Optimal Pharmacological Treatment Research Articles

Intraduodenal levodopa-carbidopa intestinal gel infusion improves both motor performance and quality of life in advanced Parkinson’s disease

We report the efficacy and adverse effect profile of intraduodenal levodopa-carbidopa intestinal gel (LCIG) infusion from patients treated in a single Australian movement disorder centre. We conducted an open-label, 12month prospective study of treatment with LCIG in patients with advanced Parkinson’s disease in a single tertiary referral hospital unit specialising in movement disorders. Patients with levodopa-responsive, advanced Parkinson’s disease with motor fluctuations despite optimal pharmacological treatment were enrolled and underwent a 16hour daily infusion of LCIG for 12months. Fifteen participants completed the trial. The mean (±standard deviation) improvement in Unified Parkinson’s Disease Rating Scale part III was 37±11%, mean daily “off” period reduced from 6.3±2 to 1.9±2hours, total daily “on” time increased from 10.2±3 to 13.7±2hours, “on” period without dyskinesia increased from 4.5±3 to 7.5±5hours, and 39-item Parkinson’s Disease Questionnaire Summary Index score improved by 32.5±35%. The most common adverse event was reversible peripheral neuropathy secondary to vitamin B12±B6 deficiency (40%), local tube problems (40%), and impulse control disorder (ICD) (27%). No patient had stoma bleeding or peritonitis. All patients with ICD had a past psychiatric diagnosis of depression with or without anxiety and a higher daily levodopa intake at 6 and 12months of LCIG infusion. Intraduodenal LCIG improves motor performance, quality of life and daily “on” period. Prior to and during duodenal LCIG infusion, clinicians should monitor for peripheral neuropathy and vitamin B12 and B6 deficiency, as supplementation can reverse peripheral neuropathy. This trial is registered at Clinicaltrials.gov as CT00335153.

Paracetamol for the Treatment of Patent Ductus Arteriosus in Very Low Birth Weight Infants

Persistent patent ductus arteriosus (PDA) is associated with significant co-morbidities and increased mortality in preterm infants, especially very low birth weight (VLBW) infants. A large number of studies on the management of PDA have been published. Despite PDA being such a common condition in preterm infants, there is no consensus on which PDAs to treat, when to treat and how best to treat. Nonspecific cyclo-oxygenase inhibitors such as indomethacin and ibuprofen have been the mainstay of medical treatment of PDA for decades. Ibuprofen has similar efficacy and higher safety profile when compared to indomethacin, as it is associated with fewer gastrointestinal and renal side effects, and is considered the drug of choice for PDA closure. Recently, there is a growing interest in paracetamol for PDA closure and it has been suggested as an alternative drug to treat PDA. Finding the optimal pharmacological treatment for PDA closure in VLBW continues to remain challenging. In this review article, we assessed the evidence of paracetamol for PDA closure VLBW infants.

Evidence-Based Guideline: Treatment of Convulsive Status Epilepticus in Children and Adults: Report of the Guideline Committee of the American Epilepsy Society.

The optimal pharmacologic treatment for early convulsive status epilepticus is unclear. To analyze efficacy, tolerability and safety data for anticonvulsant treatment of children and adults with convulsive status epilepticus and use this analysis to develop an evidence-based treatment algorithm. Structured literature review using MEDLINE, Embase, Current Contents, and Cochrane library supplemented with article reference lists. Randomized controlled trials of anticonvulsant treatment for seizures lasting longer than 5 minutes. Individual studies were rated using predefined criteria and these results were used to form recommendations, conclusions, and an evidence-based treatment algorithm. A total of 38 randomized controlled trials were identified, rated and contributed to the assessment. Only four trials were considered to have class I evidence of efficacy. Two studies were rated as class II and the remaining 32 were judged to have class III evidence. In adults with convulsive status epilepticus, intramuscular midazolam, intravenous lorazepam, intravenous diazepam and intravenous phenobarbital are established as efficacious as initial therapy (Level A). Intramuscular midazolam has superior effectiveness compared to intravenous lorazepam in adults with convulsive status epilepticus without established intravenous access (Level A). In children, intravenous lorazepam and intravenous diazepam are established as efficacious at stopping seizures lasting at least 5 minutes (Level A) while rectal diazepam, intramuscular midazolam, intranasal midazolam, and buccal midazolam are probably effective (Level B). No significant difference in effectiveness has been demonstrated between intravenous lorazepam and intravenous diazepam in adults or children with convulsive status epilepticus (Level A). Respiratory and cardiac symptoms are the most commonly encountered treatment-emergent adverse events associated with intravenous anticonvulsant drug administration in adults with convulsive status epilepticus (Level A). The rate of respiratory depression in patients with convulsive status epilepticus treated with benzodiazepines is lower than in patients with convulsive status epilepticus treated with placebo indicating that respiratory problems are an important consequence of untreated convulsive status epilepticus (Level A). When both are available, fosphenytoin is preferred over phenytoin based on tolerability but phenytoin is an acceptable alternative (Level A). In adults, compared to the first therapy, the second therapy is less effective while the third therapy is substantially less effective (Level A). In children, the second therapy appears less effective and there are no data about third therapy efficacy (Level C). The evidence was synthesized into a treatment algorithm. Despite the paucity of well-designed randomized controlled trials, practical conclusions and an integrated treatment algorithm for the treatment of convulsive status epilepticus across the age spectrum (infants through adults) can be constructed. Multicenter, multinational efforts are needed to design, conduct and analyze additional randomized controlled trials that can answer the many outstanding clinically relevant questions identified in this guideline.

Economic Evaluation of Cardiac Contractility Modulation (CCM) Therapy with the Optimizer IVs in the Management of Heart Failure Patients

<p class="NICEnormal"><strong>Background: </strong>Heart failure represents a major burden for health systems and societies. Cardiac contractility modulation (CCM) therapy was developed in recent years for patients with normal QRS in whom optimal pharmacological (OMT) treatment has failed to control symptoms adequately. This study presents an economic evaluation of CCM therapy for the UK.</p><p class="NICEnormal"><strong>Methods: </strong>A Markov model was built to simulate the management of patients under two therapy scenarios, on OMT alone and CCM+OMT respectively. The horizon is the patient’s life time and the cycle is 4 weeks. The model estimates life year (LYs), quality adjusted life years (QALYs) and overall treatment costs. Data to populate it came from relevant CCM trials, the literature and other sources.</p><p class="NICEnormal"><strong>Results: </strong>The total mean life-time cost was £37,467 in the CCM+OMT arm and £16,885 in the OMT arm. Patients in the OMT arm gained 7.00 LYs and 4.00 QALYs and those on CCM+OMT 7.96 and 5.26 respectively. The incremental cost per QALY was £16,405and the incremental cost per LY £21,415. Sensitivity analysis indicates that the results are pretty stable and stochastic analysis indicates that at a £30,000 per QALY threshold the likelihood of CCM+OMT being cost-effective is 99.8% and at £25,000 per QALY 97%.</p><p class="NICEnormal"><strong>Conclusion: </strong>The present analysis indicates that CCM may be cost-effective therapy. This early conclusion should be viewed in the light of the caveats of the modeling methods used, due to data availability. Long-term studies directly collecting hospitalization and mortality data should be undertaken to provide more robust evidence.</p>

Diagnosis and treatment of type 2 diabetes mellitus in children and adolescents

With the obesity epidemic, children and adolescents with type 2 diabetes mellitus(T2DM)significantly increased throughout the world, screening and diagnosis of T2DM in the high-risk population is very important.In addition to lifestyle modification, the recommended optimal pharmacologic treatment of children and adolescents with T2DM is Metformin and Insulin.To reduce the risk of cardiovascular diseases, should fully understand the comorbidities and complications of T2DM, and take better assessment and management. Key words: Type 2 diabetes mellitus; Children and adolescents; Diagnosis and appropriate screening; Management and treatment

The Impact of Combination Therapy with a-Blockers and 5ARIs on the Progression of BPH.

Benign prostatic hyperplasia (BPH) can be a progressive disease for some men with significant impact on their quality of life due to worsening of symptoms, risk of acute urinary retention (AUR) and surgery. Certain clinical parameters such as age, prostate volume and PSA are able to predict those patients with BPH-associated LUTS that are at risk of disease progression. These patients will likely benefit most from medical therapy that provides symptom relief while at the same time may prevent disease progression. Studies have shown that a-blockers, although able to rapidly alleviate symptoms, have no effect on prostate volume, risk for AUR and BPH-related surgery. On the other hand 5ARIs have proven their efficacy in reducing prostate size, the risk of AUR and prostate surgery. Therefore combination therapy with an a-blocker and a 5ARI can be the mainstay of treatment for those patients at risk of BPH progression. Patients' perspective and their needs and expectations from treatment are other crucial parameters to consider in order selecting the optimal management of BPH. Therefore physicians should take into consideration the drug properties and also the patients' preferences before deciding on the optimal pharmacological treatment for BPH-associated LUTS.

Perioperative Treatment of Patients with Rheumatoid Arthritis.

Rheumatoid arthritis is an autoimmune disease mediated by a widespread chronic systematic inflammatory process that causes joint deterioration, which leads to pain, disability, and poor quality of life. The increased use of disease-modifying antirheumatic drugs has been shown to markedly slow disease progression, which has translated into a decrease in the need for orthopaedic intervention in this population. However, a substantial percentage of patients with the disease fail optimal pharmacologic treatment and still require surgical intervention. A thorough understanding of medical considerations in these patients and improved knowledge of the medical complications caused by the disease process and the pharmacologic therapy used to treat it may lead to improved preoperative planning and medical clearance, which may ultimately improve the overall postoperative outcome.

Pregnancy course in patients with intrahepatic cholestasis of pregnancy treated with very low doses of ursodeoxycholic acid

Objective. Ursodeoxycholic acid (UDCA) has been proposed as the optimal pharmacological treatment for intrahepatic cholestasis of pregnancy (ICP). The lowest effective dosage of UDCA in women with ICP has not been established. The objective is to determine the risk of adverse pregnancy outcomes resulting from ICP and to measure changes in liver function parameters and pruritus severity in ICP patients treated with low doses of UDCA. Material and methods. ICP was diagnosed in 203 patients on the basis of pruritus and elevated liver biochemical parameters. Patients with total bile acids (TBA) ≥10 μmol/l (n = 157) received UDCA (300–450 mg/day; 4–6 mg/kg/day) until delivery. Maternal and fetal outcomes of women with ICP were compared with 100 patients without cholestasis. Patients with ICP were hospitalized for treatment and fetal surveillance. Results. There was no correlation between fetal and neonatal complication rates in ICP patients and biochemical markers of cholestasis. Significant declines in serum TBA (p = 0.003), bilirubin concentration (p = 0.026) and aminotransferase activity (p < 0.001) were observed during treatment with low doses of UDCA. Moreover, severity of pruritus was ameliorated during the 2 weeks of therapy (p = 0.037). A total of 17 patients (10.9%) did not respond to treatment. Conclusions. UDCA at low doses improved biochemical markers and clinical symptoms in almost 90% of ICP patients.

Contemporary Outcome in Patients With Idiopathic Dilated Cardiomyopathy

Outcome is better in patients with idiopathic dilated cardiomyopathy (IDC) than in ischemic heart failure (HF), but morbidity and mortality are nevertheless presumed to be substantial. Most data on the prognosis in IDC stem from research performed before the widespread use of current evidence-based treatment, including implantable devices. We report outcome data from a cohort of patients with IDC treated according to current HF guidelines and compare our results with previous figures: 102 consecutive patients referred to our tertiary care hospital with idiopathic IDC and a left ventricular ejection fraction <40% were included in a prospective cohort study. After extensive baseline work-up, follow-up was performed after 6 and 13 months. Vital status and heart transplantation were recorded. Over the first year of follow-up, the patients were on optimal pharmacological treatment, and 24 patients received implantable devices. Left ventricular ejection fraction increased from 26 ± 10% to 41 ± 11%, peak oxygen consumption increased from 19.5 ± 7.1 to 23.4 ± 7.8 ml/kg/min, and functional class improved substantially (all p values <0.001). After a median follow-up of 3.6 years, 4 patients were dead, and heart transplantation had been performed in 9 patients. According to our literature search, survival in patients with IDC has improved substantially over the last decades. In conclusion, patients with IDC have a better outcome than previously reported when treated according to current guidelines.

Limited effects of intravenous paracetamol on patent ductus arteriosus in very low birth weight infants with contraindications for ibuprofen or after ibuprofen failure.

Finding the optimal pharmacological treatment of a patent ductus arteriosus (PDA) in preterm neonates remains challenging. There is a growing interest in paracetamol as a new drug for PDA closure. In this prospective observational cohort study, we evaluated the effectiveness of intravenous paracetamol in closing a PDA in very low birth weight infants with a hemodynamically significant PDA who either did not respond to ibuprofen or had a contraindication for ibuprofen. They received high-dose paracetamol therapy (15 mg/kg/6 h intravenous) for 3–7 days. Cardiac ultrasounds were performed before and 3 and 7 days after treatment. Thirty-three patients were included with a median gestational age of 251/7 weeks (IQR 1.66), a median birth weight of 750 g (IQR 327), and a median postnatal age of 14 days (IQR 12). Paracetamol was ineffective in 27/33 patients (82 %). Even more, after previous exposure to ibuprofen, this was even 100 %.Conclusion: In this study, paracetamol after ibuprofen treatment failure was not effective for PDA closure in VLBW infants. From the findings of this study, paracetamol treatment for PDA closure cannot be recommended for infants with a postnatal age >2 weeks. Earlier treatment with paracetamol for PDA might be more effective. What is known: • The ductus arteriosus fails to close after birth in 30 to 60 % of prematurely born neonates and is a significant cause of morbidity and mortality in these infants. • Paracetamol gained importance as an alternative drug in PDA closure. What is new: • Paracetamol for PDA closure after ibuprofen treatment failure was not effective in VLBW infants. • Effect of paracetamol on PDA closure was observed when given as primary treatment.

Acupuncture as a Complementary Treatment in a Patient with a Wide Range of Diseases Involving Inflammation and Underlying Immune-System Dysregulation Syndrome

Abstract Background: Patients with multiple chronic medical conditions are often treated with multiple medications in conventional medicine. Many of these patients still do not feel well and have poor quality of life (QoL), because of the ineffectiveness and/or the side-effects of the medications. This article describes acupuncture as a complementary therapy in a patient with a wide range of conditions involving inflammation and an underlying immune-system dysregulation syndrome. Case: The patient was a 41-year-old, chronically ill male with a wide range of conditions, including Crohn's disease, idiopathic thrombocytopenia purpurea, hypertension, and frequent upper-respiratory tract infections (URIs). Despite this optimal pharmacologic treatment, he still had chronic abdominal pain, knee pain, and fatigue. He also had hypertension and frequent URIs. He chose to receive medical acupuncture treatment. His goals were to reduce his steroid dependence; counteract steroid-associated side-effects, such as hypert...

RESISTANT ARTERIAL HYPERTENSION: IS THE CONSENSUS BETWEEN CONSERVATIVE AND INTERVENTIONAL THERAPY POSSIBLE?

Resistant hypertension is defined as hypertension uncontrolled with optimal doses of three antihypertensive agents, one of which is a diuretic. The up-to-date approaches to optimal pharmacologic and interventional treatment are discussed. Special emphasis is placed on some controversial aspects of new interventional procedures for resistant hypertension correction.

Prolonged CRP Increase After Percutaneous Coronary Intervention Is Associated with High Thrombin Concentrations and Low Platelet' Response to Clopidogrel in Patients with Stable Angina.

Inflammation is involved in all stages of development of atherosclerotic plaques. Currently, percutaneous coronary intervention (PCI) is a widely used method of treatment of coronary artery disease (CAD) when combined with optimal medical therapy (OMT). However, there is still controversy over invasive versus optimal pharmacological treatment in stable CAD (SCAD). Systemic inflammatory response triggered by PCI may limit its effectiveness in patients with SCAD. We aimed to evaluate plasma CRP and its relation to thrombin generation and platelet reactivity both early after the procedure and in a one-month observation following successful PCI with stent implantation, in patients with SCAD and OMT, including statins. We conducted a prospective study, in which CRP, platelet activation, thrombin generation and time course of prothrombin activation were determined at baseline, 3-5 days and 30 days after successful PCI with stent implantation, in 50 consecutive patients with SCAD, on chronic statin therapy. Early after PCI CRP increased by 176% as compared with baseline (p < 0.001) and one-month after angioplasty CRP was still 54% higher than before the procedure (p = 0.002). In multivariate model prolonged increase in CRP 1 month after PCI was independently associated with P2Y12-reactivity index (PRI) (p = 0.04) and maximum concentration of thrombin (p = 0.003), both measured 30 days after the procedure. Post-procedural CRP increase, which persists at least one month in patients with SCAD, after elective PCI with stent implantation, is one of the main finding of our study. We demonstrated the relationship between prolonged post-PCI inflammatory reaction, reflected by elevated CRP, and increased thrombin generation and low platelets' response to clopidogrel, which may account for limited benefits of PCI in stable coronary patients. It may be advisable to assay post-procedural CRP in each patient with SCAD, who underwent PCI to predict those, with potentially low response to clopidogrel.

Unmet needs in allergic rhinitis: international survey on management of allergic rhinitis by physician and patient: the optimal management (ISMAR 2 study)

Methods ISMAR is an international, multicenter, non-interventional, cross-sectional study conducted in adults and children (≥ 6 years) with physician diagnosis-AR of at least 1 year of duration. Physicians recruited consecutive patients to whom the ISMAR questionnaire was administered. Data collection was performed during a single visit. Other 2 additional documents (the investigator’s questionnaire and Case Record Form) were also filled in. Statistical analysis was descriptive. For statistical inferences, Student tor Wilcoxon test were performed according to the variables normality. Herein we show the results on Patient Optimal Management. Patients fulfilling the following criteria were considered as optimally managed: Patient education, environmental control and allergen avoidance Optimal pharmacological treatment according to ARIA guidelines Results Two thousand three hundred patients (2298 were analyzed), mean age 28.8 ± 15.9 years, 54.4% of males were included in 5 new countries and in 4 countries (new centres) that already participated in ISMAR phase 1. The nasal symptoms frequency was 4 days per week (29.1%) and > 4 consecutive weeks (21.8%) [N=2207]. 85.7% of patients had never smoked. Current smokers suffered most commonly of persistent rhinitis (61.3%). Patients reported having within the past 12 months, most frequently: recurrent cough (57.1%), nocturnal cough (40.8%), recurrent dyspnea/breathlessness (36.5%), dyspnea/breathlessness after exercise (33.1%), recurrent wheezing (32.1%), cough after exercise (29.8%), nocturnal dyspnea/breathlessness (29.5%). AR symptoms impaired sleep (63.5%), mood (61.9%), physical activities (50.4%), and working performance (42.1%). 96.3% of patients received recommendations to avoid allergens and irritants. 96.6% were receiving AR treatment, mainly antihistamines and nasal corticosteroids but also anti-leukotrienes and nasal and oral decongestants. 55.8% of patients had an optimal treatment. Patients with a frequency of nasal symptoms > 4 days per week and > 4 consecutive weeks and those with recurrent dyspnea/breathlessness appeared as more frequently optimally managed (p<0.001 and P<0.018, respectively).

Korábban és hatékonyabban: a mély agyi stimuláció szerepe a munkaképesség megôrzésében

[Background – The recently published “EarlyStim” study demonstrated that deep brain stimulation (DBS) for the treatment of Parkinson’s disease (PD) with early fluctuations is superior to the optimal pharmacological treatment in improving the quality of life and motor symptoms, and preserving sociocultural position. Our retrospective investigation aimed to evaluate if DBS therapy was able to preserve the working capabilities of our patients. Methods – We reviewed the data of 39 young (<60 years-old) PD patients who underwent subthalamic DBS implantation at University of Pécs and had at least two years follow-up. Patients were categorized into two groups based on their working capabilities: Patients with active job (“Job+” group, n=15) and retired patients (without active job, “Job-” group, n=24). Severity of motor symptoms (UPDRS part 3), quality of life (EQ-5D) and presence of active job were evaluated one and two years after the operation. Results – As far as the severity of motor symptoms were concerned, similar (approximately 50%) improvement was achieved in both groups. However, the postoperative quality of life was significantly better in the Job+ group. Majority (12/15, 80%) of Job+ group members were able to preserve their job two years after the operation. However, only a minimal portion (1/24, 4.2%) of the Job- group members was able to return to the world of active employees (p<0.01, McNemar test). Conclusion – Although our retrospective study has several limitations, our results fit well with the conclusions of “EarlyStim” study. Both of them suggest that with optimal timing of DBS implantation we may preserve the working capabilities of our patients.]

Exercise training in the management of patients with resistant hypertension.

Hypertension is a very prevalent risk factor for cardiovascular disease. The prevalence of resistant hypertension, i.e., uncontrolled hypertension with 3 or more antihypertensive agents including 1 diuretic, is between 5% and 30% in the hypertensive population. The causes of resistant hypertension are multifactorial and include behavioral and biological factors, such as non-adherence to pharmacological treatment. All current treatment guidelines highlight the positive role of physical exercise as a non-pharmacological tool in the treatment of hypertension. This paper draws attention to the possible role of physical exercise as an adjunct non-pharmacological tool in the management of resistant hypertension. A few studies have investigated it, employing different methodologies, and taken together they have shown promising results. In summary, the available evidence suggests that aerobic physical exercise could be a valuable addition to the optimal pharmacological treatment of patients with resistant hypertension.

Clinical and laboratory determinants of low serum level of 25-hydroxyvitamin D during escalation of pharmacotherapy in heart failure patients.

IntroductionThe activation of the renin-angiotensin-aldosterone (RAA) system is a main element of the pathophysiology of chronic heart failure (CHF), determining its symptoms and prognosis. Vitamin D is an RAA inhibitor, and its deficiency frequently accompanies CHF. The factors determining the concentration of 25-hydroxyvitamin D [25(OH)D] in CHF are not well understood, although an association has been suggested between the deficiency and the advancement of CHF. Also unknown is the influence of therapeutic escalation using recommended agents on the serum level of 25(OH)D. The aim of this study was to examine the incidence of abnormal 25(OH)D concentrations in CHF patients and to establish the clinical and laboratory determinants of low activity of this metabolite.Material and methodsThe retrospective analysis included the data of 412 CHF patients not receiving optimal pharmacological treatment who were initially in NYHA (New York Heart Association) class III or IV. Over the period of 3 months the therapy was escalated until reaching maximum tolerated doses or those recommended by the current guidelines. After optimizing the therapy, the incidence of 25(OH)D deficiency (< 30 ng/ml) and insufficiency (< 20 ng/ml) was established, and clinical and laboratory determinants for these abnormal concentrations were analyzed.ResultsNormal serum level, insufficiency, and deficiency of 25(OH)D were observed in, respectively, 41.5%, 26.0% and 32.5% of patients. The NYHA class improved by at least 1 class in 63.6% of patients, remained unchanged in 32.8% of patients, and deteriorated in 3.6% of patients. In multivariables analysis, low availability of natural ultraviolet B (UVB) radiation, loss of body mass during the CHF, higher concentrations of phosphates and albumins, and the presence of diabetes increased the risk of 25(OH)D deficiency, while higher concentrations of uric acid reduced this risk. In patients with a positive response to therapy, the concentration of 25(OH)D was borderline significantly higher (p = 0.055), while insufficiency and deficiency were less frequent (p = 0.02) than in patients without a treatment response, but this pertained only to patients with higher exposure to UVB. These differences were not observed in patients with low UVB exposure.ConclusionsThe concentration of 25(OH)D in CHF patients is not associated with the advancement of the disease, but is strongly determined by the potential availability of UVB radiation. A positive response to therapy increases the concentration of 25(OH)D only in the case of high UVB exposure; other determinants of 25(OH)D level include the patient's metabolic profile and the presence of diabetes.

Korábban és hatékonyabban: a mély agyi stimuláció szerepe a munkaképesség megôrzésében

The recently published "EarlyStim" study demonstrated that deep brain stimulation (DBS) for the treatment of Parkinson's disease (PD) with early fluctuations is superior to the optimal pharmacological treatment in improving the quality of life and motor symptoms, and preserving sociocultural position. Our retrospective investigation aimed to evaluate if DBS therapy was able to preserve the working capabilities of our patients. We reviewed the data of 39 young (< 60 years-old) PD patients who underwent subthalamic DBS implantation at University of Pécs and had at least two years follow-up. Patients were categorized into two groups based on their working capabilities: Patients with active job ("Job+" group, n = 15) and retired patients (without active job, "Job-" group, n = 24). Severity of motor symptoms (UPDRS part 3), quality of life (EQ-5D) and presence of active job were evaluated one and two years after the operation. As far as the severity of motor symptoms were concerned, similar (approximately 50%) improvement was achieved in both groups. However, the postoperative quality of life was significantly better in the Job+ group. Majority (12/15, 80%) of Job+ group members were able to preserve their job two years after the operation. However, only a minimal portion (1/24, 4.2%) of the Job- group members was able to return to the world of active employees (p < 0.01, McNemar test). Although our retrospective study has several limitations, our results fit well with the conclusions of "EarlyStim" study. Both of them suggest that with optimal timing of DBS implantation we may preserve the working capabilities of our patients.

High-throughput screening assays to identify small molecules preventing photoreceptor degeneration caused by the rhodopsin P23H mutation.

High-throughput screening (HTS) is one of the major techniques for discovering promising molecules for drug development. Rhodopsin mutations cause the most common autosomal dominant form of retinitis pigmentosa, an inherited retinal degenerative disease that currently has no effective treatment. To find an optimal pharmacological treatment for rhodopsin-associated retinitis pigmentosa, we performed two cell-based HTSs with mammalian cells expressing the P23H rod opsin mutant and identified two sets of novel compounds for further validation and characterization. The first HTS screen identified pharmacological chaperones of P23H opsin that increased its translocation from the endoplasmic reticulum to the plasma membrane. The second HTS screen selected small molecules that enhanced the clearance of the mutant opsin while vision could be sustained by the healthy gene allele expressing wild-type rhodopsin. Here we describe the methodology of these two HTS assays in detail.

Abstract 20086: Influence of Central Apneas and Chemoreflex Activation on Heart Failure Related Pulmonary Arterial Hypertension

Introduction: Pulmonary arterial hypertension (PAH) is an acknowledged independent prognostic factor in patients with heart failure (HF). Beyond a “passive” component due to the increased left ventricular pressure, an “active” component due to pulmonary vascular reactivity is frequently observed. However, the mechanism behind pulmonary vasoconstriction is not fully understood. Hypothesis: We hypothesized that central apneas (Cheyne-Stokes respiration [[Unable to Display Character: &amp;#8211;]] CSR) through chemoreflex stimulation may contribute to PAH in HF. Methods: we studied 56 HF patients (left ventricular ejection fraction &lt;50%), on stable optimal pharmacological treatment, without increased left ventriculare pressure (excluding patients with severe mitral disease and severe diastolic dysfunction). All patients underwent echocardiographic and neurohormonal assessment, 24-hour cardiorespiratory screening for CSR (patients with obstructive events were excluded) and chemoreflex test for hypoxic (HVR) and hypercapnic (HCVR) ventilatory responses (by rebreathing technique) . Results: Thirteen patients (23%) showed CSR, as defined by a 24 hour AHI &gt; of 15. HF patients with CSR compared with patients with normal breathing, presented higher systolic arterial pulmonary pressure (SPAP: 40.1±7.6 vs 33.1±5.9, p&lt;0.01) at echocardiography, despite similar systolic and diastolic function (data not shown). Furthermore, patients with central apneas also presented with enhanced HVR (median 0.78, interquartile range -IR 0.48-1.22 vs 0.43, IR 0.19-0.69 L/min/%, p&lt;0.05) and HCVR (1.18, IR 0.98-1.35 vs 0.75, IR 0.51-0.95 L/min/mmHg, p&lt;0.01) as well as increased plasma norepinephrine levels (546, IR 371-732 vs 393, IR 229-538 pg/mL, p&lt;0.05). SPAP was indeed correlated with AHI (Spearman’s Rho, R=0.44, p&lt;0.01), HCVR (R=0.48, p&lt;0.001), HVR (R=0.33, p&lt;0.05) and norepinephrine levels (R=0.31, p&lt;0.05). Conclusions: In patients with systolic HF, the presence of diurnal-nocturnal CSR, likely via recurrent hypoxia and hypercapnia cycles, may determine a chemoreflex mediated adrenergic discharge and a consequent pulmonary vasoconstriction, responsible of the undesirable increase in pulmonary arterial pressure.