Borrowing Transcriptional Kinases to Activate Apoptosis.

Protein kinases are disease drivers whose therapeutic targeting traditionally centers on inhibition of enzymatic activity. Here chemically induced proximity is leveraged to convert kinase inhibitors into context-specific activators of therapeutic genes. Bivalent molecules that link ligands of the transcription factor B-cell lymphoma 6 (BCL6) to ATP-competitive inhibitors of cyclin-dependent kinases (CDKs) were developed to re-localize CDK to BCL6-bound loci on chromatin and direct phosphorylation of RNA Pol II. The resulting BCL6-target proapoptotic gene expression translated into killing of diffuse large B-cell lymphoma (DLBCL) cells at 72 h with EC50s of 0.9 - 10 nM and highly specific ablation of the BCL6-regulated germinal center response in mice. The molecules exhibited 10,000-fold lower cytotoxicity in normal lymphocytes and are well tolerated in mice. Genomic and proteomic evidence corroborated a gain-of-function mechanism where, instead of global enzyme inhibition, a fraction of total kinase activity is borrowed and re-localized to BCL6-bound loci. The strategy demonstrates how kinase inhibitors can be used to context-specifically activate transcription, accessing new therapeutic space.

Rewiring cancer drivers to activate apoptosis.

Genes that drive the proliferation, survival, invasion and metastasis of malignant cells have been identified for many human cancers1-4. Independent studies have identified cell death pathways that eliminate cells for the good of the organism5,6. The coexistence of cell death pathways with driver mutations suggests that the cancer driver could be rewired to activate cell death using chemical inducers of proximity (CIPs). Here we describe a new class of molecules called transcriptional/epigenetic CIPs (TCIPs) that recruit the endogenous cancer driver, or a downstream transcription factor, to the promoters of cell death genes, thereby activating their expression. We focused on diffuse large B cell lymphoma, in which the transcription factor B cell lymphoma 6 (BCL6) is deregulated7. BCL6 binds to the promoters of cell death genes and epigenetically suppresses their expression8. We produced TCIPs by covalently linking small molecules that bind BCL6 to those that bind to transcriptional activators that contribute to the oncogenic program, such as BRD4. The most potent molecule, TCIP1, increases binding of BRD4 by 50% over genomic BCL6-binding sites to produce transcriptional elongation at pro-apoptotic target genes within 15 min, while reducing binding of BRD4 over enhancers by only 10%, reflecting a gain-of-function mechanism. TCIP1 kills diffuse large B cell lymphoma cell lines, including chemotherapy-resistant, TP53-mutant lines, at EC50 of 1-10 nM in 72 h and exhibits cell-specific and tissue-specific effects, capturing the combinatorial specificity inherent to transcription. The TCIP concept also has therapeutic applications in regulating the expression of genes for regenerative medicine and developmental disorders.

Characteristics of Pharmacists' Interventions Related to Proton-Pump Inhibitors in French Hospitals: An Observational Study.

Methods: The study was based on a retrospective analysis of pharmacist interventions for DRPs detected during the medication order review and documented into the French Act-IP© database over a 12-year period. DRPs and PIs were analyzed, and independent factors of physician acceptance were assessed via multiple logistic regression. Results: Out of the 620,620 PIs registered, 29,694 targeted a PPI (4.8%). PPI's DRPs were mostly related to the prescription of a "drug not available at the hospital" (26.1%) and a "drug use without indication" (18.3%); PIs were mostly "drug switch" (35.9%) and "drug discontinuation" (26.1%). In all, 18,919 PIs were accepted by physicians (63.7%). Acceptance was significantly associated with patient age: less accepted for the 18-75 years group (OR = 0.59, 95 CI [0.46-0.76]), and the >75 years group (OR = 0.57, 95 CI [0.44-0.73]) vs. <18 years group; for the type of DRP, "drug use without indication" was the less accepted (OR = 0.73, 95 CI [0.63-0.85]); for the type of PI, "dose adjustment" was the less accepted (OR = 0.32, 95 CI [0.23-0.45]). Conclusion: Pharmacists contribute to preventing DRPs associated with PPI prescriptions during the medication order review process. Moreover, they often detect PPIs used without indication and they propose drug discontinuation, which contributes to the PPI deprescribing process. PIs should be further developed in the future to reduce PPI overprescription.

Diagnostic yield of active case finding for tuberculosis at human immunodeficiency virus testing in Haiti.

SETTING: The Groupe Haïtien d'étude du Sarcome de Kaposi et des Infections Opportunistes (GHESKIO) Centres, Port-au-Prince, Haiti, facilitate "test and treat" strategies by screening all patients for tuberculosis (TB) at human immunodeficiency virus (HIV) testing.OBJECTIVE: 1) To determine the proportion of patients with chronic cough at HIV testing diagnosed with TB, stratified by HIV test results; and 2) to evaluate the additional diagnostic yield of Xpert® MTB/RIF vs. sputum microscopy.DESIGN: We conducted a retrospective cohort analysis including all adults tested for HIV at GHESKIO from August 2014 to July 2015.RESULTS: Of 29 233 adult patients tested for HIV, 2953 (10%) were diagnosed as HIV-positive. Chronic cough lasting ≥2 weeks was reported by 1116 (38%) HIV-positive patients; 984 (88%) were tested and 265 (27%) were diagnosed with TB. Chronic cough was reported by 5985 (23%) HIV-negative patients; 5654 (94%) were tested and 1179 (21%) were diagnosed with TB. Of all bacteriologically confirmed cases, 27% were smear-negative and Xpert-positive. Among all TB patients, 81% were HIV-negative.CONCLUSIONS: Screening for TB at HIV testing was high-yield, among both HIV-infected and HIV-negative individuals. Testing for both diseases should be conducted among patients who present with chronic cough at HIV testing.

Blood transcriptomic markers of Mycobacterium tuberculosis load in sputum.

BACKGROUND: Peripheral blood transcriptome signatures that distinguish active pulmonary tuberculosis (TB) from control groups have been reported, but correlations of these signatures with sputum mycobacterial load are incompletely defined. METHODS: We assessed the performance of published TB transcriptomic signatures in Haiti, and identified transcriptomic biomarkers of TB bacterial load in sputum as measured by Xpert® MTB/RIF molecular testing. People in Port au Prince, Haiti, with untreated pulmonary TB (n = 51) formed the study cohort: 19 people with low and 32 with high sputum Mycobacterium tuberculosis load. Peripheral whole blood transcriptomes were generated using RNA sequencing. RESULTS: Twenty of the differentially expressed transcripts in TB vs. no TB were differentially expressed in people with low vs. high sputum mycobacterial loads. The difference between low and high bacterial load groups was independent of radiographic severity. In a published data set of transcriptomic response to anti-tuberculosis treatment, this 20-gene subset was more treatment-responsive at 6 months than the full active TB signature. CONCLUSION: We identified genes whose transcript levels in the blood distinguish active TB with high vs. low M. tuberculosis loads in the sputum. These transcripts may reveal mechanisms of mycobacterial control of M. tuberculosis during active infection, as well as identifying potential biomarkers for bacterial response to anti-tuberculosis treatment.

Catatonia with schizophrenia: From ECT to rTMS.

BACKGROUND: Electroconvulsive therapy is indicated in cases of catatonic schizophrenia following a failure of the challenge test with lorazepam or Zolpidem®. Some patients need maintenance treatment with ECT. Repetitive Transcranial Magnetic Stimulation (rTMS) and anodal Transcranial direct-current stimulation (tDCS) might be effective against catatonia. OBJECTIVE: Consider an alternative to ECT for a refractory patient. REVIEW: Twenty-one articles were identified mainly based on case reports series were found using search on Medline, Google Scholar, PsychInfo, CAIRNS. Key words were:"catatonia", and "rTMS", and more generally with"ECT","tDCS","Zolpidem®". At the end there were only six case reports with rTMS and three with tDCS. We discussed the alternative to ECT and follow up rTMS strategies illustrated by these case reports. FINDINGS: Patients mean age was 35; numbers of previous ECT vary from zero to 556; the most common motor threshold (MT) is 80%, with two patients with 110%, the most common treatment placement is L DLPFC. In one of them, ECT was the only acute-state or maintenance treatment effective in this patient, who underwent 556 ECT sessions over 20 years. High-frequency rTMS was considered as a possible alternative, given the potential adverse effects of chronic maintenance ECT in a patient with comorbid epilepsy. rTMS treatment was 3-4×/week and over time extended to once every two weeks. A persistent objective improvement in catatonia was observed on the Bush-Francis Catatonia Rating Scale. CONCLUSION: rTMS is helpful for acute and maintenance treatment for catatonic schizophrenia who both failed multiple pharmacologic interventions and had safety concerns with continuing maintenance ECT. Clinicians should consider rTMS as a potential treatment option for refractory catatonia.

Diagnostic yield of active case finding for tuberculosis and HIV at the household level in slums in Haiti.

SETTING: Haiti has the highest burden of tuberculosis (TB) in the Americas, with an estimated prevalence of 254 per 100 000 population. The Haitian Group for the Study of Kaposi's Sarcoma and Opportunistic Infections (Groupe Haïtien d'Etude du Sarcome de Kaposi et des Infections Opportunistes, GHESKIO) conducted active case finding (ACF) for TB at the household level in nine slums in Port-au-Prince. OBJECTIVE: We report on the prevalence of undiagnosed TB detected through GHESKIO's ACF campaign. DESIGN: From 1 August 2014 to 31 July 2015, we conducted a retrospective cohort analysis using GHESKIO's ACF campaign data. All individuals who reported chronic cough (cough 2 weeks) were tested for TB at GHESKIO, and those aged 10 years were included in the analyses. RESULTS: Of 104 097 individuals screened in the community, 5598 (5%) reported chronic cough and satisfied the study inclusion criteria. A total of 1110 (20%) were diagnosed with active TB disease (prevalence of 1066/100 000). Of the 5472 (98%) patients tested for human immunodeficiency virus (HIV), 528 (10%) were HIV-positive; 143 (3%) patients were diagnosed with both diseases. CONCLUSION: Household-level screening for cough with TB and HIV testing for symptomatic patients was a high-yield strategy, leading to the detection of a prevalence of undiagnosed disease exceeding national estimates by more than four-fold for TB, and by five-fold for HIV.

Prevalence of Canine Obesity, Obesity-Related Metabolic Dysfunction, and Relationship with Owner Obesity in an Obesogenic Region of Spain.

The main objective of this study was to evaluate the prevalence of canine obesity and obesity-related metabolic dysfunction (ORMD) in the obesogenic area in Spain. The prevalence of overweight/obesity among owners of obese pets was also evaluated. In the sample population studied (93 client-owned dogs), 40.9% of dogs presented obesity (body condition score 7-9/9), 40.9% of dogs presented hypertension, 20.4% of dogs presented fasting hypertriglyceridemia, 20.4% fasting hypercholesterolemia, and 5.4% of dogs presented fasting hyperglycemia. The overall prevalence of ORMD was of 22.6%. Seventy-eight percent of overweight/obese owners had overweight/obese dogs (P < 0.001) including all dogs diagnosed with ORMD. In conclusion, in the studied obesogenic region of Spain, the prevalence of canine obesity and ORMD was shown to be elevated and related to the presence of overweight/obesity in owners. All dogs with ORMD were owned by overweight/obese persons. These results provide new inputs for future studies highlighting the relationship between owner and pet obesity and indicating the need of further efforts to control and reduce obesity prevalence in both.

[How to act when an alpha-blocker is associated with a potent inhibitor of CYP3A4]. / Conduite à tenir en cas d'association d'un alpha-bloquant et d'un inhibiteur puissant du cytochrome 3A4.

OBJECTIVE: Combination of alpha-blockers with potent CYP3A4 inhibitors is either contra-indicated or not recommended. We searched data supporting this classification and guiding prescribers when such an interaction occurs. METHODS: We analyzed reports published by the French agency for drug safety, reference books and performed search in databases of pharmacokinetics studies and case or case series related with these interactions. RESULTS: The classification of the potential severity of these interactions defined by the French agency for drug safety evolved over time. Our literature search did not identify any cases or case series reporting serious clinical consequences of such interactions and no pharmacoepidemiological studies on the association between alpha-blockers and inhibitors of CYP3A4. The content of the summaries of product characteristics indicate that the combination of ketoconazole with alfuzosin, silodosin and tamsulosin increases the area under the curve of the alpha-blocker 3 fold. CONCLUSION: Data demonstrating the clinical consequences of an association between alpha-blocker and a potent CYP3A4 inhibitor are lacking. The 3 fold increase of the area under the curve for alfuzosin, silodosin and tamsulosin associated with ketoconazole while the association with the two first is contra-indicated and is not recommended with the third raises questions. This lack of data leaves doctors and pharmacists in a situation of uncertainty on how to proceed when such an interaction occurs.

Trends in pharmacists' medication order review in French hospitals from 2006 to 2009: analysis of pharmacists' interventions from the Act-IP© website observatory.

WHAT IS KNOWN AND OBJECTIVES: The French Society of Clinical Pharmacy has developed a website, named Act-IP©, enabling hospital pharmacists to document and analyse pharmacists' interventions (PIs) proposed during medication order review when a drug-related problem is detected. This study analyses PIs documented in Act-IP© and assesses factors associated with physicians' acceptance of PIs. METHODS: PIs documented into Act-IP© over a 30-month period were analysed. Independent predictors of physicians' acceptance were assessed using multiple logistic regression. RESULTS AND DISCUSSION: A total of 34,522 PIs were registered by 201 pharmacists working in 59 hospitals. PIs were mostly related to 'dose adjustment' (25%), 'drug discontinuation' (20%) and 'drug switch' (19%). Of the 43,343 medications involved, 28% targeted drugs acting on the central nervous system, 17% anti-infective drugs and 16% cardiovascular drugs. Sixty-eight per cent of PIs were accepted by physicians (15% refusals and 17% non-assessable). Physicians' acceptance was significantly associated with 1/ drug group: antineoplastics and immunomodulators (OR = 2.29, CI 95[1.94-2.69]), anti-infectives (OR = 1.19, CI 95 [1.11-1.28]); 2/ type of intervention: drug switch (OR = 1.54, CI 95 [1.43-1.65]), drug discontinuation (OR = 1.38, CI 95 [1.29-1.48]), administration modality optimization (OR = 1.19, CI 95 [1.11-1.29]), addition of a new drug (OR = 1.12, CI 95 [1.00-1.24]); 3/ ward specialty: paediatrics (OR = 1.83, CI 95 [1.24-2.70]) and intensive care (OR = 1.34, CI 95 [1.10-1.64]); 4/ level of pharmacist integration in the ward: higher when the pharmacist is regularly in the ward compared with occasionally (OR = 0.74, CI 95 [0.70-0.79]) or never (OR = 0.68, CI 95 [0.60-0.75]) present. WHAT IS NEW AND CONCLUSION: This study highlights the role of routine pharmacist review of medication orders to prevent drug-related problems and gives new insights for a successful collaboration between physicians and pharmacists.

CD4 deficit and tuberculosis risk persist with delayed antiretroviral therapy: 5-year data from CIPRA HT-001.

SETTING: Port-au-Prince, Haiti. OBJECTIVE: To determine long-term effects of early vs. delayed initiation of antiretroviral therapy (ART) on immune recovery and tuberculosis (TB) risk in human immunodeficiency virus (HIV) infected individuals. DESIGN: Open-label randomized controlled trial of immediate ART in HIV-infected adults with CD4 counts between 200 and 350 cells/mm(3) vs. deferring ART until the CD4 count was <200 cells/mm(3). The primary comparisons were CD4 counts over time and risk for incident TB, with 5 years of follow-up. RESULTS: A total of 816 participants were enrolled, with 408 in each treatment arm. The early treatment group started ART within 2 weeks, while the deferred treatment group started ART a median of 1.3 years after enrollment. After 5 years, the mean CD4 count in the early treatment group was significantly higher than in the deferred treatment group (496 cells/mm(3), 95% confidence interval [CI] 477-515 vs. 373 cells/mm(3), 95%CI 357-389; P < 0.0001). TB risk was higher in the deferred treatment group (unadjusted HR 2.41, 95%CI 1.56-3.74; P < 0.0001) and strongly correlated with lower CD4 counts in time-dependent multivariate analysis. CONCLUSION: Delays in ART initiation for HIV-infected adults with CD4 counts of 200-350 cells/mm(3) can result in long-term immune dysfunction and persistent increased risk for TB.

[Pharmacists' interventions conducted by hospital pharmacists on psychotropic drugs pharmacotherapy]. / Interventions pharmaceutiques émises par les pharmaciens sur les médicaments psychotropes.

INTRODUCTION: The French Society of Clinical Pharmacy (SFPC) through the special interest group "standardization and optimization of clinical pharmacy activities" stated that the study of pharmacists' interventions (PIs) conducted during prescription analysis was a priority. The SFPC developed an internet website named Act-IP(®) (http://www.sfpc.eu/fr/) where French speaking pharmacists were able to document PIs using a normalized codification. The objective of this study was to analyze medication-related problems linked to psychotropic drugs in hospital and to investigate PIs performed during prescription analysis. MATERIALS AND METHODS: This is a multicenter, retrospective, observational study using PIs involving psychotropic medications recorded between September 2006 and February 2009 on the Act-IP(®) website. RESULTS: Four thousand six hundred and twenty PIs recorded by 165 pharmacists in 57 hospitals were related to psychotropic drugs. Patients concerned by these drug-related problems were 64 years old on average. Seven categories of medication-related problems represented more than 69% of PIs (1.1-Non Conformity of the drug choice compared to the formulary; 4.1 Supratherapeutic dose; 5.3 Therapeutic redundancy; 6.2 Drug interaction (all levels of severity); 7.0 Adverse drug reaction; 8.3 Inappropriate drug form; 8.5 Inappropriate timing of administration). The PIs related to 9.2 Patient's non compliance, 2.0 Untreated indication and 3.2 Length of the treatment too short were infrequent (less than 1%). The most common type of intervention was the dose adjustment. Almost 45% of these PIs involved Zopiclone or Zolpidem prescription in elderly patients. Seven hundred and nine drug interactions were identified by pharmacists. The most common type of drug interaction considered the risk of cardiac arrhythmias due to antipsychotic medications. One hundred and thirty-three PIs concerned adverse drug reaction. The most frequent adverse drug reactions were a fall (36 PIs), hemorrhage/bleeding (32 PIs), drowsiness (12 PIs) and extrapyramidal syndrome (12 PIs). Antidepressant drugs were the greatest pharmacological class concerning adverse drug reaction. The overall acceptance rate was 57%. Eight hundred and seventy-four PIs (19%) were refused and 1111 (24%) were non-assessable. DISCUSSION: PIs avoids drug-related problems, such as the polyprescription of benzodiazepine or supratherapeutic dose. However, few PIs concern compliance to therapy or polyprescription of antipsychotic drugs. These two categories of medication-related problems are known to be an issue in mental health therapy. The lack of guidelines describing mental health pathology (such as the HAS guideline) is an obstacle for performing evidence-based PIs. The lack of information describing the context of the prescription is a limitation of this study. In order to improve their practice, pharmacists have to focus more on the context in which patients are evolving, and to take into account its entire situation based on Anglo-Saxon approaches. A second way is to identify clinical settings where PIs are useful and to describe PIs needed. Doctors and pharmacists should get together and talk about these clinical situations and PIs, because some may be misunderstood or disapproved by prescribers. This collaboration could take the form of a thesaurus combining clinical situation and PIs. CONCLUSION: It appears important for pharmacists to show their daily involvement in the quality of medical care. This feedback on medication problems encountered and PIs proposed should help prescribers to identify clinical situations at risk. Nevertheless, this study also suggests that progress is possible. Dialogue must allow pharmacists and physicians to delete misunderstandings about their practices.

Evaluation of cardiopulmonary biomarkers during classic adulticide treatment versus the American Heartworm Society recommended treatment protocol in dogs infected by Dirofilaria immitis.

Adulticide treatment of dogs with canine heartworm disease causes the death of the adult Dirofilaria immitis lodged in the vascular system of the host. During the death of the worms, pulmonary thromboembolisms (PTE), pulmonary inflammation, congestive heart failure, or renal disease are possible consequences. The aim of this study was to evaluate cardiopulmonary biomarkers and renal parameters during adulticide treatment of canine heartworm to compare the classic two-injection treatment protocol versus the American Heartworm Society (AHS) recommended protocol. Fourteen heartworm-infected dogs with high parasite burdens were divided in three groups and allocated to adulticide protocols as follows: Group A (n=5) was treated with the classic two-injection protocol; group B (n=5) was treated using the AHS recommended protocol, and group C (n=4) was treated as for group B but received diminishing anti-inflammatory doses of prednisone. To assess cardiorespiratory status, cardiac troponin I (cTnI), myoglobin, and D-dimer were measured. Renal function was evaluated by measuring urea, creatinine, and urine protein:creatinine (UP:C). Serum and urine samples were collected day 0 (day of diagnosis), 7 and 14 days after the first dose of adulticide, and 1 month after the last adulticide injection. Dogs that received classic treatment presented pathologic concentrations of D-dimer more frequently and showed higher average D-dimer levels, which may indicate the presence of more severe PTE. Group C showed the highest levels of D-dimer during treatment, which may be due to an exacerbation of PTE caused by the administration of prednisone. CTnI and myoglobin values remained above reference values in all groups during the study but reached the lowest values 1 month after the last injection. Levels of urea and creatinine were within normal ranges in all groups, and 28.5% of the dogs were proteinuric on day 0, progressing to better UP:C values at the end of the treatment, except in group A. The results of this study justify the treatment of canine heartworm disease using the AHS recommended adulticide guidelines and recommends re-evaluation of the role of glucocorticosteroids in the prevention and treatment of PTE.

Cardiopulmonary and inflammatory biomarkers in the assessment of the severity of canine dirofilariosis.

The prognosis and success of adulticide treatment depends on the baseline severity of infection with Dirofilaria immitis in dogs and can influence the therapeutic protocol to choose. A study was conducted to assess the utility of the cardiopulmonary biomarkers N-terminal of the prohormone brain natriuretic peptide (NT-proBNP), cardiac troponin I (cTnI), myoglobin, and D-dimer, as well as the biomarker of inflammation C-reactive protein (CRP) to evaluate the severity of canine heartworm disease in different stages. Serum samples were collected from 20 heartworm-infected dogs for measurement of these biomarkers. Dogs were assigned to four groups (n=5/group) according to the severity of the disease: Class I and Class II dogs showed concentrations of biomarkers generally within normal ranges for healthy dogs, except CRP in dogs classified as Class II, which showed values slightly above laboratory reference values (19.46±5.69mg/l). Dogs of Class III showed elevated levels of NT-proBNP (1220.12±465.18pmol/l) (p<0.05), cTnI (0.99±0.39ng/ml), CRP (33.98±7.99mg/l) (p<0.05), and 40% of these dogs (2/5) presented pathological values of D-dimer and myoglobin (p<0.05). Dogs of Class IV (caval syndrome) presented elevated levels of NT-proBNP (>2530.8pmol/l), cTnI (1.99±0.32ng/ml), and CRP (80.24±47.69mg/l); all Class IV dogs showed pathological elevations of D-dimer (0.81±0.46ng/ml), and 60% (3/5) of these dogs showed pathological elevations of myoglobin (significant elevations [p<0.05] for all biomarkers with respect to reference values and values for dogs in Classes I, II, and III). In canine heartworm disease, chronic presence of D. immitis causes a proliferative endoarteritis, thromboembolisms, pulmonary hypertension, and right-sided congestive heart failure. As the severity of the disease worsens, serum values of cTnI, myoglobin, and NT-proBNP increase, indicating significant cardiac damage. The finding of pathological concentrations of D-dimer suggests the presence of thromboembolism and/or disseminated intravascular coagulation. CRP increases according to the severity of the disease, indicating inflammatory processes that could contribute to the progression of the disease. These preliminary results demonstrate the utility of cardiopulmonary and inflammation biomarkers to assist in the establishment of the severity of canine heartworm disease.

Effects of low-fat high-fibre diet and mitratapide on body weight reduction, blood pressure and metabolic parameters in obese dogs.

The aim of the present study was to compare the impact on blood pressure and different metabolic parameters of a weight-loss program on obese dogs fed on a low-fat high-fibre diet and treated with and without mitratapide. The study sample consisted of 36 obese dogs, randomly assigned to a control group (n=17), which were fed on a low-fat high-fibre diet, and an intervention group (n=19), fed on the same diet and treated with mitratapide. Variables measured included body condition score, body weight, heart rate, systolic and diastolic blood pressures; total cholesterol, triglycerides and glucose levels; alanine aminotransferase and alkaline phosphatase activity, measured both at baseline (day 0) and at the end of the weight loss program (day 85). All the studied parameters had decreased in both groups at the end of the study; these being diastolic blood pressure, total cholesterol and alanine aminotransferase, significantly lower in dogs treated with mitratapide. The use of mitrapide in addition to low-fat high-fibre diet does not seem to offer any further useful effect in the loss of weight during the treatment of canine obesity. On the other hand, mitratapide seems to present certain beneficial effects on pathologies associated with obesity, these being mainly related to blood pressure, lipids and hepatic parameters.

Pharmacists' interventions on intravenous to oral conversion for potassium.

BACKGROUND: Guidelines recommend use of the oral route whenever possible to treat or prevent hypokalemia. Although a myriad of papers have been published regarding intravenous to oral (IV to PO) therapy conversion programs and about clinical pharmacy services provided in hospitals, little is known on the role of hospital pharmacists in promoting the oral route for potassium administration. OBJECTIVE: The aim of this work was to describe the frequency of interventions related to IV to PO potassium therapy conversions performed by hospital pharmacists. Setting French hospitals recording pharmacist's interventions on the website tool of the French Society of Clinical Pharmacy. METHODS: From the pharmacist's interventions (PI) dataset recorded we extracted all interventions related to potassium IV to PO conversion. We assessed the acceptance rate of these PI by prescribers. Additional free text information in the dataset was analysed. MAIN OUTCOME MEASURES: IV to PO potassium therapy conversions related to potassium chloride. RESULTS: From January 2007 to December 2010, 87 hospitals recorded 1,868 PIs concerning IV to PO therapy conversion. Among these, 16 (<1 %) concerned potassium chloride. They were recorded by four hospitals (4.6 %) with respectively 12, 2, 1 and 1 PIs. Six PIs were accepted by physicians and the prescriptions were modified. CONCLUSION: PIs to promote the administration of potassium by the oral route are extremely rare. Our results and scarce previously published data reveal that this field of practice remains almost unexplored. These findings highlight an important gap in the field of intravenous to oral therapy programs. This situation must be regarded as unsatisfactory and should lead to setting up more education and research programs.

Overdosed paracetamol (acetaminophen) prescriptions and subsequent pharmacist interventions in French hospitals.

INTRODUCTION: Little is known about the manner in which hospital pharmacists intervene for overdosed paracetamol prescriptions. The aim of this retrospective study was to describe the number and nature of pharmacists' interventions (PIs) for overdosed paracetamol adult prescriptions in hospitals. METHODS: We studied PIs that had been documented by pharmacists on the French Society of Clinical Pharmacy website tool between 2007 and 2010. We identified PIs that were related to paracetamol-containing prescriptions of one brand name only (type 1) particularly for patients with body weight ≤ 50 kg who were prescribed 4 g/day, and PIs that concerned the co-prescription of two paracetamol-containing products (type 2). RESULTS: Among 60 hospitals, seven did not report any paracetamol overdose-related PIs. Of the 53 hospitals that had at least one PI, 16 did not report any type 1 PIs. Bodyweight, liver disease, cirrhosis and chronic alcoholism were absent recorded criterion by most of the hospitals included in this study. DISCUSSION: Previously published studies have highlighted that the most frequent PIs are type 1, especially for patients whose body weight is ≤ 50 kg. We observed a broad variability in the number or type of PI that were related to overdosed paracetamol prescriptions compared with the total of all recorded types of PI. These data suggest that a significant number of hospital pharmacists are unaware of the risks that adult patients with low body weight are exposed to when receiving four grams paracetamol/day over several days. CONCLUSION: Pharmacist educational programs are needed.

Utility of cardiac biomarkers during adulticide treatment of heartworm disease (Dirofilaria immitis) in dogs.

Heartworm disease (Dirofilaria immitis) is a parasitic disease of dogs and other carnivores, characterized by the presence of adult worms in the pulmonary arteries and right ventricle, leading to pulmonary hypertension which may progress to congestive heart failure. Cardiac biomarkers are biological parameters that can be objectively measured as indicators of pathological processes, or to assess the response to therapeutic interventions. To evaluate the myocardial damage during the adulticide treatment in 15 heartworm-infected dogs with ivermectin, doxycycline and melarsomine, measurements of cardiac troponin I (cTnI), myoglobin, MB isoenzyme of creatine kinase (CK-MB) and aspartate aminotransferase (AST) were carried out on days 0, 60 and afterwards weekly on days 67, 75, 82, 91, 106, 113 and 120. Dogs were divided by low parasite burden (n=9) and high parasite burden (n=6). On day 0, dogs with high worm burden showed increased cTnI concentrations (3.62 ± 4.78 ng/ml) while dogs with low worm burden had concentrations similar to those of healthy dogs (0.78 ± 0.22 ng/ml), CK-MB concentrations were increased only in dogs with high parasite burden as well (54.4 ± 54.2U/l) and 26.6% (4/15) of the dogs showed pathological concentrations of myoglobin. On day 91, most dogs showed pathological concentrations of myoglobin, CK-MB and AST, probably due to the myositis associated to the intramuscular injection of melarsomine. The rest of the measurements made in the study, the biomarkers concentrations were within normal values, except for cTnI in dogs with high parasite burden, which remained above reference concentrations for healthy dogs during all the study. The evaluation of cardiac biomarkers seems to be a helpful test in the assessment of the myocardium in dogs with heartworm disease during the adulticide treatment.