Aerosolization of tobramycin (TOBI) with the PARI LC PLUS reusable nebulizer: which compressor to use? Comparison of the CR60 to the PortaNeb compressor

Aerosol output, aerosol output rate, and aerosol size distribution are influenced by the compressed air flow rate through the nebulizer cup. Testing a nebulizer-compressor with a drug for inhalation in cystic fibrosis (CF) patients is mandatory prior to starting therapy. Tobramycin solution for inhalation (TSI), TOBI, is licensed in Europe with a recommendation for a "suitable" compressor connected to the PARI LC Plus nebulizer. To select a compressor, five devices were tested in a previous in vitro study and this resulted in a subsequent in vivo study. Two compressors [CR60 and PortaNeb (PN)] were compared in an open, randomized, crossover single dose pilot study in 10 CF patients to assess the most suitable device for inhalation of a tobramycin solution (TSI), TOBI, with the PARI LC Plus nebulizer. Lung function (FEV1 and FVC), pharmacokinetics [PK; safety (Cmax, Ctrough)], lung deposition (indirect method AUC0-6), nebulization time, and patients' experiences (questionnaire) were determined and compared. It was found that values of Cmax and AUC0-6 were higher with the CR60 than with the PortaNeb: 0.70 versus 0.54 mg/L, p = 0.005, and 2.54 versus 2.01 h.mg/L, p = 0.017, respectively. Tmax after use of the CR60 appeared earlier (0.64 vs. 0.85 h, p = 0.005). Transient airway narrowing was measured in three patients (2 x PN;1 x CR60) versus subjective chest tightness in seven patients (CR60 > PN). A shorter nebulization time for CR60 of 13.2 min compared to PN 16.1 min (p = 0.022) was observed, which was the main reason why patients preferred the CR60 (n = 7). No toxic serum levels were reached after inhalation of TSI. The CR60 compressor may seem advantageous based on a higher lung deposition and a shorter nebulization time, but a study in a large CF population to provide information on a possible higher risk of toxicity of TSI is called for.     

A Technical Feasibility Study of Dornase Alfa Delivery with eFlow® Vibrating Membrane Nebulizers: Aerosol Characteristics and Physicochemical Stability

Dornase alfa (Pulmozyme®) is an inhaled mucus-active drug that decreases viscoelasticity of sputum in vitro, improves lung function and reduces respiratory exacerbations in cystic fibrosis (CF) patients of 5 years age and older. The regulatory approval of dornase alfa 15 years ago stipulated that only certain jet nebulizer-compressor combinations should be used to deliver the drug. Since that time there have been significant advances in aerosol delivery technology, including development of electronic perforated vibrating membrane devices. Three independent laboratories studied aerosol characteristics, nebulization time, dose delivery, and stability of dornase alfa after nebulization to determine the feasibility of using perforated vibrating membrane devices to deliver the drug. These studies determined that the eFlow® vibrating membrane technology delivers dornase alfa more rapidly and efficiently than jet nebulizers, and does not affect the physicochemical properties of the drug. These in vitro results demonstrate only the technical feasibility of using vibrating membrane devices to deliver dornase alfa. Clinical studies will be required before any conclusions can be made regarding clinical safety and efficacy of these drug-device combinations for cystic fibrosis.     

Comparison of experimentally measured and computational fluid dynamic predicted deposition and deposition uniformity of monodisperse solid particles in the Vitrocell® AMES 48 air-liquid-interface in-vitro exposure system

Accurately determining the delivered dose is critical to understanding biological response due to cell exposure to chemical constituents in aerosols. Deposition efficiency and uniformity of deposition was measured experimentally using monodisperse solid fluorescent particles with mass median aerodynamic diameters (MMAD) of 0.51, 1.1, 2.2 and 3.3 μm in the Vitrocell® AMES 48 air-liquid-interface (ALI) in vitro exposure system. Experimental results were compared with computational fluid dynamic, (CFD; using both Lagrangian and Eulerian approaches) predicted deposition efficiency and uniformity for a single row (N = 6) of petri dishes in the Vitrocell® AMES 48 system. The average experimentally measured deposition efficiency ranged from 0.007% to 0.43% for 0.51–3.3 μm MMAD particles, respectively. There was good agreement between average experimentally measured and the CFD predicted particle deposition efficiency, regardless of approach. Experimentally measured and CFD predicted average uniformity of deposition was greater than 45% of the mean for all particle diameters. During this work a new design was introduced by the manufacturer and evaluated using Lagragian CFD. Lagragian CFD predictions showed better uniformity of deposition, but reduced deposition efficiency with the new design. Deposition efficiency and variability in particle deposition across petri dishes for solid particles should be considered when designing exposure regimens using the Vitrocell® AMES 48 ALI in vitro exposure system.     

Aerosol tribocharging and its relation to the deposition of Oxis™ Turbuhaler® in the electrical next generation impactor

Although there have been published electrostatic characterisation studies of drug‐only Turbuhaler® and lactose carrier–drug formulations, there has not been an investigation into spheronised agglomerates containing micronised lactose and eformoterol, such as in Oxis® Turbuhaler®. Ten doses of Oxis® (12 µ g eformoterol) were dispersed into an electrical next generation impactor (eNGI) in a single run, and runs were conducted in triplicate to determine the aerosol performance and aerosol charge distribution at flow rates of 30, 60 and 90 L/min. Eformoterol fine particle fraction (FPF) reached a maximum of 50%–60% at 60 and 90 L/min, whereas lactose FPF increased from 31% to 42% when flow rate was increased from 30 to 90 L/min. Specific net charge (C/µ g) within the eNGI stages increased from 30 to 60 L/min, but then decreased at 90 L/min. These results were attributed to the shift in balance between surface charging after interparticle and particle–surface collision (dominant at 30 and 60 L/min) and charge separation after impact fragmentation of agglomerates (dominant at 90 L/min). However, the aerosol charge profiles do not suggest that electrostatic forces play a major role in the deposition of Oxis® Turbuhaler® dry powder formulation.     

A comparison of some pharmacological actions of morphine and Δ9-tetrahydrocannabinol in the mouse

The effects of morphine and ⁹-tetrahydrocannabinol (THC) on the tail-flick reflex, body temperature, and catecholamine synthesis were examined in the mouse in order to compare their effects in a single species and strain under uniform conditions. Naloxone antagonism of THC and cross-tolerance between morphine and THC were also studied. Both morphine and THC produced antinociception, hypothermia, and increased catecholamine synthesis at 30 min after s.c. injection. Morphine produced greater increases in dopamine synthesis and was a more potent antinociceptive agent, while THC produced greater increases in norepinephrine synthesis and was a more potent hypothermic agent. Naloxone pretreatment (1 mg/kg) partially antagonized the hypothermia and increase in catecholamine synthesis produced by THC. There was also crosstolerance between morphine and THC, but it was asymmetric in that THC-tolerant animals were crosstolerant to only the hypothermic action of morphine and morphine-tolerant animals cross-tolerant to only the antinociceptive action of THC.     

A comparison of the psychometric properties of the hooked on nicotine checklist and the modified Fagerström tolerance questionnaire

We compared the psychometric properties of the Hooked on Nicotine Checklist (HONC) and the Modified Fagerström Tolerance Questionnaire (MFTQ). Adolescent current smokers (n = 215) completed both instruments three times, at baseline and 6- and 12-month follow-up. Internal consistency of the HONC was high (α = 0.92), as was its stability over the follow-up interval (intraclass correlation (ICC) = 0.93 over 6 months and 0.91 over 1 year). Internal consistency of the MFTQ was acceptable (α = 0.83), and its stability over the follow-up interval was similar to that reported previously (ICC = 0.79 at 6 months and 0.76 at 1 year). The HONC predicted smoking at both follow-up points, while the MFTQ did so only at 6 months. The HONC compared favorably with the MFTQ in all respects. The most important advantage of the HONC is that it is measuring a clearly defined concept, diminished autonomy over tobacco, which begins when the sequelae of tobacco use present a barrier to quitting.     

A comparison of the content-, construct- and predictive validity of the cigarette dependence scale and the Fagerström test for nicotine dependence

BACKGROUND: Research showed that the widely used Fagerstrom test for nicotine dependence (FTND) does not cover important aspects of dependence. A new test, the cigarette dependence scale (CDS-12), covers the main elements in DSM-IV and ICD-10 definitions of dependence. We compared the psychometrics of CDS-12, FTND, and CDS-5 and the heaviness of smoking index (HSI), which are short versions of CDS-12 and FTND, respectively. METHODS: Internet survey in 2002-2003. Participants were invited one month after answering the first survey to answer a second survey on smoking status and withdrawal symptoms. RESULTS: Eight hundred two smokers answered both surveys. Cronbach's alpha coefficients were higher for CDS-12 (0.91) and CDS-5 (0.77) than for FTND (0.68) and HSI (0.63). Among 231 smokers who quit smoking at follow-up, higher baseline CDS-12 scores predicted higher withdrawal ratings at follow-up, for all withdrawal symptoms except appetite. FTND and HSI predicted higher craving in quitters, but did not predict the intensity of other withdrawal symptoms. Neither CDS-5, FTND or HSI predicted smoking cessation, but higher CDS-12 scores marginally predicted smoking cessation at follow-up (area under the receiver operating characteristic (ROC) curve = 0.55, 95% confidence interval = 0.51-0.59). CONCLUSIONS: CDS-12 had better content validity and internal consistency than FTND and was a slightly better predictor of withdrawal symptoms. Unexpectedly, higher (not lower) CDS-12 scores predicted subsequent smoking cessation, perhaps because endorsement of some CDS-12 items implies accepting that one is dependent, which in turn could reflect motivation to quit. CDS-12 may represent an alternative to FTND for measuring cigarette dependence.     

A comparison of the autonomy over tobacco scale and the Fagerström test for nicotine dependence

The Autonomy over Tobacco Scale (AUTOS) is a 12-item theory-based instrument used to measure tobacco dependence in smokers. It provides separate measures of three factors that make smoking cessation more difficult: withdrawal symptoms, psychological dependence, and cue-induced urges to use tobacco. We compared the internal reliability and concurrent validity of the AUTOS to those of the Fagerström Test for Nicotine Dependence (FTND). Adult current smokers (n = 422; 62% female; 86.8% white; mean age 33.3 years, SD = 13.7; 57% daily smokers) completed an anonymous web-based survey that included the AUTOS, the FTND and 11 smoking-related behavioral measures. Cronbach's α was .94 for the AUTOS and α > .75 for each of the 3 subscales; α = .73 for the FTND. The AUTOS and its subscales correlated with all measures of concurrent validity (r = .70 between AUTOS &; FTND). The AUTOS correlated better than the FTND with the Hooked on Nicotine Checklist, the longest period of abstinence, latency to wanting, percentage of time a person smokes because of momentary need, pleasure from smoking, days smoked per month, and concern about deprivation. The measures showed similar correlations with the latencies to craving and needing. The FTND correlated better with the duration of smoking and cigarettes smoked per day. Based on these results and those from prior studies, we conclude that the AUTOS offers researchers a valid and highly reliable, theory-based measure that is more versatile in its applications than the FTND.     

A comparison of pre- and postsynaptic α-adrenergic effects of phenylephrine and tramazoline on blood vessels of the rabbit in vivo

Summary Pre- and postsynaptic -adrenergic effects of phenylephrine and tramazoline were studied in hindlegs of rabbits. The legs were autoperfused at a constant rate of flow. Phenylephrine and tramazoline were infused intraarterially. Increases in perfusion pressure evoked by the drugs were taken to represent activation of postsynaptic -adrenoceptors. Inhibition of the pressor response to low frequency stimulation of the lumbar sympathetic chain (1 and 2 Hz) without a decrease of the response to intraarterial injection of low doses of noradrenaline (60–450 ng) was considered to reflect activation of presynaptic -adrenoceptors.Phenylephrine produced vasoconstriction at concentrations of 10^–7–3×10^–6 M. Phenylephrine 10^–7 and 3×10^–7 M did not change pressor responses to nerve stimulation or noradrenaline, whereas higher concentrations selectively inhibited the effect of nerve stimulation. The maximal inhibition amounted to about 30%. Tramazoline caused vasoconstriction at concentrations of 3×10^–8–10^–6 M. All these concentrations, and also the lower concentration of 10^–8 M, diminished the response to nerve stimulation without a change in the effect of injected noradrenaline. The inhibition maximally amounted to about 80%. The sum of the vasoconstrictor effects of phenylephrine and of nerve stimulation exceeded the effect of nerve stimulation alone, whereas the sum of the vasoconstrictor effects of low concentrations of tramazoline and of nerve stimulation was lower than the effect of nerve stimulation alone. Except for tramazoline 10^–6 M, the effects were limited to the leg that received the intraarterial infusion; there was no change in the contralateral leg.The results are compatible with the view that not only in vitro, but also in vivo pre- and postsynaptic -adrenoceptors show different pharmacological properties. In the hindleg vasculature of the rabbit as well as in some other tissues tramazoline preferentially activates the presynaptic, whereas phenylephrine preferentially activates the postsynaptic receptors. There is not sufficient evidence, however, to allow generalization of these findings and to consider all presynaptic -adrenoceptors as one pharmacologically homogeneous group and all postsynaptic -adrenoceptors as the second, distinct homogeneous group.     

A comparison of the opacifying effects of carteolol·HCl and 8-hydroxycarteolol·HCl in the isolated porcine cornea

Using an in vitro method the authors have investigated whether 8-hydroxycarteolol·HCl (8-OH carteolol) and 8-OH carteolol with benzalkonium chloride affected intact isolated porcine corneas to the same or to a different degree as carteolol·HCl (carteolol) or carteolol with benzalkonium chloride. These ophthalmically used drugs were applied as solutions of varying concentrations to the epithelial surface only, to the endothelial surface only, or to both surfaces of porcine corneas. The resultant opacities were determined using an opacitometer. In general, 8-OH carteolol and 8-OH carteolol with benzalkonium chloride caused less opacity to develop than carteolol and carteolol with benzalkonium chloride. This suggests that 8-OH carteolol may be a safer drug than carteolol for ophthalmic use. It is very interesting to note that compounds with two nitrogens, e.g., 8-OH carteolol, caused greater opacity in the intact cornea when applied to the endothelial surface than when applied to both the epithelial and endothelial surfaces; however, compounds with none or one nitrogen caused greater opacity in the intact cornea when applied to both surfaces than when applied to the endothelial surface.     

Development and validation of an LC–MS/MS method for the determination of quetiapine and four related metabolites in human plasma

Pharmacokinetic measurement of the psychotropic compound quetiapine and four related metabolites in human plasma was conducted using a sensitive and specific liquid–chromatography tandem mass spectrometry (LC–MS/MS) assay that has been developed and validated for this purpose. The assay employs a single liquid–liquid extraction of quetiapine and its N-desalkyl (norquetiapine, M211,803, M1), 7-hydroxy (M214,227, M2), 7-hydroxy N-desalkyl (M236,303, M3), and sulfoxide (M213,841, M4) metabolites from human plasma, and utilizes dual-column separation, using Luna C₁₈ columns (50 mm × 2.0 mm, 5 μm) and positive ionization tandem MS detection in the multiple reaction monitoring (MRM) mode of the analytes and their respective stable labeled internal standards. The method provides a linear response from a quantitation range of <0.70 ng/ml to at least 500 ng/ml for each analyte using 40 μl of plasma. The applicable range was extended by dilution up to 100-fold with blank matrix. The accuracy and precision for quetiapine were less than 6.0% and 6.4% for quetiapine, respectively. The accuracy (and precision) was less than 9.4% (5.9%) for norquetiapine; 6.4% (6.2%) for M2; and 10.0% (6.4%) for M3; and 8.6% (9.5%) for M4. This methodology enabled the determination of the pharmacokinetics of quetiapine and its metabolites in human plasma, and an example of its application is presented.     

Rationalizing between the efficiency and greenness of solvents – A computational study of their influence on TBATB

In recent years, hazards associated with organic solvents have become a subject matter of concern. Studies have been done to assess their levels of greenness and legislations have been imposed on a number of solvents. However, solvents are an integral part of many organic reactions, having substantial impact on reagent behavior and cannot be done away with. Therefore, comprehensive studies which provide information on the influence of a solvent on important reagent parameters while highlighting the hazards associated with it, are also quite necessary. In order to rationalize this assertion, a computational assessment of important reactivity parameters of a well-known brominating agent, tetrabutylammonium tribromide (TBATB), was done in different solvent systems and thereafter the GlaxoSmithKline (GSK) guide was referred to analyze the reported greenness associated with each of these studied solvents. While the prime objective of this work is to make a correlation between the greenness and efficiency of the solvents, the toxic solvents were also studied as well so as to understand the reason behind their repeated use.     

A comparison of the concentration–effect relationships of PAHs on CYP1A induction in HepG2 and Mcf7 cells

Polycyclic aromatic hydrocarbons (PAHs) are environmental pollutants. Some compounds belonging to this group are considered carcinogenic to people. In order to yield carcinogenic properties, these compounds must be metabolically transformed by enzymes of cytochrome P450 family to oxy-derivatives. In this study, the ability of the following six PAHs: anthracene (Ant), benz(a)anthracene (BA), naphthacene (Nap), benzo(a)pyrene (BaP), dibenz(a,c)anthracene (DB(a,c)A) and dibenz(a,h)anthracene (DB(a,h)A) to induce enzymes of cytochrome P450 (CYP450), in particular CYP1A1 and CYP1A2 in Mcf7 and HepG2 cells was studied. The induction of CYP1A enzymes was assessed at the level of enzymatic protein and enzymatic activity. The change in CYP1A1 and CYP1A2 protein level was assessed by means of confocal microscopy. The ethoxyresorufin-O-deethylase (EROD) and methoxyresorufin-O-deethylase (MROD) assays were applied to determine the CYP1A1 and CYP1A2 activity. The Induction Equivalency Factors (IEFs) were also determined. According to EROD and MROD assay and calculated IEFs the following order of the inducing potency was determined in HepG2 cells: DB(a,h)A > BaP > DB(a,c)A ≈ BA > Nap > Ant, and in Mcf7 cells: DB(a,h)A > DB(a,c)A > BaP > Nap > BA > Ant. The assessment of the protein levels revealed that DB(a,h)A was also the strongest inducer of protein level, however the correlation between enzymatic activity and protein level induction by other PAHs was not always evident. The EROD and MROD activities were higher in Mcf7 than in HepG2 cells, however the CYP1A2 protein level was shown to be higher in HepG2 cells. The results obtained indicate possible catalytic enzymatic activity alterations induced by PAHs.     

A comparison of the application of STOPP/START to patients’ drug lists with and without clinical information

Background A European screening tool (STOPP/START) has been formulated to identify the prescribing of potentially inappropriate medicines (PIMs) and potential prescribing omissions (PPOs). Pharmacists working in community pharmacies could use STOPP/START as a guide to conducting medication use reviews; however, community pharmacists do not routinely have access to patients’ clinical records. Objective To compare the PIM and PPO detection rates from application of the STOPP/START criteria to patients’ medication details alone with the detection rates from application of STOPP/START to information on patients’ medications combined with clinical information. Setting Community Pharmacy. Method Three pharmacists applied STOPP/START to 250 patient medication lists, containing information regarding dose, frequency and duration of treatment. The PIMs and PPOs identified by each pharmacist were compared with those identified by consensus agreement of two other pharmacists, who applied STOPP/START criteria using patients’ full clinical records. Main outcome measure The main outcome measures were: (1) PIM and PPO detection rates among pharmacists with access to patients’ clinical information compared to PIM and PPO detection rates among pharmacists using patients’ medication information only, and (2) the levels of agreement (calculated using Cohen’s kappa statistic (k)) for the three most commonly identified PIMs and PPOs. Results Pharmacists with access to patients’ clinical records identified significantly fewer PIMs than pharmacists without (p = 0.002). The three most commonly identified PIMs were benzodiazepines, proton pump inhibitors and duplicate drug classes, with kappa (k) statistic agreement ranges of 0.87–0.97, 0.60–0.68 and 0.39–0.85 respectively. PPOs were identified more often (p < 0.001) when clinical information was considered. The three most commonly identified PPOs were: bisphosphonates, β₂-agonists and anti-platelets, with kappa (k) statistic agreement ranges of 0.89–1.0, 0.50–0.80 and 0.5–1.0 respectively. Conclusions PIM detection is likely to be overestimated using STOPP and PPO detection underestimated using START when STOPP/START is used in isolation of clinical information. Agreement for a selected number of criteria for which clinical information is not required is good, suggesting that some criteria may be reliably deployed without clinical information during a medicines use review. However, for STOPP/START criteria to be deployed more effectively by pharmacists, access to the full clinical record is recommended.     

A Randomised,Single-blind,Crossover Comparison of the Acceptability of the Calcium and Vitamin D3 Supplements Calcichew D3 Forte® and Ad Cal D3® in Elderly Patients

Summary

Background: Supplements of calcium and vitamin D are given to elderly patients in order to reduce the likelihood of osteoporotic fractures. The acceptability of the preparation is an important component of the compliance of such patients with their treatment.

Aim: To compare the acceptability of Calcichew D3 Forte (CDF) and Ad Cal D3 (ACD).

Method: This was a randomised, crossover, comparative study of two formulations of calcium and vitamin D. Patients took CDF for seven days followed by ACD for seven days, or vice versa, according to the randomisation schedule. At the end of each treatment period, patients used visual analogue scales (VAS) to indicate the grittiness, chalkiness, taste, ease of chewing, ease of swallowing and stickiness of each preparation.

Results: One hundred and two elderly patients taking calcium supplements were recruited. Of these, 94 were suitable for inclusion in the efficacy analysis. The VAS scores were significantly lower for CDF than for ACD for grittiness (p = 0.0051), chalkiness (p = 0.0005), ease of chewing (p = 0.0001), ease of swallowing (p = 0.0001) and stickiness (p = 0.0001). These findings indicate that patients found CDF more acceptable than ACD. There was no difference between the groups for the taste score (p = 0.64).

Overall, 79.8% of patients stated a preference for CDF, 10.6% preferred ACD and 9.6% had no preference. Conclusion: Patients preferred CDF and found it more acceptable than ACD.