Parkinson’s disease (PD) is one of the most common neurodegenerative disorders and it is caused by a loss of dopamine (DA) producing neurons in the basal ganglia in the brain. The PD patient suffers from motor symptoms such as tremor, bradykinesia and rigidity and treatment with levodopa (LD), the precursor of DA, has positive effects on these symptoms. Several factors affect the availability of orally given LD. Gastric emptying (GE) is one factor and it has been shown to be delayed in PD patients resulting in impaired levodopa uptake. Different enzymes metabolize LD on its way from the gut to the brain resulting in less LD available in the brain and more side effects from the metabolites. By adding dopa decarboxylase inhibitors (carbidopa or benserazide) or COMT-inhibitors (e.g. entacapone) the bioavailability of LD increases significantly and more LD can pass the blood-brain-barrier and be converted to DA in the brain. It has been considered of importance to avoid high levodopa peaks in the brain because this seems to induce changes in postsynaptic dopaminergic neurons causing disabling motor complications in PD patients. More continuously given LD, e.g. duodenal or intravenous (IV) infusions, has been shown to improve these motor complications. Deep brain stimulation of the subthalamic nucleus (STN DBS) has also been proven to improve motor complications and to make it possible to reduce the LD dosage in PD patients. In this doctoral thesis the main purpose is to study the pharmacokinetics of LD in patients with PD and motor complications; in blood and subcutaneous tissue and study the effect of GE and PD stage on LD uptake and the effect of continuously given LD (CDS) on LD uptake and GE; in blood and cerebrospinal fluid (CSF) when adding the peripheral enzyme inhibitors entacapone and carbidopa to LD infusion IV; in brain during STN DBSand during oral or IV LD treatment. To conclude, LD uptake is more favorable in PD patients with less severe disease and GE is delayed in PD patients. No obvious relation between LD uptake and GE or between GE and PD stage is seen and CDS decreases the LD levels. Entacapone increases the maximal concentration of LD in blood and CSF. This is more evident with additional carbidopa and important to consider in avoiding high LD peaks in brain during PD treatment. LD in brain increases during both oral and IV LD treatment and the DA levels follows LD well indicating that PD patients still have capacity to metabolize LD to DA despite probable pronounced nigral degeneration. STN DBS seems to increase putaminal DA levels and together with IV LD treatment also increases LD in brain possibly explaining why it is possible to decrease LD medication after STN DBS surgery. Parkinsons sjukdom (PS) är en av de vanligaste s.k. neurodegenerativasjukdomarna och orsakas av förlust av dopamin(DA)producerande nervceller i hjärnan. Detta orsakar motoriska symptom såsom skakningar, stelhet och förlångsammade rörelser. Levodopa (LD) är ett ämne, som kan omvandlas till DA i hjärnan och ge symptomlindring och det är oftast förstahandsval vid behandling av patienter med PS. Flera faktorer påverkar tillgängligheten av LD, bl.a. den hastighet som magsäcken tömmer sig med och denna verkar förlångsammad hos personer med PS vilket ger sämre tillgänglighet av LD i blodet och därmed i hjärnan. LD bryts även ner i hög grad av olika enzym ute i kroppen vilket leder till mindre mängd LD som hamnar i hjärnan och till fler nedbrytningsprodukter som orsakar biverkningar. Tillägg av enzymhämmare leder till ökad mängd LD som kan nå hjärnan och omvandlas till DA. Det anses viktigt att undvika höga toppar av LD i hjärnan då dessa verkar bidra till utvecklandet av besvärliga motoriska komplikationer hos patienter med PS. Om LD ges mer kontinuerligt, exempelvis som en kontinuerlig infusion in i tarmen eller i blodet, så minskar dessa motoriska komplikationer. Inopererande av stimulatorer i vissa delar av hjärnan (DBS) har också visat sig minska dessa motoriska komplikationer och även resultera i att man kan minska LD-dosen. Huvudsyftet med den här avhandlingen är att studera LD hos patienter med PS; i blod och fettvävnad då LD ges i tablettform och se om det finns något samband med LD-upptag och hastigheten på magsäckstömningen (MT) och om kontinuerligt given LD påverkar LD-upptaget eller MT; i blod och i ryggmärgsvätska då enzymhämmarna entakapon och karbidopa tillsätts LD; i hjärna vid behandling med DBS och då LD ges både som tablett och som infusion i blodet. Sammanfattningsvis kan vi se att LD-upptaget är mer gynnsamt hos patienter med PS i tidigare skede av sjukdomens komplikationsfas. MT är förlångsammad hos patienter med PS och det är inget tydligt samband mellan LD-upptag och MT eller mellan MT och sjukdomsgrad. Kontinuerligt given LD minskar LDnivåerna. Enzymhämmaren entakapon ökar den maximala koncentrationen av LD i blod och ryggmärgsvätska och effekten är mer tydlig vid tillägg av karbidopa vilket är viktigt att ta i beaktande vid behandling av PS för att undvika höga toppar av LD i hjärnan. LD ökar i hjärnan då man behandlar med LD i tablettform och som infusion i blodet och DA-nivåerna i hjärnan följer LD väl vilket visar på att patienter med PS fortfarande kan omvandla LD till DA trots trolig uttalad brist av de DA-producerande nervcellerna i hjärnan. DBS verkar öka DA i vissa områden i hjärnan och tillsammans med LD-infusion i blodet verkar det även öka LD i hjärnan och det kan förklara varför man kan sänka LDdosen efter DBS-operation.

Parkinson’s Disease and Nonmotor Dysfunction fills a major gap in the current rapidly growing body of knowledge concerning Parkinson’s disease. Drs. Pfeiffer and Bodis-Wollner have correctly perceived that many nonmotor features of Parkinson’s disease are given insufficient attention in the medical literature. Unfortunately, they are often also given insufficient attention by the practicing neurologists who see these patients. As recently pointed out, there is clearly much more to Parkinson’s disease than depletion of the nigrostriatal dopamine system (1). Parkinson’s disease (not just m- tiple system atrophy) is a multisystem disorder, both pathologically and in its clinical manifestations. This is clearly true for the various motor system abnormalities, which are not fully corrected by dopamine replacement therapy strategies, but also for the nonmotor system abnormalities that are the subject of this volume. Although recently there has been increased awareness of the cognitive, psychiatric, and sleep disorders commonly associated with Parkinson’s disease, many of their manifestations remain under-recognized and their importance in managing patients is underestimated. Even less attention is paid to the myriad of other nonmotor disturbances that plague these patients. For example, among the autonomic disorders, although orthostatic hypotension is well recognized, it is usually attributed to dopaminergic medications rather than to effects of the underlying disease. Urologic disorders are also very familiar in these patients, but may not be properly understood or well managed.

Patients with Parkinson's disease (PD) are known to suffer from motor symptoms of the disease, but they also experience non-motor symptoms (NMS) that are often present before diagnosis or that inevitably emerge with disease progression. The motor symptoms of Parkinson's disease have been extensively researched, and effective clinical tools for their assessment and treatment have been developed and are readily available. In contrast, researchers have only recently begun to focus on the NMS of Parkinson's Disease, which are poorly recognized and inadequately treated by clinicians. The NMS of PD have a significant impact on patient quality of life and mortality and include neuropsychiatric, sleep-related, autonomic, gastrointestinal, and sensory symptoms. While some NMS can be improved with currently available treatments, others may be more refractory and will require research into novel (non-dopaminergic) drug therapies for the future. Edited by members of the UK Parkinson's Disease Non-Motor Group (PD-NMG) and with contributions from international experts, this new edition summarizes the current understanding of NMS symptoms in Parkinson's disease and points the way towards future research.

This book provides a reference guide describing the current status of medication in all major psychiatric and neurological indications, together with comparisons of pharmacological treatment strategies in clinical settings in Europe, USA, Japan and China. In addition, it highlights herbal medicine as used in China and Japan, as well as complementary medicine and nutritional aspects. This novel approach offers international readers a global approach in a single dedicated publication and is also a valuable resource for anyone interested in comparing treatments for psychiatric disorders in three different cultural areas. There are three volumes devoted to Basic Principles and General Aspects, offering a general overview of psychopharmacotherapy (Vol. 1); Classes, Drugs and Special Aspects covering the role of psychotropic drugs in the field of psychiatry and neurology (Vol. 2) and Applied Psychopharmacotherapy focusing on applied psychopharmacotherapy (Vol. 3). These books are invaluable to psychiatrists, neurologists, neuroscientists, medical practitioners and clinical psychologists.

Oral Drug Absorption, Second Edition thoroughly examines the special equipment and methods used to test whether drugs are released adequately when administered orally. The contributors discuss methods for accurately establishing and validating in vitro/in vivo correlations for both MR and IR formulations, as well as alternative approaches for MR an

The fundamental guide to the most effective treatments for Parkinson's Disease, from a Mayo Clinic doctor with thirty years of clinical and research experience. In this second edition follow-up to the extremely successful first edition, Dr. Ahlskog draws on thirty years of clinical experience to present the definitive guide to dealing with all aspects of Parkinson's Disease, from treatment options and side effects to the impact of the disease on caregivers and family. Dr. Ahlskog's goal is to educate patients so that they can better team up with their doctors to do battle with the disease, streamlining the decision-making process and enhancing their treatment. To do this, Dr. Ahlskog offers a gold mine of information, distilled from his years of experience treating people with Parkinson's at the Mayo Clinic. In addition to providing a comprehensive account of Parkinson's medications, this book also examines additional aspects of treatment, such as the role of nutrition, exercise, and physical therapy. Although many commendable texts have been written on the subject of Parkinson's Disease, their discussions of treatment have not been in depth. Dr. Ahlskog sifts through aspects of the disease in order to give the reader a comprehensive sense of Parkinson's and the best available treatment options. With a broader understanding of the disease and the available options, patients are able to make more informed choices, and doctors are able to provide more tailored care. This book delivers hopeful, helpful, and extensive information to all parties concerned: patients, caregivers, and doctors. The ultimate guide to symptoms and treatment, this thoroughly updated second edition is the first place patients should turn for reliable, easy-to-grasp information on Parkinson's Disease.

The Gut-Brain Axis: Dietary, Probiotic, and Prebiotic Interventions on the Microbiota examines the potential for microbial manipulation as a therapeutic avenue in central nervous system disorders in which an altered microbiota has been implicated, and explores the mechanisms, sometimes common, by which the microbiota may contribute to such disorders. - Focuses on specific areas in which the microbiota has been implicated in gut-brain communication - Examines common mechanisms and pathways by which the microbiota may influence brain and behavior - Identifies novel therapeutic strategies targeted toward the microbiota in the management of brain activity and behavior

Oxidative stress is the result of an imbalance in pro-oxidant/antioxidant homeostasis that leads to the generation of toxic reactive oxygen species. Brain cells are continuously exposed to reactive oxygen species generated by oxidative metabolism, and in certain pathological conditions defense mechanisms against oxygen radicals may be weakened and/or overwhelmed. DNA is a potential target for oxidative damage, and genomic damage can contribute to neuropathogenesis. It is important therefore to identify tools for the quantitative analysis of DNA damage in models on neurological disorders. This book presents detailed information on various neurodegenerative disorders and their connection with oxidative stress. This information will provide clinicians with directions to treat these disorders with appropriate therapy and is also of vital importance for the drug industries for the design of new drugs for treatment of degenerative disorders.* Contains the latest information on the subject of neurodegenerative disorders* Reflects on various factors involved in degeneration and gives suggestions for how to tackle these problems

The Encyclopedia of Movement Disorders is a comprehensive reference work on movement disorders, encompassing a wide variety of topics in neurology, neurosurgery, psychiatry and pharmacology. This compilation will feature more than 300 focused entries, including sections on different disease states, pathophysiology, epidemiology, genetics, clinical presentation, diagnostic tools, as well as discussions on relevant basic science topics. This Encyclopedia is an essential addition to any collection, written to be accessible for both the clinical and non-clinical reader. Academic clinicians, translational researchers and basic scientists are brought together to connect experimental findings made in the laboratory to the clinical features, pathophysiology and treatment of movement disorders. The Encyclopedia targets a broad readership, ranging from students to general physicians, basic scientists and Movement Disorder specialists. Published both in print and via Elsevier’s online platform of Science Direct, this Encyclopedia will have the enhanced option of integrating traditional print with online multimedia. Connects experimental findings made in the laboratory to the clinical features, pathophysiology, and treatment of movement disorders Encompasses a wide variety of topics in neurology neurosurgery, psychiatry, and pharmacology Written for a broad readership ranging from students to general physicians, basic scientists, and movement disorder specialists