• Canada
• 030226 pharmacology & pharmacy close

Several cases have been described in the literature where different ligands enhanced lead (Pb) bioavailability over what would have been expected on the basis of equilibrium models such as the biotic ligand model (BLM). These exceptions compromise the development of BLMs for this metal, and mechanistic knowledge of the involved processes is still insufficient. The present study shows that the hydrophilic organic ligand citrate enhances Pb internalization by Chlamydomonas reinhardtii for both the wild and the wall-less strains. Despite the high Pb internalization fluxes shown by this alga, which may be near the limits set by diffusion through the boundary layer, and its capacity to assimilate citrate (and potentially Pb-citrate complexes), neither of these mechanisms could quantitatively account for the observed increase in Pb internalization in the presence of this ligand. However, algal-driven pH increases in the boundary layer and concomitant changes in Pb speciation successfully explained the observed results. This study suggests that information on bulk solution chemistry is not enough to predict metal bioavailability for organisms that can substantially modify the chemical composition of their boundary layer, as observed for C. reinhardtii.

Abstract Background Medication safety risks are the most important preventable factors jeopardizing patient safety. To manage these risks, extending pharmacists’ involvement in patient care and patient safety work has been systematically addressed in patient safety initiatives since the early 2000s. Objective To explore the extent and range of clinical pharmacy services in Finnish hospitals to promote medication safety: 1) in 2011, when the first National Patient Safety Strategy, the new Health Care Act and the Medicines Policy 2020 had been recently enacted; and 2) five years later in 2016. Methods The study was conducted in 2011 and 2016 as a national online survey targeted to hospital pharmacies (n = 24) and medical dispensaries (n = 131 in 2011; n = 28 in 2016). The questions were analyzed using descriptive statistics and qualitative content analysis. Results Overall response rate was 60% in 2011 and 52% in 2016. Clinical pharmacy services were provided by 51% of the responding units in 2011, whereas by 85% in 2016. The reported number of clinical pharmacists had increased during the five years. The most notable increase in reported tasks occurred in conducting medication reconciliations (+63% increase in the number of providing units). By 2016 pharmacists had extended their tasks particularly towards system-based medication safety work: e.g. developing instructions for medication-use (91% of the responding units), creating and updating medication safety plans (87%) and using medication error reports in developing the process of medication use safer (78%). Pharmacists’ participation in long-term continuing education became more common in 2016, which was perceived as helpful in extending their responsibilities to improve medication safety. Conclusion Pharmacists’ involvement in patient care and system-based medication safety work was reported to become more common in Finnish hospitals during 2011–2016. This development is in line with patient safety policy initiatives and its impact on patient care outcomes should be followed up.

Abstract Background and Objective The introduction of cannabis as a legalized recreational drug in Canada has led to significant changes in public health policy. Tetrahydrocannabinol (THC) is the primary psychoactive compound in cannabis and its absorption, distribution, metabolism, and elimination are poorly understood. The use of THC can impair an individual's ability to operate a motor vehicle, leading to an increased risk of accidents. Thus, additional research must be conducted to gauge the inter-individual differences in effect and duration of THC's effect. Methods In this study, a comprehensive whole-body physiologically-based pharmacokinetic (PBPK) model for THC metabolism was developed to track blood THC concentrations accounting for interindividual variations such as age, sex, body composition, bioavailability and drug metabolizing enzyme (DME) polymorphisms after various dosages. This model was fitted and validated with clinical human cannabis smoking data. Results Using this model, we found effects of various factors on THC concentrations in different tissue compartments, and that the wild-type form of Cytochrome P450 2C9 (CYP2C9) DME showed faster metabolism of THC than other isoforms. The nature of the our PBPK model allowed for the investigation of non-blood compartments as well. To gauge the effects on driving, we compared the Standard Deviation of Lateral Position under the effects of THC and ethanol, and found that ethanol has a stronger but shorter-lasting effect. Conclusion We anticipate that this model can be used to better predict the effects of a “standard THC unit” and help advise public health policies for safe cannabis usage.

Resume Introduction Le preparateur en pharmacie hospitaliere est un collaborateur essentiel et des reflexions sont en cours pour etendre son role. L’objectif principal etait de decrire et de comparer la formation des preparateurs en pharmacie hospitaliere en France et au Quebec. L’objectif secondaire etait de decrire et comparer l’activite des preparateurs en pharmacie hospitaliere en France et au Quebec. Materiels et methodes Etude descriptive et comparative. Une revue de la litterature a permis d’identifier une liste de themes pertinents a la comparaison. Un panel franco-quebecois de pharmaciens et preparateurs a identifie et discute les similitudes et les differences entre la formation et l’activite des preparateurs en pharmacie hospitaliere en France et au Quebec. Resultats sur les 35 themes compares, 30 differences et cinq similitudes ont ete recensees entre la France et le Quebec. Discussion Dans les deux pays, les programmes de formation sont etablis par le ministere de l’education et les preparateurs contribuent a la plupart des activites du circuit du medicament, de l’approvisionnement a la preparation en passant par la dispensation. Parmi les differences identifiees, on note l’obtention d’un diplome specifique, une date de creation plus ancienne, un programme plus long, des connaissances plus fondamentales, des effectifs plus reduits, une gestion d’activites specifiques en France et davantage d’activites de soutien au pharmacien clinicien au Quebec. Conclusion Cette etude descriptive comparative met en evidence davantage de differences en ce qui concerne la formation et davantage de similitudes en ce qui concerne les activites des preparateurs en pharmacie hospitaliere entre la France et le Quebec. Une meilleure comprehension des pratiques au sein d’autres pays est utile a la reflexion.

Abstract A new formulation of levothyroxine sodium has been developed in the form of an oral solution contained in unit‐dose ampules. A study has been conducted to compare the bioavailability of levothyroxine sodium oral solution and levothyroxine sodium soft capsule in healthy volunteers under fasting conditions. The rate and extent of absorption of the new levothyroxine solution were also evaluated when administered on dilution in water or directly into the mouth without water. In each period, according to the randomization scheme, subjects were administered single oral doses of either test, as 4 × 150‐μg unit‐dose ampules, with or without water, or reference, as 4 × 150‐μg capsules in a crossover design. Thirty‐six subjects were randomized and dosed in this study; of these, 31 completed all study periods. When comparing the solution with the capsule (both products administered with water), the 90% confidence intervals for the ratio of log‐transformed values of AUC0‐48 and Cmax were within 90.00% and 111.11%, respectively, for baseline‐corrected levothyroxine. Moreover, the administration of levothyroxine oral solution without water did not affect the rate and extent of its absorption. In conclusion, levothyroxine oral solution unit‐dose ampules were bioequivalent to the levothyroxine capsule when administered with or without water. All formulations were well tolerated, with no major side effects.

Purpose There has been less attention to the transparency of postmarket evidence of harmful effects of medicines than of premarket clinical trial data. This is a case study of requests for Australian "direct health professional communications" (DHPCs). These letters are used by regulators and manufacturers to inform clinicians of emergent evidence of harm. DHPCs are not made public by Australia's Therapeutic Goods Administration (TGA). Methods We requested all DHPCs sent out in Australia from 2007 to 2016 inclusive for 207 drugs that were subject to safety advisories over this decade in Canada, the United Kingdom, and/or the United States. We contacted 39 manufacturers (February to May 2018), with repeat requests to nonrespondents, and a follow-up freedom-of-information (FOI) request to the TGA. Results Fifteen companies provided information, either sending DHPCs (n = 4, on five drugs) or affirming none were sent out (n = 11). The remaining 24 of 39 (62%) companies did not provide DHPCs: nine (23%) refused the request, often citing commercial confidentiality; the rest provided no answer despite repeat requests. In total, we had no information for 170 of 207 (82%) of the drugs. Our FOI request to the TGA was unsuccessful. Conclusions Our experience highlights unacceptable secrecy concerning safety warnings previously sent to thousands of Australian clinicians. In the absence of explicit regulatory policy supporting disclosure, companies differed in their response. These letters warn of serious and often life-threatening harm and guide safer care; full ongoing public access is needed, ideally in searchable online databases.

Characteristics of metrics are defined in order to assist the effective assessment of bioequivalence as well as the evaluation of metrics and the development of new ones. Metrics should show specificity by reflecting only the kinetic quantity which they are expected to represent. An ideal metric should be linear with respect to the underlying kinetic quantity, and should exhibit high kinetic sensitivity and low statistical responsiveness. The area under the curve for the time course of plasma concentrations (AUC) is demonstrated to have features of an ideal metric. In contrast, Cmax (the maximum plasma concentration) is shown to deviate strongly, in all respects, from having ideal characteristics for the assessment of bioequivalence. Notably, the kinetic sensitivity of Cmax is not only very low but, as a consequence of nonlinearity, also uncertain.

Positron emission tomography (PET) using 2-deoxy-2-[18 F]fluoro-d-glucose ([18 F]FDG), a marker of energy metabolism and cell proliferation, is routinely used in the clinic to assess patient response to chemotherapy and to monitor tumor growth. Treatment with some tyrosine kinase inhibitors (TKIs) causes changes in blood glucose levels in both nondiabetic and diabetic patients. We evaluated the interaction of several classes of TKIs with human glucose transporter-1 (hGLUT-1) in FaDu and GIST-1 cells by measuring [3 H]2-deoxy-d-glucose ([3 H]2-DG) and [3 H]FDG uptake. Uptake of both was inhibited to varying extents by the TKIs, and representative TKIs from each class showed competitive inhibition of [3 H]2-DG uptake. In GIST-1 cells, [3 H]FDG uptake inhibition by temsirolimus and nilotinib was irreversible, whereas inhibition by imatinib, gefitinib, and pazopanib was reversible. Molecular modeling studies showed that TKIs form multiple hydrogen bonds with polar residues of the sugar binding site (i.e., Q161, Q282, Q283, N288, N317, and W388), and van der Waals interactions with the H-pocket site. Our results showed interaction of TKIs with amino acid residues at the glucose binding site to inhibit glucose uptake by hGLUT-1. We hypothesize that inhibition of hGLUT-1 by TKIs could alter glucose levels in patients treated with TKIs, leading to hypoglycemia and fatigue, although further studies are required to evaluate roles of other SLC2 and SLC5 members. In addition, TKIs could affect tumor [18 F]FDG uptake, increasingly used as a marker of tumor response. The hGLUT-1 inhibition by TKIs may have implications for routine [18 F]FDG-PET monitoring of tumor response in patients.

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