Rotary Bend Fatigue of Nitinol to One Billion Cycles.

Nitinol implants, especially those used in cardiovascular applications, are typically expected to remain durable beyond 108 cycles, yet literature on ultra-high cycle fatigue of nitinol remains relatively scarce and its mechanisms not well understood. To investigate nitinol fatigue behavior in this domain, we conducted a multifaceted evaluation of nitinol wire subjected to rotary bend fatigue that included detailed material characterization and finite element analysis as well as post hoc analyses of the resulting fatigue life data. Below approximately 105 cycles, cyclic phase transformation, as predicted by computational simulations, was associated with fatigue failure. Between 105 and 108 cycles, fractures were relatively infrequent. Beyond 108 cycles, fatigue fractures were relatively common depending on the load level and other factors including the size of non-metallic inclusions present and the number of loading cycles. Given observations of both low cycle and ultra-high cycle fatigue fractures, a two-failure model may be more appropriate than the standard Coffin-Manson equation for characterizing nitinol fatigue life beyond 108 cycles. This work provides the first documented fatigue study of medical grade nitinol to 109 cycles, and the observations and insights described will be of value as design engineers seek to improve durability for future nitinol implants.

The effect of the acute phase of infection on absorption of and exposure to orally administered antibiotics in non-critically ill, hospitalized patients.

OBJECTIVES: During the acute phase of infection, IV antibiotics are preferred to ensure adequate systemic exposure. To assess whether adequate exposure may also be achieved with oral antibiotics, we investigated exposure to oral antibiotics and PTA during the acute phase of infection and after defervescence. METHODS: We enrolled hospitalized, non-critically ill febrile patients treated with IV antibiotics other than amoxicillin or ciprofloxacin. The study consisted of two visits: when patients had received <24 h IV treatment; and when patients had become afebrile. On both visits, patients received one additional dose of 750 mg amoxicillin, or 500 mg ciprofloxacin, depending on the presumed infection, after which serial blood samples were obtained. The primary endpoint was the ratio of the AUC during the febrile and the afebrile phase. The AUCs were considered to be equivalent when the ratio of the mean AUCs and its 90% CI was contained within the acceptance interval of 80%-125%. The secondary endpoint was PTA. RESULTS: Forty-four patients (15 amoxicillin, 29 ciprofloxacin) completed both study visits. The median time between the two study visits was 65.8 h (range 33.8-427.4). The ratio of the mean AUCs (study visit 1/study visit 2) was 97% (90% CI of 80%-117%) for amoxicillin and 112% (90% CI of 108%-116%) for ciprofloxacin. The PTA for amoxicillin and ciprofloxacin did not differ between the two phases and was adequate to treat common pathogens. CONCLUSIONS: The acute phase of infection in non-critically ill febrile patients does not influence the exposure to, or PTA of, orally administered amoxicillin and ciprofloxacin. This might justify earlier IV-to-oral switching.

Safety and feasibility of post-stroke care and exercise after minor ischemic stroke or transient ischemic attack: MotiveS & MoveIT.

BACKGROUND: Despite the beneficial effect of cardiac rehabilitation after myocardial infarction, a rehabilitation program to improve cardiorespiratory fitness and influence secondary prevention has not been implemented for ischemic stroke and transient ischemic attack (TIA). OBJECTIVE: To investigate the safety and feasibility of a post-stroke care including an exercise program after minor ischemic stroke or TIA. METHODS: In a randomised controlled trial, 20 patients with a recent minor stroke or TIA without cardiac contraindications were randomly assigned to one of the two interventions; post-stroke care without exercise or post-stroke care with exercise. Patients were evaluated at baseline, 6 and 12 months. RESULTS: Eighteen patients completed the intervention. In none of the patients cardiopulmonary contraindications for the maximal exercise test and exercise program were found. No cardiovascular events occurred during the maximal exercise tests and exercise program. After one year, significantly more patients in the post-stroke care with exercise group achieved the composite endpoint of optimal medical therapy. CONCLUSIONS: Post-stroke care including an exercise program is safe and feasible in the acute phase after minor stroke or TIA and might be a way to increase effectiveness of secondary stroke prevention. We are currently conducting a larger trial to validate these results.

A randomised controlled trial of aerobic exercise after transient ischaemic attack or minor stroke to prevent cognitive decline: the MoveIT study protocol.

INTRODUCTION: Patients with transient ischaemic attack (TIA) or stroke are at risk for cognitive impairment and dementia. Currently, there is no known effective strategy to prevent this cognitive decline. Increasing evidence exists that physical exercise is beneficial for cognitive function. However, in patients with TIA or stroke who are at risk of cognitive impairment and dementia, only a few trials have been conducted. In this study, we aim to investigate whether a physical exercise programme (MoveIT) can prevent cognitive decline in patients in the acute phase after a TIA or minor ischaemic stroke. METHODS AND ANALYSIS: A single-blinded randomised controlled trial will be conducted to investigate the effect of an aerobic exercise programme on cognition compared with usual care. 120 adult patients with a TIA or minor ischaemic stroke less than 1 month ago will be randomly allocated to an exercise programme consisting of a 12-week aerobic exercise programme and regular follow-up visits to a specialised physiotherapist during the period of 1 year or to usual care. Outcome measures will be assessed at the baseline, and at the 1-year and 2-year follow-up. The primary outcome is cognitive functioning measured with the Montreal Cognitive Assessment (MoCA) test and with additional neuropsychological tests. Secondary outcomes include maximal exercise capacity, self-reported physical activity and measures of secondary prevention. ETHICS AND DISSEMINATION: The study received ethical approval from the VU University Amsterdam Ethics committee (2011/383). The results of this study will be published in peer-reviewed journals and presented at international conferences. We will also disseminate the main results to our participants in a letter. TRIAL REGISTRATION NUMBER: The Nederlands Trial Register NTR3884.

A young woman with a severe bilateral pneumonia as the presenting sign of an adrenal carcinoma.

A severe bilateral, culture-negative pneumonia was diagnosed in a 22-year-old woman. Additional diagnostic procedures accidentally revealed a large adrenal carcinoma and hypercortisolism. The adrenal carcinoma was surgically removed, and she received mitotane treatment. This severe and life-threatening infection was the first sign of an immunosuppressive state as part of Cushing's syndrome due to the adrenal carcinoma.

Three vs. 10 days of amoxycillin-clavulanic acid for type 1 acute exacerbations of chronic obstructive pulmonary disease: a randomised, double-blind study.

The optimal duration of antibiotic treatment for acute exacerbations of chronic obstructive pulmonary disease (AECOPD) is unknown. This study compared the outcome of treatment for 3 vs. 10 days with amoxycillin-clavulanic acid of hospitalised patients with AECOPD who had improved substantially after initial therapy for 3 days. Between November 2000 and December 2003, 56 patients with AECOPD were enrolled in the study. Unfortunately, because of the low inclusion rate, the trial was discontinued prematurely. Patients were treated with oral or intravenous amoxycillin-clavulanic acid. Patients who showed improvement after 72 h were randomised to receive oral amoxycillin-clavulanic acid 625 mg or placebo, four times daily for 7 days. The primary outcome measure of the study was clinical cure after 3 weeks and 3 months. Of 46 patients included in the final analysis, 21 were in the 3-day treatment group and 25 were in the 10-day treatment group. After 3 weeks, 16 (76%) of 21 patients in the 3-day treatment group were cured, compared with 20 (80%) of 25 in the 10-day treatment group (difference -3.8%; 95% CI -28 to 20). After 3 months, 13 (62%) of 21 patients were cured, compared with 14 (56%) of 25 (difference 5.9%; 95% CI -23 to 34). Microbiological success, symptom recovery, the use of corticosteroids, the duration of oxygen therapy and the length of hospital stay were comparable for both treatment groups. It was concluded that 3-day treatment with amoxycillin-clavulanic acid can be a safe and effective alternative to the standard 10-day treatment for hospitalised patients with AECOPD who have improved after initial therapy for 3 days.

Pharmacokinetic/pharmacodynamic modelling of the eosinopenic and hypokalemic effects of formoterol and theophylline combination in healthy men.

Interactions of formoterol and theophylline were evaluated with the use of pharmacokinetic-pharmacodynamic (PK/PD) modelling. Oral doses of 144 microg of formoterol and 375 mg of theophylline were given separately or combined to healthy subjects. As effect parameters, plasma eosinophil and potassium concentrations were used. Kinetic interactions between formoterol and theophylline were not found. Plasma drug concentrations were linked to the observed effects via an effect compartment model with a sigmoid E max model. The E max values+/-SD for the hypokalemic effects were 2.29+/-0.78 mmol/l for formoterol and 1.64+/-1.16 mmol/l for theophylline (P>0.05). The E max values for the eosinopenic effects were fixed at zero. The EC 50 values of the eosinopenic and hypokalemic effects were respectively 91.4+/-38.2 pg/ml and 128.4+/-52.9 pg/ml for formoterol, and 11. 9+/-4.6 microg/ml and 15.5+/-4.8 microg/ml for theophylline. Effects of both drugs combined were described with a non-competitive interaction model. The correlation coefficients of the fits of the eosinopenic and hypokalemic effects were respectively 0.9520+/-0. 0311 and 0.9371+/-0.0227, supporting our hypothesis of non-competitive interaction.

Pharmacokinetics and effects of formoterol fumarate in healthy human subjects after oral dosing.

OBJECTIVE: To evaluate the effects of formoterol after oral administration on plasma eosinophils and plasma potassium in healthy subjects. METHODS: Plasma concentrations of formoterol, peripheral eosinophil count and plasma potassium were determined during 7 h after oral administration of 168 microg of formoterol to eight healthy subjects. Descriptions of the concentration-time course of formoterol are given using a one-compartment pharmacokinetic model with first-order absorption in four subjects and a two-compartment model in the other four subjects. Effects on potassium and eosinophils are described using pharmacokinetic/pharmacodynamic (PK/PD) modelling with the 'effect-compartment' approach. RESULTS: The values of the kinetic parameters were: Ka: 6.9 (h(-1)), t1/2, 8.5 (h), AUC: 741 (pg x h(-1) x l(-1), V(area/f): 1470 (l). Formoterol concentrations were related to dynamic data using a sigmoid Emax model. CONCLUSION: Plasma concentrations of formoterol can be measured in plasma of healthy subjects after oral administration. These data can be used for describing concentration-effect relations with respect to plasma potassium and eosinophils. With comparable EC50 values for the two effects, remarkable differences were found for k(e0) and n values.

Hypokalaemia in healthy volunteers after single and multiple doses of formoterol or salbutamol.

A specific beta(2)-adrenoceptor-mediated effect, hypokalaemia, was studied in healthy volunteers after single as well as multiple dosages of the long-acting agonist formoterol and the short-acting agent salbutamol. The purpose of the study was to test with simple methodologies if rapidly induced tachyphylaxis for this well known systemic effect can be shown and if it will then be more pronounced for the long-acting compound. Hypokalaemia induced by inhalation of, respectively, 72microg formoterol and 1200microg of salbutamol was studied before and after 1 week of medication. Potassium-time curves were described by a biexponential equation and also analysed with a deconvolution technique. Both drugs induced a statistically significant hypokalaemia, the duration of this effect being considerably shorter for salbutamol than for formoterol (p < 0.05 with both methods of analysis). After multiple doses for 1 week, both maximal hypokalaemia and the area under the curve of the hypokalaemic effect had decreased after inhalation of formoterol (p < 0.05) but not after inhalation of salbutamol.It was concluded that plasma potassium as an effect measurement can be used to study in a simple but reproducible way differences of pharmacological interest between various beta(2)-adrenoceptor agonists.

Biphasic effect-time courses in man after formoterol inhalation: eosinopenic and hypokalemic effects and inhibition of allergic skin reactions.

The kinetics of inhaled racemic formoterol and its effects on the size of the early cutaneous reaction to intradermal injection of an allergen, eosinopenia and hypokalemia were assessed by pharmacokinetic-pharmacodynamic modeling. After inhalation of either 120 microg of formoterol or placebo, blood samples were taken and skin tests were performed in seven healthy subjects. A two-compartment model was needed to describe the observed formoterol plasma concentration-time curves. To describe the observed biphasic concentration, two absorption routes with different absorption rate constants were incorporated in the model. These two phases were explained by rapid absorption via the respiratory tract together with a slower and delayed oral absorption. For the description of the concentration-effect relations, an Emax (the maximum obtainable effect) formula for competitive agonism, with an effect compartment, had to be used. Fitting the wheal and flare, an apparent diurnal variation had to be taken into account by incorporating in the model rising base-line values. For the flare responses, influence of the location on the forearm appeared to be operative. Systemic formoterol absorbed via the oral route behaved differently from the fraction absorbed via the lungs, with EC50 (steady state concentration that gives 50% of maximum effect) values for all three systemic effects being three times lower after oral absorption than after absorption via the respiratory tract. Pharmacodynamic parameters can probably only be estimated quantitatively when the kinetics of the separate enantiomers of formoterol can be taken into account.

Evaluation of different doses of formoterol from a newly developed powder inhalation device in asthmatic patients.

Administration of different doses of formoterol from a recently developed multiple dose dry powder device was tested in a placebo-controlled, single-centre, double-blind, within-patient trial. Eighteen patients of both sexes, aged 18-65 years, with a FEV1 of 50-80% and a reversibility of at least 15% were randomized. During four treatment periods of 8 days each, divided by approximately 6 days, patients received placebo or 6, 12 or 24 micrograms (PL, F6, F12 and F24, respectively) of formoterol from the powder device. Efficacy parameters (FEV1) and safety parameters (primarily pulse rate, electrocardiogram [ECG] and subjective experiences) were evaluated during 24 hours on the last day of each treatment period. Peak flow and the number of puffs of used rescue medication (100 micrograms of salbutamol) were registered during treatment periods. For efficacy analysis, 17 patients remained. For FEV1 0.5 hour before the last dose and 12 and 24 hours after the last dose all formoterol doses were statistically significant superior to placebo. Clinically relevant differences from placebo were found up to 8 hours (F6) and 12 hours (F12 and F24). The difference between doses was clinically relevant for the area under the FEV1 curve between F6 and F24. PEF on the treatment days corresponded to these findings. In three cases of 13 reported adverse effects, the relation to trial medication was probable (tremor) or possible (insomnia and hyperaesthesia). All other safety measurements showed no significant differences. We conclude that formoterol dry powder in the newly developed multiple dose inhalation device is an effective and safe beta 2-stimulant with a long duration of action in doses of 6, 12 and 24 micrograms. The 24 micrograms dose is superior to the 6 micrograms dose. Efficacy decreased considerably between the 12th and 24th hour after dosing.

First high-performance liquid chromatography assay of formoterol concentrations in the low-picogram-per-milliliter range.

A method for the assay of plasma concentrations of the long-acting beta 2-adrenoceptor agonist, formoterol is described. This method, in which high-performance liquid chromotography is used with electrochemical detection, enables, for the first time, pharmacokinetic and pharmacodynamic research with this drug. After column extraction of plasma samples, the eluent is injected on the chromatographic system. Retention times of formoterol and the internal standard, bromo-formoterol, were 5.6 and 10 min, respectively. Our results show that this is a sensitive and reproducible method with a very low limit of detection (20 pg/ml), which creates the possibility of measuring concentrations in a range achievable in humans.