Drug uptake in a rodent sarcoma model after intravenous injection or isolated lung perfusion of free/liposomal doxorubicin.

The distribution of free and liposomal doxorubicin (Liporubicin) administered by intravenous injection (IV) or isolated lung perfusion (ILP) was compared in normal and tumor tissues of sarcoma bearing rodent lungs. A single sarcomatous tumor was generated in the left lung of 35 Fischer rats, followed 10 days later by left-sided ILP (n=20) or IV drug administration (n=12), using 100 microg and 400 microg free or liposomal doxorubicin, respectively. The tumor and lung tissue drug concentration was measured by HPLC. Free doxorubicin administered by ILP resulted in a three-fold (100 microg) and 10-fold (400 microg) increase of the drug concentration in the tumor and normal lung tissue compared to IV administration. In contrast, ILP with Liporubicin resulted in a similar drug uptake in the tumor and lung tissue compared to IV injection. For both drug formulations and dosages, ILP resulted in a higher tumor to lung tissue drug ratio but also in a higher spatial heterogeneity of drug distribution within the lung compared to IV administration. ILP resulted in a higher tumor to lung tissue drug ratio and in a more heterogeneous drug distribution within the lung compared to IV drug administration.

Protective effect of intravitreal administration of tresperimus, an immunosuppressive drug, on experimental autoimmune uveoretinitis.

PURPOSE: To test the efficiency of locally administrated tresperimus in experimental autoimmune uveoretinitis (EAU). METHODS: EAU was induced in Lewis rats by S-antigen (S-Ag) immunization. Three intravitreal injections of tresperimus (prevention or prevention/treatment protocols) were performed at different time points after immunization. The pharmacokinetics of tresperimus was evaluated in the ocular tissues and plasma. The in vitro effect of tresperimus was evaluated on macrophages. EAU was graded clinically and histologically. Blood ocular barrier permeability was evaluated by protein concentration in ocular fluids. Immune response to S-Ag was examined by delayed type hypersensitivity, the expression of inflammatory cytokines in lymph nodes, ocular fluids and serum by multiplex ELISA, and in ocular cells by RT-PCR. RESULTS: In vitro, tresperimus significantly reduced the production of inflammatory cytokines by lipopolysaccharide-stimulated macrophages. In vivo, in the treatment protocol, efficient tresperimus levels were measured in the eye but not in the plasma up to 8 days after the last injection. Tresperimus efficiently reduced inflammation, retinal damage, and blood ocular barrier permeability breakdown. It inhibited nitric oxide synthase-2 and nuclear factor κBp65 expression in ocular macrophages. IL-2 and IL-17 were decreased in ocular media, while IL-18 was increased. By contrast, IL-2 and IL-17 levels were not modified in inguinal lymph nodes draining the immunization site. Moreover, cytokine levels in serum and delayed type hypersensitivity to S-Ag were not different in control and treated rats. In the prevention/treatment protocol, ocular immunosuppressive effects were also observed. CONCLUSIONS: Locally administered tresperimus appears to be a potential immunosuppressive agent in the management of intraocular inflammation.

Health services utilization associated with cognitive impairment and dementia in older patients undergoing post-acute rehabilitation.

OBJECTIVE: To investigate the relationship between levels of cognitive impairment and health services utilization in older patients undergoing post-acute rehabilitation. DESIGN: Cross-sectional study. SETTING: Post-acute rehabilitation facility. PARTICIPANTS: Patients (N = 1764) aged 70 years and older admitted over 3 years. MEASUREMENTS: Sociodemographic, medical, and functional data were collected upon admission. Based on discharge diagnoses, patients were classified as cognitively intact, cognitively impaired with no dementia (CIND), and demented. RESULTS: Dementia and CIND were diagnosed in 425 (24.1%) and 301 (17.1%) patients, respectively. Gradients from cognitively intact to cognitively impaired to demented patients were observed in median length of stay (19, 22, and 25 days, P < .001), and institutionalization rates at discharge (4.2%, 7.6%, and 28.8%, P < .001). Among patients discharged home, similar gradients were observed in utilization of home care (68.2%, 79.7%, and 83.3%, P < .001) and day care (3.1%, 7.1%, and 14.3%, P < .001). After adjustment, compared with cognitively intact patients, only those with dementia still had longer stays (+2.7 days) and increased odds of institutionalization (adjOR 6.1, 95% CI 4.0-9.3, P < .001). Among patients discharged home, use of home and day care remained higher in those with dementia (adjOR 1.8, 95% CI 1.2-2.7, P = .005, and adjOR 1.8, 95% CI 1.2-2.7, P = .005, respectively), while CIND patients had higher odds of using home care (adjOR 1.6, 95% CI 1.1-2.4, P = .028). CONCLUSION: Among patients undergoing post-acute rehabilitation, those with dementia had increased use of both institutional and community care, whereas those with CIND had increased use of home care services only. Future studies should investigate specific strategies susceptible to reduce the related burden on health care systems.

Off-label utilization of antipsychotics

Résumé Ce travail s'inscrit dans un programme de recherche centré sur la pharmacovigilance en psychiatrie. Buts de l'étude Les nouveaux antipsychotiques atypiques sont prescrits avec beaucoup de succès, parce qu'ils présentent une sécurité dans leur emploi bien supérieure à celle des antipsychotiques classiques. Cette situation a conduit à une large prescription «off-label» (hors indication admise). Le but de ce travail a été d'étudier la pratique en matière de prescription des psychiatres hospitaliers en ce qui concerne les antipsychotiques en comparant des patients traités pour des psychoses ou d'autres indications officielles aux patients recevant un traitement antipsychotique «off-label». Méthode Dans le cadre d'un programme de pharmacovigilance - pharmacoépidemiologie, tous les médicaments prescrits à 5 jours de référence (entre 1999 et 2001) à l'hôpital psychiatrique universitaire de Lausanne (98 lits) ont été enregistrés, avec des données sur l'âge, le sexe et le diagnostic des patients. Les prescriptions de 202 patients ont été évaluées. Les patients ont été classés dans 3 groupes diagnostiques : (1) patient présentant des troubles psychotiques, (2) patient présentant des épisodes maniaques et des épisodes dépressifs avec des symptômes psychotiques, et (3) patient présentant d'autres troubles. Les groupes (1) et (2) forment une classe de patients recevant un antipsychotique pour une indication officielle, et les prescriptions dans le groupe (3) ont été considérées comme «off-label». Résultats principaux Moins de patients psychotiques ont reçu un antidépresseur (p<0.05) ou des hypnotiques non-benzodiazepine (p<0.001) comparés aux patients des deux autres groupes. Les patients présentant des troubles affectifs recevaient seulement exceptionnellement une combinaison d'un antipsychotique atypique et conventionnel, tandis qu'un nombre inférieur de patients avec des indications « off-label » ont reçu moins .souvent des antipsychotiques atypiques que ceux des deux groupes de comparaison (p<0.05). L'analyse statistique (stepwise logistic regression) a révélé que les patients présentant des troubles psychotiques avaient un risque plus élevé de recevoir un médicament antipsychotique d'une dose moyenne ou élevée, (p<0.001) en comparaison aux deux autres groupes. Conclusion Les nouveaux médicaments antipsychotiques semblent être prescrits avec moins d'hésitation principalement pour des indications admises. Les médecins prescrivent de nouveaux médicaments « off-label » seulement après avoir acquis une certaine expérience dans le domaine des indications approuvées, et ils étaient plus prudents en ce qui concerne la dose en traitant sur la base «off-label». Abstract Objective The new brands of atypical antipsychotics are very successfully prescribed because of their enhanced safety profiles and their larger pharmacological profile in comparison to the conventional antipsychotic. This has led to broad off-label utilisation. The aim of the present survey was to study the prescription practice of hospital psychiatrists with regard to antipsychotic drugs, comparing patients treated for psychoses or other registered indications to patients receiving an off-label antipsychotic treatment. Method As part of a pharmacovigilance/pharmacoepidemiology program, all drugs given on 5 reference days (1999 - 2001) in the 98-bed psychiatric hospital of the University of Lausanne, Switzerland, were recorded along with age, sex and diagnosis. The prescriptions of 202 patients were assessed. Patients were classified in 3 diagnostic groups: (1) patient with psychotic disorders, (2) patients with manic episodes and depressive episodes with psychotic symptoms, and (3) patients with other disorders. Group (1) and (2) formed the class of patients receiving an antipsychotic for a registered indication, and the prescriptions in group (3) were considered as off-label. Main results A lesser number of psychotic patients received antidepressant (p<0.05) and nonbenzodiazepine hypnotics (p<0.001) compared to the patients of the other two groups. The patients with affective disorders received only exceptionally a combination of an atypical and a conventional antipsychotic, whereas a lesser number of patients with off-label indications received less often atypical antipsychotics than those of the two comparison groups (p<0.05). Stepwise logistic regression revealed that patients with psychotic disorder were at higher risk of receiving an antipsychotic medication in medium or high dose (p<0.001), in comparison to the two other groups. Conclusions The new antipsychotic drugs seem to be prescribed with less hesitation mainly for approved indications. Physicians prescribe new drugs on off-label application only after having gained some experience in the field of the approved indications, and were more cautious with regard to dose when treating on an off-label basis.

Effect of changes in the deuterium content of drinking water on the hydrogen isotope ratio of urinary steroids in the context of sports drug testing.

The hydrogen isotope ratio (HIR) of body water and, therefore, of all endogenously synthesized compounds in humans, is mainly affected by the HIR of ingested drinking water. As a consequence, the entire organism and all of its synthesized substrates will reflect alterations in the isotope ratio of drinking water, which depends on the duration of exposure. To investigate the effect of this change on endogenous urinary steroids relevant to doping-control analysis the hydrogen isotope composition of potable water was suddenly enriched from -50 to 200 0/00 and maintained at this level for two weeks for two individuals. The steroids under investigation were 5β-pregnane-3α,20α-diol, 5α-androst-16-en-3α-ol, 3α-hydroxy-5α-androstan-17-one (ANDRO), 3α-hydroxy-5β-androstan-17-one (ETIO), 5α-androstane-3α,17β-diol, and 5β-androstane-3α,17β-diol (excreted as glucuronides) and ETIO, ANDRO and 3β-hydroxyandrost-5-en-17-one (excreted as sulfates). The HIR of body water was estimated by determination of the HIR of total native urine, to trace the induced changes. The hydrogen in steroids is partly derived from the total amount of body water and cholesterol-enrichment could be calculated by use of these data. Although the sum of changes in the isotopic composition of body water was 150 0/00, shifts of approximately 30 0/00 were observed for urinary steroids. Parallel enrichment in their HIR was observed for most of the steroids, and none of the differences between the HIR of individual steroids was elevated beyond recently established thresholds. This finding is important to sports drug testing because it supports the intended use of this novel and complementary methodology even in cases where athletes have drunk water of different HIR, a plausible and, presumably, inevitable scenario while traveling.

A biodegradable drug delivery system for the treatment of postoperative inflammation

Cataract surgery is often performed in patients suffering from associated pathologies. Our goal is to develop a biodegradable drug delivery system (DDS) combined with the artificial intraocular lens (IOL). DDS were manufactured using poly(D,L-lactide-co-glycolide), or PLGA, and were loaded with triamcinolone acetonide (TA). The loading capacity was approximately 1050 microg of TA per DDS. The higher the molecular weight of PLGA (34,000, 48,000 and 80,000Da), the slower was the release of TA in vitro. Cataract surgery was performed on the right eye of rabbits. IOL was inserted with (i) no DDS, (ii) unloaded DDS PLGA48000, (iii) one loaded DDS PLGA48000, (iv) two loaded DDS. The number of inflammatory cells and the protein concentration were measured in the aqueous humor (AH). Unloaded DDS showed good ocular biocompatibility. One DDS PLGA48000 loaded with TA significantly reduced postoperative ocular inflammation. Two loaded DDS PLGA48000 was even more effective in inhibiting such inflammation. On long-term observation (days 63 and 84), reduction of inflammation could be obtained by insertion of one DDS PLGA48000 and a second DDS PLGA80000. Therefore, our "all in one" system is very promising since it could replace oral treatment and reduce the number of intraocular injections

Illicit drug profiling, reflection on statistical comparisons

This paper presents reflexions about statistical considerations on illicit drug profiling and more specifically about the calculation of threshold for determining of the seizure are linked or not. The specific case of heroin and cocaine profiling is presented with the necessary details on the target profiling variables (major alkaloids) selected and the analytical method used. Statistical approach to compare illicit drug seizures is also presented with the introduction of different scenarios dealing with different data pre-treatment or transformation of variables.The main aim consists to demonstrate the influence of data pre-treatment on the statistical outputs. A thorough study of the evolution of the true positive rate (TP) and the false positive rate (FP) in heroin and cocaine comparison is then proposed to investigate this specific topic and to demonstrate that there is no universal approach available and that the calculations have to be revaluate for each new specific application.

Alveolar echinococcosis: from a deadly disease to a well-controlled infection. Relative survival and economic analysis in Switzerland over the last 35 years.

BACKGROUND/AIMS: Alveolar echinococcosis (AE) is a serious liver disease. The aim of this study was to explore the long-term prognosis of AE patients, the burden of this disease in Switzerland and the cost-effectiveness of treatment. METHODS: Relative survival analysis was undertaken using a national database with 329 patient records. 155 representative cases had sufficient details regarding treatment costs and patient outcome to estimate the financial implications and treatment costs of AE. RESULTS: For an average 54-year-old patient diagnosed with AE in 1970 the life expectancy was estimated to be reduced by 18.2 and 21.3 years for men and women, respectively. By 2005 this was reduced to approximately 3.5 and 2.6 years, respectively. Patients undergoing radical surgery had a better outcome, whereas the older patients had a poorer prognosis than the younger patients. Costs amount to approximately Euro108,762 per patient. Assuming the improved life expectancy of AE patients is due to modern treatment the cost per disability-adjusted life years (DALY) saved is approximately Euro6,032. CONCLUSIONS: Current treatments have substantially improved the prognosis of AE patients compared to the 1970s. The cost per DALY saved is low compared to the average national annual income. Hence, AE treatment is highly cost-effective in Switzerland.

Zeitpunkt der Medikamenten-einnahme bei Hypertonie und Angina pectoris. Eine kontrollierte Uberwachungsstudie. [Time of drug intake in hypertension and angina pectoris. A controlled monitoring study]

A prospective cross-over study was performed in a general practice environment to assess and compare compliance data obtained by electronic monitoring on a BID or QD regimen in 113 patients with hypertension or angina pectoris. All patients were on a BID regimen (nifedipine SR) during the first month and switched to QD regimen (amlodipine) for another month. Taking compliance (i.e. the proportion of days with correct dosing) improved in 30% of patients (95% confidence interval 19 to 41%, p < 0.001), when switching from a BID to a QD regimen, but at the same time there was a 15% increase (95% confidence interval 5 to 25%, p < 0.02) in the number of patients with one or more no-dosing days. About 8% of patients had a low compliance rate, irrespective of the dosage regimen. Actual dosage intervals were used to estimate extent and timing of periods with unsatisfactory drug activity for various hypothetical drug durations of action, and it appears that the apparent advantage of QD regimen in terms of compliance is clinically meaningful only, when the duration of activity extents beyond the dosage interval in all patients.

Stage of change of cigarette smoking in drug dependent patients

Résumé En Suisse, les programmes de désaccoutumance au tabac se réfèrent généralement au modèle de préparation au changement de Prochaska et DiClemente (1983), Les patients atteints de maladies somatiques liées au tabagisme comme les pathologies cardiovasculaires ou pulmonaires accèdent facilement à ces programmes, contrairement aux patients présentant une dépendance à des drogues illicites. La prévalence de fumeurs dans cette population est pourtant élevée et les problèmes engendrés par le tabac sont importants, non seulement d'un point de vue individuel mais aussi en terme de santé publique. Il est par conséquent intéressant d'évaluer la motivation concernant la désaccoutumance au tabac de patients toxicomanes entreprenant un sevrage de drogues illicites. Dans cette étude, nous avons évalué les stades de préparation au changement concernant la dépendance au tabac chez 100 patients toxicomanes hospitalisés sur un mode volontaire dans le cadre d'un programme de sevrage à des drogues illégales. L'évaluation s'est faite à l'aide d'un auto-questionnaire dont les résultats indiquent qu'une minorité de patients sont décidés à interrompre la consommation de tabac. En effet, seul 15% des patients se trouvaient aux stades de contemplation ou de décision. De plus, 93% des sujets considéraient l'arrêt du tabac comme difficile ou très difficile. Ces données montrent qu'il existe un décalage important entre la motivation relative au sevrage de drogues illégales et la motivation liées à l'arrêt du tabac. En effet, malgré leur motivation élevée pour se sevrer de drogues illicites, la proportion de patients restant au stade de précontemplation concernant la désaccoutumance au tabac reste élevée. Diverses hypothèses permettent d'expliquer ces résultats, notamment la perception que la désaccoutumance au tabac est plus difficile à réaliser que le sevrage de substances illicites. Abstract Nicotine cessation programmes in Switzerland, which are commonly based on the stage of change model of Prochaska and DiClemente (1983), are rarely offered to patients with illicit drug dependence. This stands in contrast to the high smoking rates and the heavy burden of tobacco-related problems in these patients. The stage of change was therefore assessed by self-administered questionnaire in 100 inpatients attending an illegal drug withdrawal programme. Only 15% of the patients were in the contemplation or decision stage. 93% considered smoking cessation to be difficult or very difficult. These data show a discrepancy between the motivation to change illegal drug consumption habits and the motivation for smoking cessation. The high pro-portion of patients remaining in the precontemplation stage for smoking cessation, in spite of their motivation for illicit drug detoxification, may be due to the perception that cessation of smoking is more difficult than illicit drug abuse cessation.

A modular approach for integrative analysis of large-scale gene-expression and drug-response data

High-throughput technologies are now used to generate more than one type of data from the same biological samples. To properly integrate such data, we propose using co-modules, which describe coherent patterns across paired data sets, and conceive several modular methods for their identification. We first test these methods using in silico data, demonstrating that the integrative scheme of our Ping-Pong Algorithm uncovers drug-gene associations more accurately when considering noisy or complex data. Second, we provide an extensive comparative study using the gene-expression and drug-response data from the NCI-60 cell lines. Using information from the DrugBank and the Connectivity Map databases we show that the Ping-Pong Algorithm predicts drug-gene associations significantly better than other methods. Co-modules provide insights into possible mechanisms of action for a wide range of drugs and suggest new targets for therapy

Photodynamic drug delivery enhancement in tumours does not depend on leukocyte-endothelial interaction in a human mesothelioma xenograft model.

OBJECTIVES: The pre-treatment of tumour neovessels by low-level photodynamic therapy (PDT) improves the distribution of concomitantly administered systemic chemotherapy. The mechanism by which PDT permeabilizes the tumour vessel wall is only partially known. We have recently shown that leukocyte-endothelial cell interaction is essential for photodynamic drug delivery to normal tissue. The present study investigates whether PDT enhances drug delivery in malignant mesothelioma and whether it involves comparable mechanisms of actions. METHODS: Human mesothelioma xenografts (H-meso-1) were grown in the dorsal skinfold chambers of 28 nude mice. By intravital microscopy, the rolling and recruitment of leukocytes were assessed in tumour vessels following PDT (Visudyne(®) 400 μg/kg, fluence rate 200 mW/cm(2) and fluence 60 J/cm(2)) using intravital microscopy. Likewise, the distribution of fluorescently labelled macromolecular dextran (FITC-dextran, MW 2000 kDa) was determined after PDT. Study groups included no PDT, PDT, PDT plus a functionally blocking anti-pan-selectin antibody cocktail and PDT plus isotype control antibody. RESULTS: PDT significantly enhanced the extravascular accumulation of FITC-dextran in mesothelioma xenografts, but not in normal tissue. PDT significantly increased leukocyte-endothelial cell interaction in tumour. While PDT-induced leukocyte recruitment was significantly blunted by the anti-pan-selectin antibodies in the tumour xenograft, this manipulation did not affect the PDT-induced extravasation of FITC-dextran. CONCLUSIONS: Low-level PDT pre-treatment selectively enhances the uptake of systemically circulating macromolecular drugs in malignant mesothelioma, but not in normal tissue. Leukocyte-endothelial cell interaction is not required for PDT-induced drug delivery to malignant mesothelioma.

Drug monographs on drugs which are frequently analysed in the context of Therapeutic Drug Monitoring = Arzneimittel-Monographien für Medikamente, die regelmässig im Rahmen des Therapeutic Drug Monitorings analysiert werden

In addition to the monographs which were published last year by the working group "Drug Monitoring" of the Swiss Society of Clinical Chemistry (SSCC) [1], new monographs have been written. The aim of these monographs is to give an overview of the most important information necessary for ordering a drug analysis or interpreting the results. Therefore, the targeted readers comprise laboratory health professionals and all receivers of laboratory reports. There is information provided on the indication for therapeutic drug monitoring, protein binding, metabolic pathways and enzymes involved, elimination half-life and elimination routes, and on therapeutic or toxic concentrations. Preanalytical considerations are of particular importance for therapeutic drug monitoring. Therefore, information is provided regarding a reasonable timing for the determination of drug concentrations as well as steady-state concentrations after changing the dose. Furthermore, the stability of the drug and its metabolite(s) after blood sampling is described. For readers with a specific interest in drug analysis, references to important publications are given. The number of monographs will be continuously enlarged. The updated files are presented on the homepage of the SSCC (www.sscc.ch).