Developing a multidisciplinary HCV direct-acting antivirals utilization management and assessment program.

BACKGROUND: The introduction of direct-acting antivirals (DAAs) for the treatment of hepatitis C virus (HCV) infections has revolutionized outcomes for patients with HCV. Cost-effective use of these antivirals in addition to ensuring patient adherence is of paramount importance. OBJECTIVES: The goal of this article is to describe the processes by which a tertiary care, multisite institution managed the complexities involved in administering DAA treatment and managing the increased cost of therapy. Specifically, the objectives of this article are to describe the development of a multidisciplinary HCV management program and the role of pharmacists in this program, including formulary management strategies and monitoring of DAAs use in our institution, development of guidelines, electronic prescribing protocols and order sets, and specific outcomes based on a concurrent medication use evaluation. PRACTICE DESCRIPTION: King Faisal Specialist Hospital and Research Centre is a tertiary care referral hospital. As a tertiary referral hospital, it offers primary and highly specialized inpatient and outpatient medical care. The process of selecting and developing institutional HCV management program is described. PRACTICE INNOVATION: This article provides key details regarding how a multidisciplinary HCV program using DAAs can be implemented successfully at a tertiary care facility. Key facets of our innovation include establishing formulary guidelines, setting up eligibility criteria for patients, and establishing an HCV taskforce and multidisciplinary HCV program clinic. EVALUATION: Medication use evaluations were regularly conducted to monitor sustained virologic response rates, adherence to guidelines, adverse reactions, and drug interactions. METHODS: Formulary guidelines, setting up an eligibility criterion for patients, and an HCV taskforce and multidisciplinary HCV program clinic were established. RESULTS: The involvement of pharmacists in a multidisciplinary HCV program in outpatient settings resulted in improved formulary decision making, reduction of costs, and improvement of adherence to institutional guidelines. PRACTICE IMPLICATIONS: The role of a pharmacist in the management of patients with HCV with DAAs is important. Pharmacists play an integral part in medication management and overall reduction in health care expenditure. Many disease management programs can be complemented with pharmacists to improve patient care and reduce cost. CONCLUSION: HCV treatment is challenging, and a multidisciplinary approach to treat HCV is critical. It is a rapidly evolving field; therefore, it requires dynamic formulary management and collaborative practice approaches to monitor pharmacotherapy carefully and efficiently. Clinical pharmacists play a pivotal role within the multidisciplinary team by providing support to both patients and health care providers with regard to the treatment of HCV.

Integrated Analysis of Whole Exome Sequencing and Copy Number Evaluation in Parkinson's Disease.

Genetic studies of the familial forms of Parkinson's disease (PD) have identified a number of causative genes with an established role in its pathogenesis. These genes only explain a fraction of the diagnosed cases. The emergence of Next Generation Sequencing (NGS) expanded the scope of rare variants identification in novel PD related genes. In this study we describe whole exome sequencing (WES) genetic findings of 60 PD patients with 125 variants validated in 51 of these cases. We used strict criteria for variant categorization that generated a list of variants in 20 genes. These variants included loss of function and missense changes in 18 genes that were never previously linked to PD (NOTCH4, BCOR, ITM2B, HRH4, CELSR1, SNAP91, FAM174A, BSN, SPG7, MAGI2, HEPHL1, EPRS, PUM1, CLSTN1, PLCB3, CLSTN3, DNAJB9 and NEFH) and 2 genes that were previously associated with PD (EIF4G1 and ATP13A2). These genes either play a critical role in neuronal function and/or have mouse models with disease related phenotypes. We highlight NOTCH4 as an interesting candidate in which we identified a deleterious truncating and a splice variant in 2 patients. Our combined molecular approach provides a comprehensive strategy applicable for complex genetic disorders.

Levodopa-Carbidopa Intestinal Gel Infusion Therapy in Advanced Parkinson's Disease: Single Middle Eastern Center Experience.

BACKGROUND: Levodopa therapy in Parkinson's disease (PD) is often associated with disabling motor and non-motor complications in patients with advanced disease due to the variable absorption of levodopa because of an irregular or erratic emptying of the gastric content. METHODS: Prospective single movement disorder center study using pre-set selection criteria, unified PD scale (UPDRS III), non-motor symptoms scale (NMSS), and PD questionnaire-8 (PDQ-8) to evaluate the efficacy, safety, and long-term treatment outcomes using levodopa-carbidopa intestinal gel (LCIG) infusion in patients with advanced PD, who were followed up every 6 months. RESULTS: Twenty patients were recruited over a period of 6 years. Disease duration prior to LCIG infusion ranged from 5 to 18 years (mean 11.4 ± 4.2). The mean follow-up time on LCIG therapy was 48.5 ± 23.2 months (range 11-83 months). Mean 'off' time, UPDRS III, NMSS, and PDQ-8 improvement were statistically significant. Two patients dropped out and 66.7% of patients required tube replacement. CONCLUSION: LCIG infusion monotherapy demonstrated significant improvement in reducing the 'off' time, reducing levodopa-induced dyskinesia, and improving non-motor symptoms and quality of life. This therapy is recommended for patients in whom motor fluctuations are inadequately treated with traditional oral PD therapy.

Parkinson's Disease in Saudi Patients: A Genetic Study.

Parkinson's disease (PD) is one of the major causes of parkinsonism syndrome. Its characteristic motor symptoms are attributable to dopaminergic neurons loss in the midbrain. Genetic advances have highlighted underlying molecular mechanisms and provided clues to potential therapies. However, most of the studies focusing on the genetic component of PD have been performed on American, European and Asian populations, whereas Arab populations (excluding North African Arabs), particularly Saudis remain to be explored. Here we investigated the genetic causes of PD in Saudis by recruiting 98 PD-cases (sporadic and familial) and screening them for potential pathogenic mutations in PD-established genes; SNCA, PARKIN, PINK1, PARK7/DJ1, LRRK2 and other PD-associated genes using direct sequencing. To our surprise, the screening revealed only three pathogenic point mutations; two in PINK1 and one in PARKIN. In addition to mutational analysis, CNV and cDNA analysis was performed on a subset of patients. Exon/intron dosage alterations in PARKIN were detected and confirmed in 2 cases. Our study suggests that mutations in the ORF of the screened genes are not a common cause of PD in Saudi population; however, these findings by no means exclude the possibility that other genetic events such as gene expression/dosage alteration may be more common nor does it eliminate the possibility of the involvement of novel genes.

Clinical and molecular characterization of ataxia with oculomotor apraxia patients in Saudi Arabia.

BACKGROUND: Autosomal recessive ataxias represent a group of clinically overlapping disorders. These include ataxia with oculomotor apraxia type1 (AOA1), ataxia with oculomotor apraxia type 2 (AOA2) and ataxia-telangiectasia-like disease (ATLD). Patients are mainly characterized by cerebellar ataxia and oculomotor apraxia. Although these forms are not quite distinctive phenotypically, different genes have been linked to these disorders. Mutations in the APTX gene were reported in AOA1 patients, mutations in SETX gene were reported in patients with AOA2 and mutations in MRE11 were identified in ATLD patients. In the present study we describe in detail the clinical features and results of genetic analysis of 9 patients from 4 Saudi families with ataxia and oculomotor apraxia. METHODS: This study was conducted in the period between 2005-2010 to clinically and molecularly characterize patients with AOA phenotype. Comprehensive sequencing of all coding exons of previously reported genes related to this disorder (APTX, SETX and MRE11). RESULTS: A novel nonsense truncating mutation c.6859 C > T, R2287X in SETX gene was identified in patients from one family with AOA2. The previously reported missense mutation W210C in MRE11 gene was identified in two families with autosomal recessive ataxia and oculomotor apraxia. CONCLUSION: Mutations in APTX , SETX and MRE11 are common in patients with autosomal recessive ataxia and oculomotor apraxia. The results of the comprehensive screening of these genes in 4 Saudi families identified mutations in SETX and MRE11 genes but failed to identify mutations in APTX gene.

CADASIL in Arabs: clinical and genetic findings.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is increasingly recognized as an inherited arterial disease leading to a step-wise decline and eventually to dementia. CADASIL is caused by mutations in NOTCH3 epidermal growth factor-like repeat that maps to chromosome 19. CADASIL cases have been identified in most countries of Western and Central Europe, the Americas, Japan, Australia, the Caribbean, South America, Tanzania, Turkey, South Africa and Southeast Asia, but not in Arabs. METHODS: We studied three families from Saudi Arabia (Family A), Kuwait (Family B) and Yemen (Family C) with 19 individuals affected by CADASIL. RESULTS: The mean age of onset was 31 +/- 6 and the clinical presentation included stroke in 68%, subcortical dementia in 17% and asymptomatic leukoariosis detected by MRI in 15%. Migraine and depression were frequently associated, 38% and 68% respectively. The mean age of death was 56 +/- 11. All NOTCH3 exons were screened for mutations, which revealed the presence of previously reported mutations c.406C>T (p.Arg110>Cys) in two families (family A&B) and c.475C>T (p.Arg133>Cys) mutation in family C. CONCLUSION: CADASIL occurs in Arabs, with clinical phenotype and genotype similar to that in other ethnic groups.