous infusion (CI) ticarcillin–clavulanate is a potential therapeutic improvement over conventional intermittent dosing because the major pharmacodynamic (PD) predictor of efficacy of β-lactams is the time that free drug levels exceed the MIC. This study incorporated a 6-year retrospective arm evaluating efficacy and safety of CI ticarcillin–clavulanate in the home treatment of serious infections and a prospective arm additionally evaluating pharmacokinetics (PK) and PD. In the prospective arm, steady-state serum ticarcillin and clavulanate levels and MIC testing of significant pathogens were performed. One hundred and twelve patients (median age, 56 years) were treated with a CI dose of 9.3–12.4 g/day and mean CI duration of 18.0 days. Infections treated included osteomyelitis (50 patients), septic arthritis (6), cellulitis (17), pulmonary infections (12), febrile neutropenia (7), vascular infections (7), intra-abdominal infections (2), and Gram-negative endocarditis (2); 91/112 (81%) of patients were cured, 14 (13%) had partial response and 7 (6%) failed therapy. Nine patients had PICC line complications and five patients had drug adverse events. Eighteen patients had prospective PK/PD assessment although only four patients had sufficient data for a full PK/PD evaluation (both serum steady-state drug levels and ticarcillin and clavulanate MICs from a bacteriological isolate), as this was difficult to obtain in home-based patients, particularly as serum clavulanate levels were found to deteriorate rapidly on storage. Three of four patients with matched PK/PD assessment had free drug levels exceeding the MIC of the pathogen. Home CI of ticarcillin–clavulanate is a safe, effective, convenient and practical therapy and is a therapeutic advance over traditional intermittent dosing when used in the home setting.

The cost effectiveness of Naltrexone added to cognitive-behavioral therapy in the treatment of alcohol dependence

he purpose of this study was to evaluate the comparative cost of treating alcohol dependence with either cognitive behavioral therapy (CBT) alone or CBT combined with naltrexone (CBT+naltrexone). Two hundred ninety-eight outpatients dependent on alcohol who were consecutively treated for alcohol dependence participated in this study. One hundred seven (36%) patients received adjunctive pharmacotherapy (CBT+naltrexone). The Drug Abuse Treatment Cost Analysis Program was used to estimate treatment costs. Adjunctive pharmacotherapy (CBT+naltrexone) introduced an additional treatment cost and was 54% more expensive than CBT alone. When treatment abstinence rates (36.1% CBT; 62.6% CBT+naltrexone) were applied to cost effectiveness ratios, CBT+naltrexone demonstrated an advantage over CBT alone. There were no differences between groups on a preference-based health measure (SF-6D). In this treatment center, to achieve 100 abstainers over a 12-week program, 280 patients require CBT compared with 160 CBT+naltrexone. The dominant choice was CBT+naltrexone based on modest economic advantages and significant efficiencies in the numbers needed to treat.

The Treatment of Neonatal Seizures: A Critical Review of the Evidence

In a critical review of the literature to assess the efficacy of monotherapy and subsequent combinant anticonvulsant therapy in the treatment of neonatal seizures, four studies were examined; three randomised control trials and one retrospective cohort study. Each study used phenobarbital for monotherapy with doses reaching a maximum of 40mg/kg. Anticonvulsant drugs used in conjunction with phenobarbitone for combinant therapy included midazolam, clonazepam, lorazepam, phenytoin and lignocaine. Each study used an electroencephalograph for seizure diagnosis and neonatal monitoring when determining therapy efficacy and final outcome assessments. Collectively the studies suggest neither monotherapy nor combinant therapy are entirely effective in seizure control. Monotherapy demonstrated a 29% - 50% success rate for complete seizure control whereas combinant therapy administered after the failure of monotherapy demonstrated a success rate of 43% - 100%. When these trials were combined the overall success for monotherapy was 44% (n = 34/78) and for combinant therapy 72% ( n = 56/78). Though the evidence was inconclusive, it would appear that combinant therapy is of greater benefit to infants unresponsive to monotherapy. Further research such as multi-site randomised controlled trials using standardised criteria and data collection are required within this specialised area.

Interactions between energy intake and expenditure in the development and treatment of obesity.

Summary There are four interactions to consider between energy intake (EI) and energy expenditure (EE) in the development and treatment of obesity. (1) Does sedentariness alter levels of EI or subsequent EE? and (2) Do high levels of EI alter physical activity or exercise? (3) Do exercise-induced increases in EE drive EI upwards and undermine dietary approaches to weight management and (4) Do low levels of EI elevate or decrease EE? There is little evidence that sedentariness alters levels of EI. This lack of cross-talk between altered EE and EI appears to promote a positive EB. Lifestyle studies also suggest that a sedentary routine actually offers the opportunity for over-consumption. Substantive changes in non exercise activity thermogenesis are feasible, but not clearly demonstrated. Cross talk between elevated EE and EI is initially too weak and takes too long to activate, to seriously threaten dietary approaches to weight management. It appears that substantial fat loss is possible before intake begins to track a sustained elevation of EE. There is more evidence that low levels of EI does lower physical activity levels, in relatively lean men under conditions of acute or prolonged semi-starvation and in dieting obese subjects. During altered EB there are a number of small but significant changes in the components of EE, including (i) sleeping and basal metabolic rate, (ii) energy cost of weight change alters as weight is gained or lost, (iii) exercise efficiency, (iv) energy cost of weight bearing activities, (v) during substantive overfeeding diet composition (fat versus carbohydrate) will influence the energy cost of nutrient storage by ~ 15%. The responses (i-v) above are all “obligatory” responses. Altered EB can also stimulate facultative behavioural responses, as a consequence of cross-talk between EI and EE. Altered EB will lead to changes in the mode duration and intensity of physical activities. Feeding behaviour can also change. The degree of inter-individual variability in these responses will define the scope within which various mechanisms of EB compensation can operate. The relative importance of “obligatory” versus facultative, behavioural responses -as components of EB control- need to be defined.

New drugs for the treatment of coronary artery syndromes

Background: Acute coronary syndromes are a major cause of mortality and morbidity. Objectives/Methods: The objective of this evaluation is to review the clinical trials of two new drugs being developed for the treatment of acute coronary syndromes. The first drug is the anti-coagulant otamixaban, and the trial compared otamixaban with unfractionated heparin and eptifibatide in acute coronary syndromes. The second drug is the anti-platelet ticagrelor, and the trial compared ticagrelor with clopidogrel in acute coronary syndromes. Results: In the SEPIA-ACS1 TIMI 42 trial, the primary efficacy endpoint occurred in 6.2% of subjects treated with unfractionated heparin and eptifibatide, and to a significantly lesser extent with otamixaban. In the PLATO trial, the primary efficacy endpoint had occurred less in the ticagrelor group (9.8%) than in the clopidogrel group (11.7%) at 12 months. Conclusions: Two new drugs for acute coronary syndromes, otamixaban and ticagrelor, have recently been shown to have benefits in subjects undergoing percutaneous interventions compared to the present standard regimens for this condition.

Good results for early treatment of clinically isolated syndrome prior to multiple sclerosis with interferon beta-1b and glatiramer

Background: The first sign of developing multiple sclerosis is a clinically isolated syndrome that resembles a multiple sclerosis relapse. Objective/methods: The objective was to review the clinical trials of two medicines in clinically isolated syndromes (interferon β and glatiramer acetate) to determine whether they prevent progression to definite multiple sclerosis. Results: In the BENEFIT trial, after 2 years, 45% of subjects in the placebo group developed clinically definite multiple sclerosis, and the rate was lower in the interferon β-1b group. Then all subjects were offered interferon β-1b, and the original interferon β-1b group became the early treatment group, and the placebo group became the delayed treatment group. After 5 years, the number of subjects with clinical definite multiple sclerosis remained lower in the early treatment than late treatment group. In the PreCISe trial, after 2 years, the time for 25% of the subjects to convert to definite multiple sclerosis was prolonged in the glatiramer group. Conclusions: Interferon β-1b and glatiramer acetate slow the progression of clinically isolated syndromes to definite multiple sclerosis. However, it is not known whether this early treatment slows the progression to the physical disabilities experienced in multiple sclerosis.

Does the p38 MAP kinase inhibitor pamapimod have potential for the treatment of rheumatoid arthritis?

Background: Methotrexate alone or in combination with other agents is the standard treatment for moderate-to-severe rheumatoid arthritis. As the biological agents are expensive, they are not usually used until methotrexate has failed to give a good response. Thus, there is scope for the development of cheaper drugs that can be used instead of methotrexate or in addition to methotrexate. Objectives/methods: Pamapimod is a p38α inhibitor being developed for use in the treatment of rheumatoid arthritis. The objective was to evaluate the recent clinical trials of pamapimod in subjects with rheumatoid arthritis. Results: There is no clear cut evidence that pamapimod alone or in the presence of methotrexate is efficacious in subjects with rheumatoid arthritis, but it does cause adverse effects. Conclusion: It is unlikely that pamapimod will be useful in the treatment of rheumatoid arthritis.

Potential of St John's Wort for the treatment of depression : the economic perspective

The burden of rising health care expenditures has created a demand for information regarding the clinical and economic outcomes associated with complementary and alternative medicines. Meta-analyses of randomized controlled trials have found Hypericum perforatum preparations to be superior to placebo and similarly effective as standard antidepressants in the acute treatment of mild to moderate depression. A clear advantage over antidepressants has been demonstrated in terms of the reduced frequency of adverse effects and lower treatment withdrawal rates, low rates of side effects and good compliance, key variables affecting the cost-effectiveness of a given form of therapy. The most important risk associated with use is potential interactions with other drugs, but this may be mitigated by using extracts with low hyperforin content. As the indirect costs of depression are greater than five times direct treatment costs, given the rising cost of pharmaceutical antidepressants, the comparatively low cost of Hypericum perforatum extract makes it worthy of consideration in the economic evaluation of mild to moderate depression treatments.

Best practice for prevention and treatment of cardiovascular disease through an equity lens : a review

Background: Despite declining rates of cardiovascular disease (CVD) mortality in developed countries, lower socioeconomic groups continue to experience a greater burden of the disease. There are now many evidence-based treatments and prevention strategies for the management of CVD and it is essential that their impact on the more disadvantaged group is understood if socioeconomic inequalities in CVD are to be reduced. Aims: To determine whether key interventions for CVD prevention and treatment are effective among lower socioeconomic groups, to describe barriers to their effectiveness and the potential or actual impact of these interventions on the socioeconomic gradient in CVD. Methods: Interventions were selected from four stages of the CVD continuum. These included smoking reduction strategies, absolute risk assessment, cardiac rehabilitation, secondary prevention medications, and heart failure self-management programmes. Electronic searches were conducted using terms for each intervention combined with terms for socioeconomic status (SES). Results: Only limited evidence was found for the effectiveness of the selected interventions among lower SES groups and there was little exploration of socioeconomic-related barriers to their uptake. Some broad themes and key messages were identified. In the majority of findings examined, it was clear that the underlying material, social and environmental factors associated with disadvantage are a significant barrier to the effectiveness of interventions. Conclusion: Opportunities to reduce socioeconomic inequalities occur at all stages of the CVD continuum. Despite this, current treatment and prevention strategies may be contributing to the widening socioeconomic-CVD gradient. Further research into the impact of best-practice interventions for CVD upon lower SES groups is required.

Alkaline hydrothermal treatment of titanate nanostructures

Since its initial proposal in 1998, alkaline hydrothermal processing has rapidly become an established technology for the production of titanate nanostructures. This simple, highly reproducible process has gained a strong research following since its conception. However, complete understanding and elucidation of nanostructure phase and formation have not yet been achieved. Without fully understanding phase, formation, and other important competing effects of the synthesis parameters on the final structure, the maximum potential of these nanostructures cannot be obtained. Therefore this study examined the influence of synthesis parameters on the formation of titanate nanostructures produced by alkaline hydrothermal treatment. The parameters included alkaline concentration, hydrothermal temperature, the precursor material‘s crystallite size and also the phase of the titanium dioxide precursor (TiO2, or titania). The nanostructure‘s phase and morphology was analysed using X-ray diffraction (XRD), Raman spectroscopy and transmission electron microscopy. X-ray photoelectron spectroscopy (XPS), dynamic light scattering (non-invasive backscattering), nitrogen sorption, and Rietveld analysis were used to determine phase, for particle sizing, surface area determinations, and establishing phase concentrations, respectively. This project rigorously examined the effect of alkaline concentration and hydrothermal temperature on three commercially sourced and two self-prepared TiO2 powders. These precursors consisted of both pure- or mixed-phase anatase and rutile polymorphs, and were selected to cover a range of phase concentrations and crystallite sizes. Typically, these precursors were treated with 5–10 M sodium hydroxide (NaOH) solutions at temperatures between 100–220 °C. Both nanotube and nanoribbon morphologies could be produced depending on the combination of these hydrothermal conditions. Both titania and titanate phases are comprised of TiO6 units which are assembled in different combinations. The arrangement of these atoms affects the binding energy between the Ti–O bonds. Raman spectroscopy and XPS were therefore employed in a preliminary study of phase determination for these materials. The change in binding energy from a titania to a titanate binding energy was investigated in this study, and the transformation of titania precursor into nanotubes and titanate nanoribbons was directly observed by these methods. Evaluation of the Raman and XPS results indicated a strengthening in the binding energies of both the Ti (2p3/2) and O (1s) bands which correlated to an increase in strength and decrease in resolution of the characteristic nanotube doublet observed between 320 and 220 cm.1 in the Raman spectra of these products. The effect of phase and crystallite size on nanotube formation was examined over a series of temperatures (100.200 �‹C in 20 �‹C increments) at a set alkaline concentration (7.5 M NaOH). These parameters were investigated by employing both pure- and mixed- phase precursors of anatase and rutile. This study indicated that both the crystallite size and phase affect nanotube formation, with rutile requiring a greater driving force (essentially �\harsher. hydrothermal conditions) than anatase to form nanotubes, where larger crystallites forms of the precursor also appeared to impede nanotube formation slightly. These parameters were further examined in later studies. The influence of alkaline concentration and hydrothermal temperature were systematically examined for the transformation of Degussa P25 into nanotubes and nanoribbons, and exact conditions for nanostructure synthesis were determined. Correlation of these data sets resulted in the construction of a morphological phase diagram, which is an effective reference for nanostructure formation. This morphological phase diagram effectively provides a .recipe book�e for the formation of titanate nanostructures. Morphological phase diagrams were also constructed for larger, near phase-pure anatase and rutile precursors, to further investigate the influence of hydrothermal reaction parameters on the formation of titanate nanotubes and nanoribbons. The effects of alkaline concentration, hydrothermal temperature, crystallite phase and size are observed when the three morphological phase diagrams are compared. Through the analysis of these results it was determined that alkaline concentration and hydrothermal temperature affect nanotube and nanoribbon formation independently through a complex relationship, where nanotubes are primarily affected by temperature, whilst nanoribbons are strongly influenced by alkaline concentration. Crystallite size and phase also affected the nanostructure formation. Smaller precursor crystallites formed nanostructures at reduced hydrothermal temperature, and rutile displayed a slower rate of precursor consumption compared to anatase, with incomplete conversion observed for most hydrothermal conditions. The incomplete conversion of rutile into nanotubes was examined in detail in the final study. This study selectively examined the kinetics of precursor dissolution in order to understand why rutile incompletely converted. This was achieved by selecting a single hydrothermal condition (9 M NaOH, 160 °C) where nanotubes are known to form from both anatase and rutile, where the synthesis was quenched after 2, 4, 8, 16 and 32 hours. The influence of precursor phase on nanostructure formation was explicitly determined to be due to different dissolution kinetics; where anatase exhibited zero-order dissolution and rutile second-order. This difference in kinetic order cannot be simply explained by the variation in crystallite size, as the inherent surface areas of the two precursors were determined to have first-order relationships with time. Therefore, the crystallite size (and inherent surface area) does not affect the overall kinetic order of dissolution; rather, it determines the rate of reaction. Finally, nanostructure formation was found to be controlled by the availability of dissolved titanium (Ti4+) species in solution, which is mediated by the dissolution kinetics of the precursor.

Cognitive behaviour therapy (CBT) for the treatment of co-occurring depression and substance use : current evidence and directions for future research

Issues and Approach: The high rates of co-occurring depression and substance use, and the negative impact of this on illness course and outcomes have been well established. Despite this, few clinical trials have examined the efficacy of cognitive behaviour therapy (CBT). This paper systematically reviews these clinical trials, with an aim of providing recommendations for how future research can develop a more robust evidence base for the treatment of these common comorbidities. Leading electronic databases, including PubMed (ISI) and PsychINFO (CSA), were searched for peer-reviewed journal articles using CBT for the treatment of co-occurring depression and substance use. Of the 55 articles identified, 12 met inclusion criteria and were included in the review. ---------- Key Findings: There is only a limited evidence for the effectiveness of CBT either alone or in combination with antidepressant medication for the treatment of co-occurring depression and substance use. While there is support for the efficacy of CBT over no treatment control conditions, there is little evidence that CBT is more efficacious than other psychotherapies. There is, however, consistent evidence of improvements in both depression and substance use outcomes, regardless of the type of treatment provided and there is growing evidence that that the effects of CBT are durable and increase over time during follow up. ---------- Conclusions. Rather than declaring the ‘dodo bird verdict’ that CBT and all other psychotherapies are equally efficacious, it would be more beneficial to develop more potent forms of CBT by identifying variables that mediate treatment outcomes.