The dosage of carvedilol will be gradually increased from the initial recommended starting dose of 3.125 mg twice/daily, the target dose will be 25mg twice daily (50 mg/day) and participants will take 50 mg/day carvedilol for 6 months.Subjects that cannot tolerate the 50 mg daily dose, will be offered to continue at the 25 mg daily dose.

REM Sleep Behavior Disorder

Pre-motor Parkinson Disease

Symptomatic Parkinson Disease

At the end of Baseline visit, carvedilol 3.125 twice daily will be initiated and maintained for 1 week, increased to 6.25twice daily (dispensed at week 1visit), to 12.5mg twice daily (dispensed at week 2) and a max dose of 25mg twice daily (dispensed at week 4 visit), as tolerated. A subject that cannot tolerate at least a 25 mg daily dose will be excluded from the study. Subjects that cannot tolerate the 50 mg daily dose, will be offered to continue at the 25 mg daily dose. The project will include a washout period at study end.

Carvedilol

Cedars Sinai Medical Center

Adrenergic Blockers for Cardiac Changes in Early Parkinson's Disease

The Effect of Adrenergic Blocker Therapy on Cardiac and Striatal Transporter Uptake in Pre-Motor and Symptomatic Parkinson's Disease

123I-MIBG reuptake will be measured by early and late Heart to Mediastinal ratio (H/M) and Washout ratio (WR) which will be calculated using the following formula: [(early heart counts/pixel - early mediastinum counts/pixel) - (late heart counts/pixel decay-corrected - late mediastinum counts/pixel decay-corrected)]/(early heart counts/pixel - early mediastinum counts/pixel). Care will be taken to exclude lung or liver from the myocardial and large vessels and lung from the mediastinum region of interest. MIBG abnormality cutoffs will be set for values of late H/M <2.2 and WR >30%.

Safety will be monitored collecting the type and frequency of adverse events, including clinical symptoms, changes in vital signs, clinical laboratory measures and EKG abnormalities.

Twenty-four-hour Holter monitoring of all patients will be conducted at two points during the study: 1) After MIBG and prior to the administration of the study drug and 2) within one week of the end of the six-month treatment trial. Two-channel Holter recordings will obtained and analyzed on a commercially available scanner in the cardiac laboratory at Cedars Sinai Medical Center, according to published guidelines.

The Movement disorder society-unified Parkinson's disease rating scale (MDS-UPDRS) Part III will be administered at baseline and 26 weeks after study medication titration. Each item of the MDS-UPDRS has a possible rating from 0 to 4, where 0 = normal, 1 = slight, 2 = mild, 3 = moderate, and 4 = severe.Clinical scales will be performed OFF medication in those subjects that might be receiving dopaminergic drugs

RBD questionnaire (RBDSQ) changes from Screening at 26 weeks after study drug titration

University of Pennsylvania Smell Identification Test (UPSIT) changes from screening at 26 weeks after study medication titration

Functional constipation will be assessed at screening and at 26 weeks after study medication titration using a questionnaire based on modified ROME III diagnostic criteria, which focuses on symptoms including straining, lumpy or hard stools, sensation of incomplete evacuation, sensation of anorectal obstruction or blockage, manual maneuvers to facilitate evacuation, and two or fewer bowel movements per week. This questionnaire is based on a six item self-report measures with a three point summated rating scale. The total score has a range of 0 to 12, with scores > 4 identifying functional constipation.

Color vision changes will be assessed using HRR Pseudochromatic Plates from screening at 26 weeks after study medication titration

DaT/SPECT uptake at baseline will be quantified at baseline and 26 weeks after study medication titration

The NMSS measures non-motor symptoms over the previous month. Each symptom is scored with respect to: Severity: 0 = None, 1 = Mild; 2 = Moderate; 3 = Severe and Frequency: 1 = Rarely (<1/wk); 2 = Often (1/wk); 3 = Frequent (several times per week); 4 = Very Frequent (daily or all the time).

The SCOPA-AUT scale consists of 25 items assessing autonomic symptoms in the following regions: gastrointestinal (7), urinary (6), cardiovascular (3), thermoregulatory (4), pupillomotor (1), and sexual (2 items for men and 2 items for women) dysfunction.

Peripheral IR will be defined by testing for fasting plasma insulin (FPI), fasting plasma glucose (FPG) and glycated hemoglobin (HbA1c) from baseline at 26 weeks after study medication titration. HOMA index will be calculated by the formula: HOMA-IR = (FPI x FPG)/405. [A cutoff HOMA index of 2.0, equivalent to <50% sensitivity, will be used to define IR. Subjects were considered to have IR if they either had a HOMA≥2.0 and/or HbA1c≥5.7.

Measures of insulin sensitivity in neuronal-origin enriched plasma EVs (central IR) will be used to test the association of changes in such sensitivity to changes in MIBG uptake and clinical scores from baseline to 26 weeks after carvedilol titration. For that purpose, plasma samples will be collected and stored and -80oC to allow for isolation of neuronal origin EVs at the completion of the study.

Michele Tagliati, MD

Professor of Neurology, Director of Movement Disorders

Treatment: carvedilol titration; Experimental treatment with carvedilol will be offered at stabilized medical treatment. The dosage of carvedilol will be gradually increased from the initial recommended starting dose of 3.125mg twice daily and will be doubled every week according to patient tolerability, as measured by subjective complaints, arterial blood pressure and heart rate. The target dose will be 25mg twice daily (50 mg/day). Subjects that cannot tolerate the 50 mg daily dose, will be offered to continue at the 25 mg daily dose.

Patients with iatrogenic chronic autonomic failure (CAF) (e.g., status-post cardiac transplantation, pre/post renal sympathetic ablation, pre/post bilateral thoracic sympathectomies)

Patients with Parkinson's disease (PD) without orthostatic hypotension (PD no OH)

Healthy Volunteers with genetic risk of PD

Includes patients with orthostatic hypotension (OH) due to sympathetic neurocirculatory failure (nOH), and people with multiple system atrophy (MSA).

Parkinson's Disease

Multiple System Atrophy

Autonomic Failure

18F-DOPA is a positron-emitting analog of the catechol amino acid, levodopa (L-DOPA, Ldihydroxyphenylalanine). 18F-DOPA PET scanning is used to visualize catecholamine terminals in the brain.

18F-Dopa

11C-MRB may be injected IV for visualizing sites of neuronal uptake of norepinephrine in the brain or periphery by PET scanning.

11C-methylreboxetine

13N-labeled ammonia is a perfusion imaging agent used to obtain perfusion-corrected values for 18F-dopamine-derived radioactivity in the heart and other organs.

13N-Ammonia

18F-Dopamine is a positron-emitting analog of the catecholamine, dopamine. 18F- Dopamine positron emission tomographic (PET) scanning may be used to visualize sympathetic innervation.

18F-Dopamne

Desipramine (DMI) is an approved tricyclic antidepressant. The drug inhibits neuronal uptake of catecholamines. DMI treatment is used to test for effects of NET inhibition on results of 11C-MRB or 18F-dopamine PET scans. The subject receives a single dose of DMI by mouth (about 125 mg per 70 kg body mass) about 2-3 hours before the subject receives the PET imaging agent.

Desipramine (DMI)

National Institutes of Health Clinical Center

Clinical Laboratory Evaluation of Chronic Autonomic Failure

Neuroimaging data are from MRI and from 18F-DOPA and 18F-dopamine PET scanning. Neurochemical data are from assays of catechols in plasma and cerebrospinal fluid. Immunofluorescence microscopy data are from analyses of immunoreactive tyrosine hydroxylase and AS in skin biopsy samples. Neurobehavioral rating scale data are from the University of Pennsylvania Smell Identification Test (UPSIT), Montreal Cognitive Assessment (MoCA), and Uniform Parkinson s Disease Rating Scale (UPDRS).

Estimated extraneuronal binding of 11C-methylreboxetine is based on studies of patients with iatrogenic CAF and desipramine-treated HVs

National Institute of Neurological Disorders and Stroke (NINDS)

Tyrosine supplementation (500 mg 2x daily) for 7 days

Placebo sugar pills (2x daily) for 7 days

Tyrosine supplementation (500 mg 2 x daily) for 7 days

Tyrosine

Placebo Comparator:Sugar Pill

New York Institue of Technology

The Effects of Supplementing Tyrosine on Blood Pressure in Parkinson's Disease

Orthostatic Blood Pressure Testing:
Subjects will sit and rest for 10 minutes. Blood pressure will be taken in this resting position after the 10 minutes. Subjects will then stand upright for 3 minutes. Blood pressure will be taken every minute for those 3 minutes. A drop in systolic BP of 20 mmHg and a 10 mmHg in diastolic drop within these 3 minutes indicates orthostatic hypotension according to the American Academy of Neurology.
Blood Samples:
Norepinephrine and tyrosine will all be examined via blood samples drawn by a medical assistant or physician from the forearm vein in vacutainer tubes. Two vacutainers of three cc's of blood will be collected and frozen until analyzed.

An exercise stress test using a Modified Bruce Protocol, which consists of five 3-minute stages on a treadmill, will be used to implement acute stress. During the test, heart rate, oxygen consumption (VO2), Respiratory Exchange Ratio (RER), and 12 lead EKG tracings will be recorded at 1-minute intervals and BP and a rate of perceived exertion (RPE) will be recorded. The treadmill test will conclude when subjects attain peak exercise. Peak exercise will be determined when a subject attains any one of the following: 1) 85% of target heart rate; 2) an RPE of 8; 3) inability to maintain the pace of the treadmill; 4) an RER of over 1.3. Additionally, the American College of Sports Medicine (ACSM) guidelines for terminating exercise testing will be followed.
Subjects will be tested on the first visit and then receive supplementation or placebo for 2x daily for 7 days. Subjects will then repeat all the tests they performed on the first visit.

New York Institute of Technology

Michael J. Fox Foundation for Parkinson's Research

Patients who are receiving vasoactive medications and/or are mechanically ventilated.

Hypotension

Respiratory Failure

17 mls of blood will be drawn over a 5 day period from either a central venous catheter/arterial line or with scheduled phlebotomy. The following labs will be run tT3, fT3, rT#, tT4, fT4, TSH, and tyrosine.

Blood draws

The Children's Hospital of Philadelphia

Thyroid Hormones in Critically Ill Children

Thyroid Hormone Deficiency in Critically Ill Children

Children's Hospital of Philadelphia

Patients not responding to high- dose zidovudine and valganciclovir alone may be treated with botezomib plus high- dose zidovudine and valganciclovir

Single agent sirolimus for patients where targeted oncolytic virotherapy seems suboptimal

EPOCH chemotherapy with rituximab may be utilized to rescue such patients, with the intent of stabilizing suchpatients

Rituximab with liposomal doxorubicin (R-Dox) followed by consolidation or lmaintenancel therapy with dose escalating interferon-alpha

Lymphoproliferative Disorder

HHV-8

Malignancy

Etoposide 50 mg/m2 /day continuous intravenous infusion (CIVI) over 24 hours x 4 days (days 1-4) of 21 day cycle. A maximum of 6 cycles of R-EPOCH-R will be administered except in exceptional circumstances.

Etoposide

Ages 18 and over: Initial dose of 7.5 million units subcutaneous, three times weekly x 14 days; subsequent dosesincrease dose as tolerated each 14 days to a maximum of 45 million units subcutaneous three times weekly; Ages 12-17: Initial dose of 5 million units/m2 subcutaneous, three times weekly x 14 days Subsequent doses: Increase dose as tolerated each 14 days to a maximum of 30 million units/m2 subcutaneous, three times weekly

Interferon-alpha

Rituximab 375 mg/m2 IV day 1, shall be administered prior to Doxil injection. When combined with EPOCH chemotherapy, Rituximab will be given on days 1 and 5.

Rituximab

Cycle 1: Zidovudine 600 mg PO QID x 7-21 days in outpatient setting;600 mg PO q6hours x 7-21 (Intravenous zidovudine 300 mg q 6 hours may be substituted) days for inpatients; Cycle 2 and beyond: 600 mg PO QID x 7 days in outpatient setting; 600 mg PO q 6 hours x 7 days (300 mg q 6 hours may be substituted)

Zidovudine

21 day cycle; 20 mg/m2 Liposomal Doxorubicin given on day 1 and shall be administered after completion of Rituximab infusion from 2 to 6 cycles.

Liposomal Doxorubicin

1.3 mg/m2 IV days 1, 4, 8, and 11. Cycle length is 21 days.

Bortezomib

Cycle 1: Valganciclovir 900 mg PO BID x 7-21 days in outpatient setting; 900 mg PO q 12 hours x 7-21 days for inpatients; Cycle 2 and beyond: 900 mg PO BID x 7 days for outpatients; 900 mg PO q 12 hours x 7 days (Intravenous ganciclovir 5 mg/kg may be substituted) for inpatients

Valganciclovir

10 mg/m2 /day CIVI over 24 hours x 4 days (days 1-4) of 21 day cycle.

Doxorubicin

0.4 mg/m2 /day CIVI over 24 hours x 4 days (days 1-4) of 21 day cycle.

Vincristine

Cyclophosphamide: if CD4 < 100 cells/mm3, 187 mg/m2 IV (Day 5) if CD4 greater than or equal to 100 cells/mm3, 375 mg/m2 IV (Day 5) of 21 day cycle.

Cyclophosphamide

Filgrastim 300 micrograms subcutaneous daily beginning day 6 until absolute neutrophil count recovery 5000 cells/mm3 (Pegfilgrastim may be substituted with PI approval, at the recommended dose of one 6mg syringe)

Filgrastim (G-CSF)

Prednisone 60 mg/m2/day PO x 5 days (days 1-5)of 21 day cycle.

Prednisone

Maximum daily dose of 40 mg given as a single agent on 21 day cycle.

Sirolimus

Observation Only

National Institutes of Health Clinical Center, 9000 Rockville Pike

Virotherapy and Natural History Study of KHSV-Associated Multricentric Castleman s Disease With Correlates of Disease Activity

Targeted Oncolytic Virotherapy and Natural History Study of KSHV-Associated Multicentric Castleman's Disease With Laboratory and Clinical Correlates of Disease Activity

Preliminarily assess the feasibility of risk-stratifying patients according to disease parameters associated with MCD

To study in a preliminary fashion the therapeutic efficacy and toxicity of several rationally designed therapeutic approaches to KSHV-MCD aimed at KSHV cytoreductive therapy, or therapy aimed at suppressing KSHV-induced pathogenic mechanisms:-High-dose zidovudine combined with valganciclovir (HDAZT+VGCV)-Bortezomib in combination with (HDAZT+VGCV)-Sirolimus-Rituximab in combination with liposomal doxorubicin followed by Interferon- or high-dose AZT with valganciclovir-EPOCH-R (rituximab combined with oral prednisone and infusional etoposide, vincristine, and doxorubicin followed by bolus cyclophosphamide, prednisone and rituximab)

Preliminarily assess additional rationally designed treatments for MCD aimed at KSHV reductive therapy

percentage of patients alive until study closure

the length of time during and after the treatment that patients live with the disease but it does not get worse

hypotension/tyrosine

Adrenergic Blockers for Cardiac Changes in Early Parkinson's Disease

Clinical Laboratory Evaluation of Chronic Autonomic Failure

The Effects of Supplementing Tyrosine on Blood Pressure in Parkinson's Disease

Thyroid Hormones in Critically Ill Children

Virotherapy and Natural History Study of KHSV-Associated Multricentric Castleman s Disease With Correlates of Disease Activity

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