Association Between Blood and Lymphocyte Levels of Cyclosporin A and Infectious Complications in Renal Transplant Patients.

OBJECTIVES: This study aims to investigate a potential association between whole blood and lymphocyte Cyclosporin A (CyA) levels and the occurrence and frequency of infectious complications in kidney transplant patients. METHODS: The study involves 130 kidney transplant recipients who received CyA in addition to Mycophenolate Mofetil and steroids. CyA whole blood trough and maximum level (CyA BL0 and CyA BLm) as well as the corresponding levels in the lymphocytes (CyA L0 and CyA Lm) were measured for 6 months post-transplantation. RESULTS: Cytomegalovirus (CMV) as well as urinary tract infections (UTIs) were the most commonly diagnosed with an incidence of 24.6% and 26.2%, respectively. Only CyA L0 showed a significant association with CMV infection occurrence (adjusted OR = 1.051, 95% CI .997-1.025, P-value 0.046). A positive linear correlation was found between CyA BL0, CyA BLm and CyA Lm and the number of CMV episodes per patient. CONCLUSION: We showed an association between the CMV infections occurrence and the trough lymphocyte level of CyA (CyA L0). Both lymphocyte CyA levels also correlated with the frequency of CMV infections. Further studies are needed to establish the optimal range of both CyA blood and lymphocyte levels and decrease the risk of opportunistic infections in high risk patients.

Frequency of ABCB1 C3435T and CYP3A5*3 Genetic Polymorphisms in the Lebanese Population.

OBJECTIVES: CYP3A5 and ABCB1 are highly implicated in the pharmacokinetics and pharmacodynamics of immunosuppressive agents, such as calcineurin inhibitors and mammalian target of rapamycin inhibitors. The polymorphisms of their coding genes play important roles in the interindividual and intraindividual differences of bioavailability of these drugs. In this study, our objective was to investigate, in a Lebanese population,the frequency of ABCB1C3435T (rs1045642) and CYP3A5*3 (rs776746) polymorphisms and to compare the results to preexisting data from other populations. MATERIALS AND METHODS: We determined the frequencies of the allelic variants of interest for 1824 Lebanese participants, and we compared these results with those from other major ethnic groups. RESULTS: The allelic frequencies were 91.4% (C) and 8.6% (T) for CYP3A5*3 and 50.8% (T) and 49.2% (C) for ABCB1 C3435T. Our results were significantly different from most other world populations, except the European population. CONCLUSIONS: The frequencies of gene variants of interest in our Lebanese population were similar to those found in European populations. Most of our study population were CYP3A5*3 carriers, and more than half may have a lower P-glycoprotein efflux pump. These characteristics might render Lebanese transplant recipients more prone to the development of drug toxicity and in need of lower drug doses.

Asthma and COPD Patients' Perception of Appropriate Metered-Dose Inhaler Technique.

OBJECTIVES: Asthma and chronic obstructive pulmonary disease (COPD) are chronic illnesses of the airways affecting a good number of people in Lebanon and the Middle East. Pressurized metered-dose inhalers (pMDIs) are important drug delivery systems used to treat such pulmonary diseases. Drugs proven to be valuable and effective may fail to act effectively if such inhalers are used incorrectly. The purpose of this study was to assess the technical use of pMDIs by patients with pulmonary diseases presenting to the community pharmacies in Lebanon. METHODS: A structured questionnaire was developed to collect data. A total of 601 patients using drugs delivered through pMDIs and presenting to 12 Lebanese community pharmacies were recruited to participate in the research project. The questionnaire items were divided into 3 subscales: subscale 1-assessing the device preparation; subscale 2-investigating the device use; and subscale 3-examining the knowledge and use of spacers. After confirming the reliability and validity of the survey tool, patients' responses were analyzed and compared according to many variables. RESULTS: Many patients answered inaccurately to questions assessing both the device preparation and use. Around 40% of patients said they do not coordinate the inhalation with pressing the canister down. The mean scores were 1.72 (± 0.73) over 6 and 5.67 (± 1.44) over 7 for subscales 1 and 2, respectively. The mean total score on all questions was 7.39 over 13, with a standard deviation of 1.75. While patients' age did not impact the results, asthmatic, well-educated, male patients had fewer wrong answers when it comes to preparing and using the device (P < .01). CONCLUSIONS: Our study showed that many patients with asthma and COPD might not be properly using their pMDIs. Appropriate inhaler use is crucial for successful pulmonary disease management. As pMDIs are one of the most difficult devices to use, proper and tailored instructions should be given to patients.

Implementing an interprofessional education programme in Lebanon: overcoming challenges.

BACKGROUND: The Lebanese American University has a well-functioning inter-professional education (IPE) programme; this is a fundamental pedagogical approach in healthcare education in which students from different professions learn together, ultimately leading to improving the skills of the health care workforce and thus improving patient outcomes. The programme includes nursing, nutrition, medicine, pharmacy and social work students, and has now been running for 6 years. AIMS: This paper aims at describing the implementation of an IPE programme in Lebanon by focusing on how to overcome the main challenges. METHODS: We describe our experience using the categories of challenges developed by Sunguya et al. (2014), where they analysed published reports of IPE programmes in developed countries. We identified three additional challenges that might be relevant throughout the Middle East/North Africa (MENA) region or in countries with similar socioeconomic characteristics. RESULTS: The challenges encountered in designing and implementing the IPE programme were similar to other programmes: curriculum, leadership, resources, stereotypes and attitudes, variety of students, IPE concept, teaching, enthusiasm, professional jargon and accreditation as well as assessment of learning, security and logistics. CONCLUSIONS: This paper provides data and successful strategies that can be used by planned or implemented programmes in similar socioeconomic contexts in the MENA region.

Thrombophilic Genetic Anomalies and Their Association With Dialysis Initiation Age in a Cohort of Lebanese Hemodialysis Patients.

OBJECTIVES: The relationship between chronic kidney disease and cardiovascular disease is complex and bidirectional. This relationship may be partially linked to thrombophilic genetic anomalies that may predispose to the progression of both diseases. MATERIALS AND METHODS: We analyzed blood samples from 102 Lebanese patients with end-stage renal disease and undergoing hemodialysis and 20 randomly selected healthy volunteers for frequencies of 12 cardiovascular disease gene mutations and traditional risk factors. The frequencies of these mutations were calculated and compared in both groups. We stratified patients by quartiles according to their mean score of genetic mutations and traditional risk factors, as well as their mean age at dialysis initiation. Correlation analyses were performed on the various patient groups. RESULTS: We observed a high frequency of mutations in patients on dialysis. Homozygous mutations (> 10% of patients) were observed in the PAI-1 (11%), MTHFR A1298C sequence variant (12.7%), and ACE genes (12%); in addition, the FXIII V34L and PAI-1 4G/5G genotypes were significantly associated with early dialysis initiation (P < .001 and P = .004, respectively). We observed a strong linear relationship between the different scores and age at dialysis initiation, with older patients exhibiting the highest genetic, traditional, and total scores versus those shown in the youngest patients (R2 = 0.72 and P < .001; R2 = 0.98 and P < .001; and R2 =0.96 and P < .001, respectively). CONCLUSIONS: Our results revealed a polygenic thrombophilic profile in our population of Lebanese patients with end-stage renal disease. This profile showed a strong association between early dialysis initiation and specific homozygous cardiovascular disease gene mutations. The cumulative load of these genetic and traditional risk factors may be partly responsible for the increased risk of cardiovascular disease and risk of progression to end-stage renal disease in patients with chronic kidney disease.

Student perceptions towards interprofessional education: Findings from a longitudinal study based in a Middle Eastern university.

The Lebanese American University Interprofessional Education (LAU IPE) Steps Framework consists of a five-step workshop-based series that is offered throughout the curriculum of health and social care students at an American university in Lebanon. The aim of the present study was to report students' perceptions of their readiness for interprofessional learning before and after completing the IPE steps, their evaluations of interprofessional learning outcomes, as well as their satisfaction with the learning experience as a whole. A longitudinal survey design was used: questionnaires were completed by students before IPE exposure and after each step. The results showed that before IPE exposure, students' perceptions of their readiness for interprofessional learning were generally favourable, with differences across genders (stronger professional identity in females compared to males) and across professions (higher teamwork and collaboration in pharmacy and nutrition students compared to other professions and lower patient centredness in nursing students compared to others). After participation in the IPE steps, students showed enhanced readiness for interprofessional learning and differences between genders and professions decreased. Participants were satisfied with the learning experience and assessment scores showed that all IPE learning outcomes were met. The LAU IPE Steps Framework may be of value to other interprofessional education course developers.

Effectiveness of a Technology-Based Intervention to Teach Evidence-Based Practice: The EBR Tool.

BACKGROUND: As the world becomes increasingly digital, advances in technology have changed how students access evidence-based information. Research suggests that students overestimate their ability to locate quality online research and lack the skills needed to evaluate the scientific literature. Clinical nurses report relying on personal experience to answer clinical questions rather than searching evidence-based sources. To address the problem, a web-based, evidence-based research (EBR) tool that is usable from a computer, smartphone, or iPad was developed and tested. The purpose of the EBR tool is to guide students through the basic steps needed to locate and critically appraise the online scientific literature while linking users to quality electronic resources to support evidence-based practice (EBP). METHODS: Testing of the tool took place in a mixed-method, quasi-experimental, and two-population randomized controlled trial (RCT) design in a U.S. and Middle East university. RESULTS: A statistically significant improvement in overall research skills was supported in the quasi-experimental nursing student group and RCT nutrition student group using the EBR tool. A statistically significant proportional difference was supported in the RCT nutrition and PharmD intervention groups in participants' ability to distinguish the credibility of online source materials compared with controls. The majority of participants could correctly apply PICOTS to a case study when using the tool. CONCLUSIONS: The data from this preliminary study suggests that the EBR tool enhanced student overall research skills and selected EBP skills while generating data for assessment of learning outcomes. LINKING EVIDENCE TO ACTION: The EBR tool places evidence-based resources at the fingertips of users by addressing some of the most commonly cited barriers to research utilization while exposing users to information and online literacy standards of practice, meeting a growing need within nursing curricula.

Prevalence of depression in Parkinson's disease in a Lebanese tertiary clinic.

INTRODUCTION: Diagnosis of Parkinson's disease can be emotionally and psychologically challenging to patients. The aim of this study is to investigate the association between Parkinson's disease and depression and the impact of the disease stage and patients' age and gender on this association. METHOD: This is a cross-sectional retrospective study on 200 patients aged above 35 years old from 10 different nationalities. RESULTS: Depression was diagnosed in 46% of the patients enrolled. Most of these patients were treated with an antidepressant. Young age, female gender, and moderate Parkinson's disease stage were found to be significantly associated with depression (odds ratio of 1.19, 1.23, and 1.22, respectively, p < .05). CONCLUSION: This study, the first of its kind in Lebanon and the Middle East and North Africa region, highlights the importance of studying depression in Parkinson's disease and the need for identifying and treating depression symptoms when treating Parkinson's disease patients.

Association of coronary artery disease and chronic kidney disease in Lebanese population.

BACKGROUND: More evidence is emerging on the strong association between chronic kidney disease (CKD) and cardiovascular disease. We assessed the relationship between coronary artery disease (CAD) and renal dysfunction level (RDL) in a group of Lebanese patients. METHODS: A total of 1268 patients undergoing cardiac catheterization were sequentially enrolled in a multicenter cross sectional study. Angiograms were reviewed and CAD severity scores (CADSS) were determined. Estimated glomerular filtration rate (eGFR) was calculated and clinical and laboratory data were obtained. CKD was defined as eGFR < 60 ml/min. Logistic regression model was performed using multivariate analysis including all traditional risk factors associated with both diseases. ANOVA and the Tukeytestswere used to compare subgroups of patients and to assess the impact of each disease on the severity of the other. RESULTS: Among the 82% patients who exhibited variable degrees of CAD, 20.6% had an eGFR < 60 ml/min. Logistic regression analysis revealed a bidirectional independent association between CAD and CKD with an OR = 2.01 (P < 0.01) and an OR = 1.99 (P < 0.01) for CAD and CKD frequencies, respectively. We observed a steady increase in the CADSS mean as eGFR declined and a progressive reduction in renal function with the worsening of CAD (P < 0.05). This correlation remained highly significant despite considerable inter-patient variability and was at its highest at the most advanced stages of both diseases. CONCLUSIONS: Our results show a strong, independent and graded bidirectional relationship between CAD severity and RDL. We propose to add CAD to the list of risk factors for the development and progression of CKD.

Preclinical impact of bevacizumab on brain and tumor distribution of irinotecan and temozolomide.

Glioblastoma (GBM) is the most common primary malignant brain tumour in adults. Prognosis of GBM patients is poor with median overall survival around 15 months. Temozolomide is the chemotherapeutic agent used in the standard of care of newly diagnosed GBM patients relying on radiotherapy with concurrent chemotherapy followed by chemotherapy alone. Irinotecan has shown some efficacy in recurrent malignant gliomas. Bevacizumab has been combined with irinotecan in the treatment of recurrent GBM and with temozolomide in newly diagnosed GBM. As the efficacy of GBM treatments relies on their brain distribution through the blood brain barrier, the aim of the present preclinical work was to study, in in vivo models, the impact of bevacizumab on brain and tumor distribution of temozolomide and irinotecan. Our results show that bevacizumab pre-treatment was associated with a reduced temozolomide brain distribution in tumor-free mice. In tumor bearing mice, bevacizumab increased temozolomide tumor distribution, although not statistically significant. In both tumor-free and tumor-bearing mice, bevacizumab does not modify brain distribution of irinotecan and its metabolite SN-38. Bevacizumab impacts brain distribution of some anti-tumor drugs and potentially their efficacy in GBM. Further studies are warranted to investigate other therapeutic combination.

Association of hypertension with coronary artery disease onset in the Lebanese population.

The onset of coronary artery disease (CAD) is influenced by cardiovascular risk factors that often occur in clusters and may build on one another. The objective of this study is to examine the relationship between hypertension and CAD age of onset in the Lebanese population. This retrospective analysis was performed on data extracted from Lebanese patients (n = 3,753). Logistic regression examined the association of hypertension with the age at CAD diagnosis after controlling for other traditional risk factors. The effect of antihypertensive drugs and lifestyle changes on the onset of CAD was also investigated. Results showed that hypertension is associated with late onset CAD (OR=0.656, 95% CI=0.504-0.853, p=0.001). Use of antihypertensive drugs showed a similar association with delayed CAD onset. When comparing age of onset in CAD patients with traditional risk factors such as hypertension, diabetes, hyperlipidemia, obesity, smoking and family history of CAD, the age of onset was significantly higher for patients with hypertension compared to those with any of the other risk factors studied (p < 0.001). In conclusion, hypertension and its treatment are associated with late coronary atherosclerotic manifestations in Lebanese population. This observation is currently under investigation to clarify its genetic and/or environmental mechanisms.

Genetic and environmental influences on total plasma homocysteine and its role in coronary artery disease risk.

BACKGROUND: Elevated levels of total plasma homocysteine are a risk factor for atherosclerotic disease. AIMS: The rationale behind this study is to explore the correlation between degree and site of coronary lesion and hyperhomocysteinemia in Lebanese CAD patients and assess environmental and genetic factors for elevated levels of total plasma homocysteine. METHODS: A total of 2644 patients were analyzed for traditional CAD risk factors. Logistic regression was performed to determine the association of hyperhomocysteinemia with degree and site of coronary lesions controlling for risk factors. Environmental and genetic factors for hyperhomocysteinemia were analyzed by logistic regression using a candidate gene approach. RESULTS: Traditional risk factors were correlated with stenosis. Hyperhomocysteinemia associated with increased risk of overall stenosis, and risk of mild and severe occlusion in major arteries. Hyperhomocysteinemia and hypertension were highly correlated suggesting that hyperhomocysteinemia acts as a hypertensive agent leading to CAD. Diuretics and genetic polymorphisms in MTHFR and SLCO1B1 were associated with hyperhomocysteinemia. CONCLUSIONS: Hyperhomocysteinemia is a medical indicator of specific vessel stenosis in the Lebanese population. Hypertension is a major link between hyperhomocysteinemia and CAD occurrence. Genetic polymorphisms and diuretics' intake explain partly elevated homocysteine levels. This study has important implications in CAD risk prediction.

P-glycoprotein expression and function are increased in an animal model of amyotrophic lateral sclerosis.

The efflux pumps located at the blood-brain barrier (BBB) prevent drugs entering the brain. As such, efflux pumps are a major obstacle to drug brain distribution. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with little therapeutics available: riluzole is the only drug approved in its treatment. The lack of response to treatment in ALS may be, at least in part, due to increased activities of efflux pumps in relation to disease, leading to subtherapeutic brain concentrations of drugs. In the present study, we used a transgenic mouse model of ALS (G86R mSOD1 mice) to test this hypothesis. Expression and functionality of P-glycoprotein (ABCB1, P-gp) and Breast Cancer Resistance Protein (ABCG2, BCRP), two major efflux pumps, were studied. We observed an increased P-gp expression (1.5-fold) in presymptomatic mSOD1 mice compared to wild-type controls. Consistent with this, P-gp function was also increased by 1.5-fold and riluzole brain disposition was decreased by 1.7-fold in mSOD1 mice. Contrasting with this, BCRP expression and function were unaltered by the pathology. These results demonstrate that BBB transport proteins are modified in G86R mSOD1 mice ALS model. Such findings underline potential problems in extrapolating the results of animal studies to humans and developing clinical trials, especially for drugs transported by P-gp.

Role of two efflux proteins, ABCB1 and ABCG2 in blood-brain barrier transport of bromocriptine in a murine model of MPTP-induced dopaminergic degeneration.

PURPOSE: MPTP-induced dopaminergic degeneration is an experimental model commonly used to explore Parkinson's disease. Cerebral drug transport by ABC transporters in MPTP models has never been reported. METHODS: We have investigated the transport of bromocriptine through the blood-brain barrier (BBB) in a MPTP model to understand the influence of the dopaminergic degeneration on ABCB1 and ABCG2. RESULTS: We have shown that in MPTP treated mice, bromocriptine is widely distributed to brain (2.3-fold versus control, p less than 0.001) suggesting either disruption of BBB or alteration of active efflux of the drug. In situ brain perfusion of [14C]- sucrose and [3H]-inulin did not evidenced a BBB disruption. Studies of ABCB1 and ABCG2 activity showed that MPTP intoxication did not alter their functionality. Conversely, ABCG2 expression studied on brain capillaries from MPTP-treated mice was decreased (1.3-fold, p less than 0.05) and ABCB1 expression increased (1.43-fold, p less than 0.05) as an off-setting of brain transport. CONCLUSIONS: These data demonstrate that MPTP intoxication does not alter the BBB permeability. However, bromocriptine brain distribution is increased in MPTP animals. Hence, MPTP may interact with another transport mechanism such as uptake and/or other efflux transporters. Inflammation and Parkinson's-like lesions induced by MPTP intoxication could lead to modification of drug pharmacokinetics and have clinical consequences, such as neurotoxicity.

Brain and plasma riluzole pharmacokinetics: effect of minocycline combination.

PURPOSE: amyotrophic lateral sclerosis is a fatal neurodegenerative disease characterized by the loss of motorneurons. The only drug approved is riluzole. Minocycline is an antibiotic with numerous neuroprotective properties. riluzole and minocycline were given to an animal model of ALS and had beneficial effect on the disease. The combination was then tested in humans in phase II and phase III studies with less beneficial effects and a faster decline of the disease in the group treated with minocycline. In a previous study, we showed that riluzole is transported out of the brain by the P-glycoprotein at the blood-brain barrier level. METHODS: in this work, we studied in CF1 mice, the plasmatic and cerebral pharmacokinetics of riluzole combined or not with minocycline. RESULTS: our results showed that the kinetics of riluzole are not linear with dose, but that cerebral AUC0-infinity increase proportionally with plasmatic AUC0-infinity. At the dose of 10 mg/kg, the cerebral AUC0-infinity /plasmatic AUC0-infinity ratio was 4.6 in mdr1a (-/-) mice and 2.4 in mdr1a (+/+) mice. The combination of minocycline (170 mg/kg) and riluzole (10 mg/kg) induced a 2 fold increase in the cerebral AUC0-infinity of riluzole and induced a neuromuscular toxicity in mice. This effect of minocycline was not found at low concentration (10 mg/kg of minocycline). CONCLUSIONS: if our results are confirmed in humans, riluzole cerebral concentrations could be predicted by plasmatic concentrations. Furthermore, the combination of high doses of minocycline with riluzole could induce neurological toxicity that lead to deceiving results in ALS clinical studies.

Interactions between riluzole and ABCG2/BCRP transporter.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative fatal disease. Drugs used in this disease need to cross the blood-brain barrier (BBB). Only riluzole is approved for ALS treatment. We have investigated riluzole as a breast cancer resistance protein (BCRP) substrate by studying its brain transport in CF1 mdr1a (-/-) mice and its intracellular uptake on BeWo cells (human placental choriocarcinoma cell line). We have also investigated the effect of riluzole on BCRP expression level and on its activity using the prazocin as a test probe for brain transport and intracellular uptake. Assays on mdr1a (-/-) mice and BeWo cells showed a higher uptake of riluzole when pretreated with a BCRP inhibitor. After repeated doses of riluzole, BCRP activity was increased in CF1 mdr1a (-/-) mice, riluzole uptake was decrease and both BCRP expression and activity were increased in BeWo cells. In conclusion, we report in this study that riluzole is transported by BCRP at the BBB level and can enhance its function. These results taken with our previous studies on riluzole and P-glycoprotein show that drug-drug interactions between riluzole and efflux transporters substrates may occur at the BBB level and should be taken into account in future clinical trial design in ALS.

Interactions between antiparkinsonian drugs and ABCB1/P-glycoprotein at the blood-brain barrier in a rat brain endothelial cell model.

Parkinson's disease is a neurodegenerative disorder that requires treatment by dopaminergic agonists, which may be responsible for central side effects. We hypothesized that the efflux transporter ABCB1/P-glycoprotein played a role in brain disposition of antiparkinsonian drugs and could control central toxicity. We aimed to evaluate antiparkinsonian drugs as ABCB1 substrates and/or inhibitors in rat brain endothelial cells GPNT, in order to predict potential clinical drug-drug interactions. Among the antiparkinsonian drugs tested, levodopa, bromocriptine, pergolide and pramipexole were ABCB1 substrates. However, only bromocriptine could inhibit ABCB1 functionality with an IC(50) of 6.71 microM on Rhodamine 123 uptake and an IC(50) of 1.71 microM on digoxine uptake. Thus, bromocriptine at 100 microM is responsible for an increase of levodopa intracellular transport of about 2.05-fold versus control. Therefore, we can conclude that bromocriptine is a potent drug for medicinal interactions in vitro. Hence, in patients with Parkinson's disease, these results may be considered to optimise treatments individually.

Minocycline and riluzole brain disposition: interactions with p-glycoprotein at the blood-brain barrier.

Amyotrophic lateral sclerosis is a neurodegenerative fatal disease. The only drug recognized to increase the survival time is riluzole(RLZ). In animal models, minocycline (MNC) delayed the onset of the disease and increased the survival time (in combination with RLZ). The objective of our work was to study the interactions between RLZ, MNC and the efflux pump p-glycoprotein (p-gp) at the blood-brain barrier. We investigated these two drugs as: (i) p-gp substrates by comparing their brain uptake in CF1 mdr1a (-/-) and mdr1a (+/+) mice, (ii) p-gp modulators by studying their effect on the cerebral uptake of digoxin. mdr1a (-/-) mice showed higher brain uptake of MNC and RLZ than mdr1a (+/+) (in a 1.6- and 1.4-fold, respectively); and in mdr1a (+/+) mice pre-treated with repeated doses of MNC, brain uptake of digoxin was increased. When both drugs were administrated to mdr1a (+/+) mice, MNC increased the brain uptake of RLZ in a 2.1-fold. In conclusion, MNC and RLZ are both p-gp substrates. MNC is also a p-gp inhibitor and increases the brain diffusion of RLZ. In vitro experiments with the GPNT cell line confirmed these results. These interactions should be taken into account in the design of future clinical trials.