A survey on the enlistment of pharmacists in a hospital battalion of the Swiss Armed Forces

Background: Pharmacists, mainly militiamen, are incorporated in the Swiss Armed Forces, for instance in hospital battalions to supply drugs and medical devices, as well as to coordinate hygiene service. Presently, their duties are only very globally defined. Aims: The objective of this survey was to investigate the tasks that were actually assumed by the military pharmacy of the 2nd Hospital Battalion. Methods: Two types of commitments, offering military and civilian interest's convergence, were considered between 2005 and 2011: (1) army camps for the disabled and (2) operations and supports provided to two nursing homes. While relieving the civil caregiver usually involved with disabled or elderly people, such missions offer indeed the possibility to the army medical service to train its care and logistical processes with real patients, even in the absence of any sanitary crisis or war in the country. Results: Two basis activities have been assumed: (1) centralized supply of drugs and medical devices and (2) coordination of hygiene monitoring and disinfection operations. New tasks were also performed: (3) support to the management of ward-based pharmacies, (4) pillboxes preparation, (5) medication review and (6) selective participation in clinical rounds. The last two were integrated in an interdisciplinary education process. Conclusions: Results shows that, apart from traditional duties, new clinical-oriented activities have been evenly developed and assumed by militia pharmacists. They call thus for a possible renewed definition of the tasks of military hospital pharmacists and of their related military education. A wider study in all hospital battalions is yet mandatory.

Population pharmacokinetic-pharmacodynamic modelling of angiotensin receptor blockade in healthy volunteers.

OBJECTIVE: To compare the pharmacokinetic and pharmacodynamic characteristics of angiotensin II receptor antagonists as a therapeutic class. DESIGN: Population pharmacokinetic-pharmacodynamic modelling study. METHODS: The data of 14 phase I studies with 10 different drugs were analysed. A common population pharmacokinetic model (two compartments, mixed zero- and first-order absorption, two metabolite compartments) was applied to the 2685 drug and 900 metabolite concentration measurements. A standard nonlinear mixed effect modelling approach was used to estimate the drug-specific parameters and their variabilities. Similarly, a pharmacodynamic model was applied to the 7360 effect measurements, i.e. the decrease of peak blood pressure response to intravenous angiotensin challenge recorded by finger photoplethysmography. The concentration of drug and metabolite in an effect compartment was assumed to translate into receptor blockade [maximum effect (Emax) model with first-order link]. RESULTS: A general pharmacokinetic-pharmacodynamic (PK-PD) model for angiotensin antagonism in healthy individuals was successfully built up for the 10 drugs studied. Representatives of this class share different pharmacokinetic and pharmacodynamic profiles. Their effects on blood pressure are dose-dependent, but the time course of the effect varies between the drugs. CONCLUSIONS: The characterisation of PK-PD relationships for these drugs gives the opportunity to optimise therapeutic regimens and to suggest dosage adjustments in specific conditions. Such a model can be used to further refine the use of this class of drugs.

Regulation of the vascular gap junctions in a mouse model of intimal hyperplasia

Objective: Intimal hyperplasia (IH) is one of the leading causes of failure¦after vascular interventions. It involves the proliferation of smooth muscle¦cells (SMCs) and the production of extracellular fibrous matrix. Gap junctional¦communication, mediated by membrane connexins (Cx), participates to the¦control of proliferation and migration. In human and mice vessels, endothelial¦cells (ECs) express Cx37, Cx40 and Cx43, whereas SMCs are coupled by Cx43.¦We previously reported that Cx43 was increased in the SMCs of a human vein¦during the development of IH.¦In our experimental model of mice carotid artery ligation (CAL), luminal¦narrowing occurred by SMCs-rich neointima after 2-4 weeks of ligation.¦This experimental model of mice allows us to decipher the regulation of the¦cardiovascular connexins in the mouse.¦Methods: C57BL/6 mice were anesthetized and the left common carotid artery¦was dissected through a neck incision and ligated near the carotid bifurcation.¦The mice were then euthanized at 7, 14 and 28 days. Morphometric analyses¦were then performed with measurements of total area, lumen and intimal area¦and media thickness. Western blots, immunocytochemistry and quantitative¦RT-PCR were performed for Cx43, Cx40 and Cx37.¦Results: All animals recovered with no symptom of stroke. Morphometric¦analysis demonstrated that carotid ligation resulted in an initial increase (after¦7 days) of the total vessel area followed by its reduction (after 28 days). This¦phenomena was associated with a progressive increase in the intimal area and a¦consecutive decrease of the lumen. The media thickness was also increased after¦14 and 28 days. This neointima formation was associated to a marked increase¦in the expression of Cx43 at both protein and RNA levels. Concomitantly,¦Cx40 and Cx37 protein expression were reduced in the endothelium. This was¦confirmed by en face analyses showing reduced Cx37 and Cx40 levels in the¦endothelial cells covering the lesion.¦Conclusion: This study assessed the regulation of the cardiovascular connexins¦in the development of IH. This model will allow us to characterize the¦involvement of gap junctions in the IH. In turn, this understanding is¦instrumental for the development of new therapeutical tools, as well as for¦the evaluation of the effects of drugs and gene therapies of this disease for which¦there is no efficient therapy available.

The role of circadian timing system on drug metabolism and detoxification.

INTRODUCTION: It has been known for a long time that the efficiency and toxicity of drugs change during a 24-h period. However, the molecular mechanisms involved in these processes have started to emerge only recently. AREAS COVERED: This review aims to highlight recent discoveries showing the direct role of the molecular circadian clock in xenobiotic metabolism at the transcriptional and post-transcriptional levels in the liver and intestine, and the different ways of elimination of these metabolized drugs via biliary and urine excretions. Most of the related literature focuses on transcriptional regulation by the circadian clock of xenobiotic metabolism in the liver; however, the role of this timing system in the excretion of metabolized drugs and the importance of the kidney in this phenomenon are generally neglected. The goal of this review is to describe the molecular mechanisms involved in rhythmic drug metabolism and excretion. EXPERT OPINION: Chronopharmacology is used to analyze the metabolism of drugs in mammals according to the time of day. The circadian timing system plays a key role in the changes of toxicity of drugs by influencing their metabolisms in the liver and intestine in addition to their excretion via bile flow and urine.

Direct analysis of dried blood spots coupled with mass spectrometry: concepts and biomedical applications.

Because of the emergence of dried blood spots (DBS) as an attractive alternative to conventional venous plasma sampling in many pharmaceutical companies and clinical laboratories, different analytical approaches have been developed to enable automated handling of DBS samples without any pretreatment. Associated with selective and sensitive MS-MS detection, these procedures give good results in the rapid identification and quantification of drugs (generally less than 3 min total run time), which is desirable because of the high throughput requirements of analytical laboratories. The objective of this review is to describe the analytical concepts of current direct DBS techniques and to present their advantages and disadvantages, with particular focus on automation capacity and commercial availability. Finally, an overview of the different biomedical applications in which these concepts could be of major interest will be presented.

Enantiomeric antidepressant drugs should be considered on individual merit

Many antidepressants have been introduced as racemic drugs, the enantiomers of which may differ in some of their pharmacodynamic and pharmacokinetic properties. This review argues that each enantiomer of a chiral antidepressant should be evaluated according to its individual characteristics rather than by extrapolation from the racemate, or by assumptions based on the stereoselective characteristics of other enantiomeric drugs. For example, in some cases the enantiomers' pharmacodynamic and therapeutic properties can be complementary, which suggests that the racemate should be used clinically. In other cases where enantiomers show qualitatively similar but quantitatively different properties to the racemate, using a single enantiomer might be more appropriate. In yet further cases, a distomer may induce the metabolism of the eutomer, enantiomers may be metabolised by different enzymes, there may be a different profile of drug-drug interactions, and therapeutic drug monitoring may be simpler. Therefore, this review exemplifies the principle that each enantiomer of a chiral antidepressant should be evaluated according to its individual pharmacological, pharmacokinetic and pharmacogenetic characteristics. These factors are discussed in relation to five chiral antidepressants: trimipramine, mianserin, mirtazapine, fluoxetine and citalopram. It is hoped that an appreciation of the stereoselective differences between enantiomers will facilitate improvements in the benefit:risk ratio of drugs used in the management of depression.

Disease identification based on ambulatory drugs dispensation and in-hospital ICD-10 diagnoses: a comparison.

BACKGROUND: Pharmacy-based case mix measures are an alternative source of information to the relatively scarce outpatient diagnoses data. But most published tools use national drug nomenclatures and offer no head-to-head comparisons between drugs-related and diagnoses-based categories. The objective of the study was to test the accuracy of drugs-based morbidity groups derived from the World Health Organization Anatomical Therapeutic Chemical Classification of drugs by checking them against diagnoses-based groups. METHODS: We compared drugs-based categories with their diagnoses-based analogues using anonymous data on 108,915 individuals insured with one of four companies. They were followed throughout 2005 and 2006 and hospitalized at least once during this period. The agreement between the two approaches was measured by weighted kappa coefficients. The reproducibility of the drugs-based morbidity measure over the 2 years was assessed for all enrollees. RESULTS: Eighty percent used a drug associated with at least one of the 60 morbidity categories derived from drugs dispensation. After accounting for inpatient under-coding, fifteen conditions agreed sufficiently with their diagnoses-based counterparts to be considered alternative strategies to diagnoses. In addition, they exhibited good reproducibility and allowed prevalence estimates in accordance with national estimates. For 22 conditions, drugs-based information identified accurately a subset of the population defined by diagnoses. CONCLUSIONS: Most categories provide insurers with health status information that could be exploited for healthcare expenditure prediction or ambulatory cost control, especially when ambulatory diagnoses are not available. However, due to insufficient concordance with their diagnoses-based analogues, their use for morbidity indicators is limited.

Contemporary perioperative care strategies.

BACKGROUND: Historically, the preoperative and postoperative care of patients with gastrointestinal cancer was provided by surgeons. Contemporary perioperative care is a truly multidisciplinary endeavour with implications for cancer-specific outcomes. METHODS: A literature review was performed querying PubMed and the Cochrane Library for articles published between 1966 to 2012 on specific perioperative interventions with the potential to improve the outcomes of surgical oncology patients. Keywords used were: fast-track, enhanced recovery, accelerated rehabilitation, multimodal and perioperative care. Specific interventions included normothermia, hyperoxygenation, surgical-site infection, skin preparation, transfusion, non-steroidal anti-inflammatory drugs, thromboembolism and antibiotic prophylaxis, laparoscopy, radiotherapy, perioperative steroids and monoclonal antibodies. Included articles had to be randomized controlled trials, prospective or nationwide series, or systematic reviews/meta-analyses, published in English, French or German. RESULTS: Important elements of modern perioperative care that improve recovery of patients and outcomes in surgical oncology include accelerated recovery pathways, thromboembolism and antibiotic prophylaxis, hyperoxygenation, maintenance of normothermia, avoidance of blood transfusion and cautious use of non-steroidal anti-inflammatory drugs, promotion of laparoscopic surgery, chlorhexidine-alcohol skin preparation and multidisciplinary meetings to determine multimodal therapy. CONCLUSION: Multidisciplinary management of perioperative patient care has improved outcomes. Copyright © 2012 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.

Critical review of cancer risk associated with angiotensin receptor blocker therapy.

The role of drugs in new cancer occurrence and cancer-related death is a major concern. Recently, a meta-analysis raised the possibility that angiotensin receptor blockers (ARBs) might have an adverse effect on patients. This generated a significant debate until the publication of two further meta-analyses, neither of which demonstrated an increased risk of new cancer occurrence or cancer-related death with the use of ARBs in patients with hypertension, heart failure, and/or nephropathy. This illustrates that the results of meta-analyses should be interpreted cautiously and critically as bias, such as selection bias, might lead to erroneous conclusions. Overall, the bulk of evidence today indicates that ARBs are not associated with increased cancer risk.

Detection of erythropoiesis-stimulating agents in human anti-doping control: past, present and future.

Stimulation of erythropoiesis is one of the most efficient ways of doping. This type of doping is advantageous for aerobic physical exercise and of particular interest to endurance athletes. Erythropoiesis, which takes place in bone marrow, is under the control of EPO, a hormone secreted primarily by the kidneys when the arterial oxygen tension decreases. In certain pathological disorders, such as chronic renal failure, the production of EPO is insufficient and results in anemia. The pharmaceutical industry has, thus, been very interested in developing drugs that stimulate erythropoiesis. With this aim, various strategies have been, and continue to be, envisaged, giving rise to an expanding range of drugs that are good candidates for doping. Anti-doping control has had to deal with this situation by developing appropriate methods for their detection. This article presents an overview of both the drugs and the corresponding methods of detection, and thus follows a roughly chronological order.

Efficacies of moxifloxacin, ciprofloxacin, and vancomycin against experimental endocarditis due to methicillin-resistant Staphylococcus aureus expressing various degrees of ciprofloxacin resistance.

The new 8-methoxyquinolone moxifloxacin was tested against two ciprofloxacin-susceptible Staphylococcus aureus strains (strains P8 and COL) and two ciprofloxacin-resistant derivatives of strain P8 carrying a single grlA mutation (strain P8-4) and double grlA and gyrA mutations (strain P8-128). All strains were resistant to methicillin. The MICs of ciprofloxacin and moxifloxacin were 0.5 and 0.125 mg/liter, respectively, for P8; 0.25 and 0.125 mg/liter, respectively, for COL; 8 and 0.25 mg/liter, respectively, for P8-4; and >or=128 and 2 mg/liter, respectively, for P8-128. In vitro, the rate of spontaneous resistance of P8 and COL was 10(-7) on agar plates containing ciprofloxacin at two times the MIC, whereas it was <or=10(-10) on agar plates containing moxifloxacin at two times the MIC. Rats with experimental aortic endocarditis were treated with doses of drugs that simulate the kinetics in humans: moxifloxacin, 400 mg orally once a day; ciprofloxacin, 750 mg orally twice a day; or vancomycin, 1 g intravenously twice a day. Treatment was started either 12 or 24 h after infection and lasted for 3 days. Moxifloxacin treatment resulted in culture-negative vegetations in a total of 20 of 21 (95%) rats infected with P8, 10 of 11 (91%) rats infected with COL, and 19 of 24 (79%) rats infected with P8-4 (P < 0.05 compared to the results for the controls). In contrast, ciprofloxacin treatment sterilized zero of nine (0%) vegetations infected with first-level resistant mutant P8-4. Vancomycin sterilized only 8 of 15 (53%), 6 of 11 (54%), and 12 of 23 (52%) of the vegetations, respectively. No moxifloxacin-resistant derivative emerged among these organisms. However, moxifloxacin treatment of highly ciprofloxacin-resistant mutant P8-128 failed and selected for variants for which the MIC increased two times in 2 of 10 animals. Thus, while oral moxifloxacin might deserve consideration as treatment for staphylococcal infections in humans, caution related to its use against strains for which MICs are borderline is warranted.

Main objectives and new aspects of combination treatment of hypertension

AIM: To review the various pharmacological approaches currently proposed for the treatment of hypertension. RESULTS: With the evolution of pharmacological treatment of hypertension, various classes of agent (diuretics, beta-blockers, angiotensin converting enzyme inhibitors, calcium antagonists and alpha 1-blockers) have become available for the initiation of antihypertensive therapy. As monotherapy, each type of agent will normalize blood pressure in about half of all hypertensive patients. Replacing one drug with another that acts through a different mechanism improves the probability of controlling blood pressure. Another way to increase the number of responders is to increase the dose; however, this often results in more side effects. A preferable way of improving efficacy is to combine low doses of drugs that have different impacts on the cardiovascular system, thus opposing the compensatory responses that tend to limit the blood pressure drop. CONCLUSION: Low-dose drug combinations are generally well tolerated and the treatment of hypertension can be simplified by using fixed-dose combinations. These combinations have the potential to become a valuable alternative in the initiation of antihypertensive therapy.

The potential of the European network of congenital anomaly registers (EUROCAT) for drug safety surveillance: a descriptive study.

BACKGROUND: European Surveillance of Congenital Anomalies (EUROCAT) is a network of population-based congenital anomaly registries in Europe surveying more than 1 million births per year, or 25% of the births in the European Union. This paper describes the potential of the EUROCAT collaboration for pharmacoepidemiology and drug safety surveillance. METHODS: The 34 full members and 6 associate members of the EUROCAT network were sent a questionnaire about their data sources on drug exposure and on drug coding. Available data on drug exposure during the first trimester available in the central EUROCAT database for the years 1996-2000 was summarised for 15 out of 25 responding full members. RESULTS: Of the 40 registries, 29 returned questionnaires (25 full and 4 associate members). Four of these registries do not collect data on maternal drug use. Of the full members, 15 registries use the EUROCAT drug code, 4 use the international ATC drug code, 3 registries use another coding system and 7 use a combination of these coding systems. Obstetric records are the most frequently used sources of drug information for the registries, followed by interviews with the mother. Only one registry uses pharmacy data. Percentages of cases with drug exposure (excluding vitamins/minerals) varied from 4.4% to 26.0% among different registries. The categories of drugs recorded varied widely between registries. CONCLUSIONS: Practices vary widely between registries regarding recording drug exposure information. EUROCAT has the potential to be an effective collaborative framework to contribute to post-marketing drug surveillance in relation to teratogenic effects, but work is needed to implement ATC drug coding more widely, and to diversify the sources of information used to determine drug exposure in each registry.

Driving under the influence of cocaine or therapeutic administration of cocaine?

Introduction: In forensic toxicology, cocaine is better known for its powerful stimulating effects of nervous system and its high potential for recreational abuse, than for his therapeutic use. However, cocaine is still use as a topical anesthetic and peripheral vasoconstrictor in surgeries of eye, ear, nose and throat. Last decade, an increase of the presence of cocaine and metabolites in blood samples of drivers suspected to drive under the influence of drugs (DUID) was observed in Switzerland (Augsburger et al., Forensic Sci Int 153 (2005) 11-15; Senna et al., Forensic Sci Int 198 (2010) 11-16). Observed blood concentration ranges of cocaine and benzoylecgonine were 10-925 μg/L and 20-5200 μg/L, respectively. Since 2005, zero-tolerance approach was introduced in the Swiss legislation for different substances, especially cocaine (analytical cutoff: 15 μg/L). Thus, the interpretation often amounts to determine if the concentration is situated above or under the limit. However, it is important for the interpretation to take into account the context and to be critical with the obtained results, at the risk of ending in erroneous conclusions. Methods: Systematical toxicological analyses were performed on blood and urine, if available, for 5 DUID cases, as already published (Augsburger et al., Forensic Sci Int 153 (2005)). Positive results were confirmed and drugs were quantified in biological samples by GCMS, GC-MS/MS or LC-MS/MS. Results: Administration of cocaine after traffic accident was identified in five cases. All people were admitted to the emergency room because of severe trauma. Maxillofacial surgery was done shortly after admission to the emergency room, involving use of nasal application of cocaine (swab). For all cases, use of cocaine swab was not mentioned in the document filled by the police and by medical staff requested for blood and urine sampling. The information was obtained retrospectively after consultation of the medical records, without precise indication of the application time or dose. Case 1. A 83-year old man (pedestrian) was hit by a car. Blood (+11h after the accident): cocaine (16 μg/L), benzoylecgonine (370 μg/L). Urine: cocaine (1700 μg/L), benzoylecgonine (560 μg/L). Case 2. A 84-year old woman (pedestrian) was hit by a car. Blood (+1.5h after the accident): cocaine (230 μg/L), benzoylecgonine (370 μg/L). Urine was not available. Hair (+4 months after the accident): segment 1 (0-2 cm), cocaine not detected; segment 2 (2-4 cm), cocaine: <0.5 ng/mg. Case 3. A 66-year old man was involved in a car/car accident. He died 2 hours and 5 minutes after the crash. Blood (+1.5h after the accident): cocaine and metabolites not detected. Blood (+2h after the accident): cocaine (1750 μg/L), benzoylecgonine (460 μg/L). Blood (post-mortem): cocaine (370 μg/L), benzoylecgonine (200 μg/L). Urine (+1.5h after the accident): cocaine not detected. Case 4. A 57-year old woman on a motor scooter was hit by a car. She died 2 hours and 10 minutes after the crash. Blood (+0.5h after the accident): cocaine and metabolites not detected. Urine (post-mortem): cocaine (<20 μg/L), benzoylecgonine (120 μg/L). Case 5. A 30-year old man was involved in a car accident. Blood (+4h after the accident): cocaine (29 μg/L), benzoylecgonine (< 20 μg/L). Urine (+4h after the accident): cocaine and metabolites not detected. Ethanol (1,32 g/kg) and cannabinoids (THC (2,0 μg/L), THCCOOH (38 μg/L)) were also detected in blood. Conclusion: To our knowledge, this is the first description of DUID cases involving therapeutic use of cocaine after an accident. These results indicate that even if a per se law is effective for prosecution case of DUID, a critical interpretation of the results is always needed, especially if a medical intervention occurs after an accident.

Administration intra-vitréenne de liposomes pour la vectorisation de principes actifs [The use of liposomes as intravitreal drug delivery system].

Liposomes are vesicular lipidic systems allowing encapsulation of drugs. This article reviews the relevant issues in liposome structure (composition and size), and their influence on intravitreal pharmacokinetics. Liposome-mediated drug delivery to the posterior segment of the eye via intravitreal administration has been addressed by several authors and remains experimental. Liposomes have been used for intravitreal delivery of antibiotics, antivirals, antifungal drugs, antimetabolites, and cyclosporin. Encapsulation of these drugs within liposomes markedly increased their intravitreal half-life, and reduced their retinal toxicity. Liposomes have also shown an attractive potential for retinal gene transfer by intravitreal delivery of plasmids or oligonucleotides.