By K. Kapotth. Massachusetts College of Pharmacy and Health Sciences.
The globus pallidus generic prednisone 10 mg, deep brain stimulation and Parkinson’s disease purchase 40mg prednisone with visa. Levy R, Ashby P, Hutchison WD, Lang AE, Lozano AM, Dostrovsky JO. Dependence of subthalamic nucleus oscillations on movement and dopamine in Parkinson’s disease. Recent physiological and pathophysiological aspects of parkinso- nian movement disorders. The Bereitschaftpotential is abnormal in Parkinson’s disease. Tatton WG, Eastovan MJ, Bedingham W, Verrier MC, Bruce IC. Defective utilization of sensory input as the basis for bradykinesia, rigidity and Copyright 2003 by Marcel Dekker, Inc. Perceptual motor dysfunction in Parkinson’s disease: a deﬁcit in sequential and predictive voluntary movement. Reaction time of patients with Parkinson’s disease with reference to asymmetry of neurological signs. Differentiation of choice reaction time performance in Parkinson’s disease on the basis of motor symptoms. The Bereitschaftspotential, L-dopa and Parkinson’s disease. Electroencephalogr Clin Neurophysiol 1987; 66:263– 274. Methods for evaluating treatment in Parkinson’s disease. Tremor and rhythmical involuntary movements in Parkinson’s disease. Electrophysiology of mammalian thalamic neurons in vitro. Animal models of physiological, essential and parkinsonian-like tremors. Resetting of tremor by mechanical perturbations: a comparison of essential tremor and parkinsonian tremor. Computer-assisted stereotactic ventralis lateralis thalamatomy with microelectrode recording control in patients with Parkinson’s disease. Tremor, the cogwheel phenomenon and clonus in Parkinson’s disease. Bernheimer H, Birkmayer W, Horrnykiewicz O, Jellinger K, Seitelberger F. Brain dopamine and the syndromes of Parkinson and Huntington: clinical Copyright 2003 by Marcel Dekker, Inc. Parkinsonian akinesia, rigidity and tremor in the monkey. Permanent human parkinsonism due to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP): seven cases. MPT: A neurotoxin relevant to the pathophysiology of Parkinson’s disease. Clinical symptoms of cerebellar disease and their interpretation. Studies on induced exacerbation of parkinsonian rigidity. Frozen shoulder and other disturbances in Parkinson’s disease. Askmark H, Edebol Eeg-Olofsson K, Johnsson A, et al. Camptocormia (bent spine) in patients with Parkinson’s disease—characterization and possible pathogenesis of an unusual phenomenon. Philadelphia: Lippincott Williams and Wilkins, 2002.
The extrinsic pathway is activated by tissue factor generic prednisone 20mg with amex. The reactions designated by “PL generic 20 mg prednisone with mastercard, Ca” are occurring through cofactors bound to phospholipids (PL) on the cell surface in a Ca2 - coordination complex. Factors XIIa, XIa, IXa, VIIa, Xa, and thrombin are serine proteases. Note the positive feedback regulation of thrombin on the activation of proteases earlier in the cascade sequence. Proteins of Blood Coagulation Coagulation Factors Factor Descriptive Name Function/Active Form I Fibrinogen Fibrin II Prothrombin Serine protease III Tissue factor Receptor and cofactor IV Ca 2 Cofactor V Proaccelerin, labile factor Cofactor VII Proconvertin Serine protease VIII Antihemophilia factor A Cofactor IX Antihemophilia factor B, Christmas factor Serine protease X Stuart-Prower factor Serine protease XI Plasma thromboplastin antecedent Serine protease XII Hageman (contact) factor Serine protease XIII Fibrin stabilizing factor Ca2 -dependent transglutaminase Prekallikrein Serine protease High-molecular-weight kininogen Cofactor Regulatory Proteins Thrombomodulin Endothelial cell receptor, binds thrombin Protein C Activated by thrombomodulin-bound thrombin; is a serine protease Protein S cofactor; binds activated protein C 834 SECTION EIGHT / TISSUE METABOLISM The initial activation of prothrom- stimulating platelet degranulation. Note that these factors are in the intrinsic path- bin to thrombin is slow, because way. The intrinsic pathway is thought to sustain the coagulation response initiated the activator cofactors, Factors by the extrinsic pathway. The major substrate of thrombin is fibrinogen, which is VIIIa and Va, are only present in small hydrolyzed to form fibrin monomers that undergo spontaneous polymerization to amounts. However, once a small amount of form the fibrin clot. This is considered a “soft” clot because the fibrin monomers thrombin is activated, it will accelerate its are not cross-linked. Cross-linking requires Factor XIIIa, which is activated by own production by cleaving Factors V and VIII to their active forms. CROSS-LINKING OF FIBRIN lys lys Factor XIIIa catalyzes a transamidation reaction between Gln and Lys side chains CH2 CH2 on adjacent fibrin monomers. The covalent cross-linking takes place in three dimen- CH CH sions, creating a strong network of fibers resistant to mechanical and proteolytic 2 2 damage. This network of fibrin fibers traps the aggregated platelets and other cells, CH2 CH2 forming the clot that plugs the vent in the vascular wall. KALLIKREIN AND HIGH-MOLECULAR-WEIGHT KININOGEN O NH2 (HMWK) CH2 C CH2 The classical intrinsic pathway begins with the assembly of prekallikrein, high- CH2 molecular-weight kininogen (HMWK), Factor XII, and Factor XI on a negatively Gln CH2 charged surface, presumably an endothelial cell in vivo (see Fig. High- Gln molecular-weight kininogen is a glycoprotein that binds prekallikrein and aids in its assembly on the endothelial cell. Prekallikrein is the zymogen form of a serine pro- Fig. Factor XII autoactivates, forming Factor XIIa, which converts prekallikrein to alyzed by Factor XIIIa, transglutaminase. Kallikrein then enhances the activation of Factor XII, which leads to the reaction cross-links fibrin monomers, allowing activation of Factors XI and VII. How important these steps are in the initiation of the coagulation cascade is unknown. Individuals lacking HMWK, prekallikrein, or Factor XII do not suffer from bleeding disorders. Under usual conditions, activation of Factor VII with sub- sequent activation of Factors IX and X is thought to be sufficient to activate the coagulation pathway. FACTOR COMPLEXES In several of the essential steps in the blood coagulation cascade, the activated pro- tease is bound in a complex attached to the surface of the platelets that have aggre- gated at the site of injury. Factors VII, IX, X, and prothrombin contain a domain in which one or more glutamate residues are carboxylated to -carboxyglutamate in a reaction requiring vitamin K (Fig 45. Prothrombin and Factor X both contain 10 or more -carboxyglutamate residues that bind Ca2. Ca2 forms a coordination complex with the negatively charged platelet membrane phospholipids and the -carboxyglutamates, thereby localizing the complex assembly and thrombin for- mation to the platelet surface. Cofactor Va contains a binding site for both Factor Xa and prothrombin, the zymogen substrate of Factor Xa. On binding to the Factor Va–platelet complex, pro- thrombin undergoes a conformational change, rendering it more susceptible to enzymatic cleavage. Binding of Factor Xa to the Factor Va–prothrombin–platelet complex allows the prothrombin-to-thrombin conversion. Complex assembly accel- erates the rate of this conversion 10,000- to 15,000-fold as compared with non–complex formation. Factor VIIIa forms a similar type of complex on the surface of activated platelets, but binds Factor IXa and its zymogen substrate, Factor X.
Oxidation of hemostatic plug order 10 mg prednisone with amex, a fibrin clot) buy 5 mg prednisone with amex, initiated by platelet binding to the damaged area, is this methionine destroys AAP’s protease- formed at the site of injury. Regulatory mechanisms limit clot formation to the site binding capacity. Cigarette smoke oxidizes of injury and control its size and stability. As the vessel heals, the clot is degraded Met-358, thereby increasing the risk for (fibrinolysis). Plasma proteins are required for these processes to occur. THE PLATELET Platelets are non-nucleated cells present in the blood whose major role is to form mechanical plugs at the site of vessel injury and to secrete regulators of the clotting process and vascular repair. In the absence of platelets, leakage of blood from vents in small vessels is common. Platelets are derived from In the nonactivated platelet (a platelet not involved in forming a clot), the plasma megakaryocytes in the bone mar- membrane invaginates extensively into the interior of the cell, forming an open row. Because the plasma membrane contains receptors from the hematopoietic stem cell. As the and phospholipids that accelerate the clotting process, the canalicular structure sub- megakaryocyte matures, it undergoes syn- stantially increases the membrane surface area potentially available for clotting chronous nuclear replication without cellular reactions. The platelet interior contains microfilaments and an extensive division, to form a cell with a multilobed nucleus and enlarged cytoplasm. Platelet activation in response to endothelial injury causes 2 imately the 8-nucleus stage, the cytoplasm Ca -dependent changes in the contractile elements, which, in turn, substantially becomes granular, and the platelets are bud- change the architecture of the plasma membrane. Long pseudopodia are generated, ded off the cytoplasm. A single megakary- increasing the surface area of the membrane as clot formation is initiated. The second type of granule is the granule, which contains a heparin antagonist (heparin interferes with blood clotting; see biochemical com- Idiopathic thrombocytopenic pur- ments), platelet-derived growth factor, -thromboglobulin, fibrinogen, von Wille- pura (ITP) is an autoimmune dis- brand factor (vWF), and other clotting factors. The third type of granule is the lyso- ease in which antibodies to platelet somal granule, which contains hydrolytic enzymes. During activation, the contents glycoproteins are produced. Antibody bind- of these granules, which modulate platelet aggregation and clotting, are secreted. PLATELET ACTIVATION is the appearance of small red spots on the skin (petechial hemorrhages) caused by Three fundamental mechanisms are involved in platelet function during blood coag- blood leakage from capillaries. Minor dam- ulation: adhesion, aggregation, and secretion. Adhesion sets off a series of reactions age to vascular endothelial cells is constantly termed platelet activation, which leads to platelet aggregation and secretion of being caused by mechanical forces related to platelet granule contents. In patients with ITP, few platelets The adhesion step refers primarily to the platelet–subendothelial interaction that are available to repair the damage. Blood vessel injury exposes collagen, subendothelial matrix-bound vWF, and other matrix components. The platelet cell membrane contains glycoproteins (GPs) that bind to collagen and to vWF, causing the platelet Von Willebrand factor is a large multimeric glycoprotein with a GPIb GPIIb GPIIIa GPIa subunit molecular weight of 220,000 daltons. Its size in the circulation Platelet ranges between 500 and 20,000 kDa, and its membrane role in circulation is to stabilize Factor VIII and protect it from degradation. The high- 2 3 1 molecular-weight forms are concentrated in Adhesion VWF Exposed by Adhesion the endothelium of blood vessels and are initial adhesion released in response to stress hormones and events endothelial damage. High-molecular-weight Subendothelial vWF released by the endothelium is cleaved collagen by a specific metalloprotease in the serum, reducing the size of the circulating vWF. Adhesion of platelets to the subendothelial cell layer.
Use of acupuncture in Parkinson’s disease: a pilot study (abstr) discount prednisone 40 mg online. Traditional and complementary therapies in Parkinson’s disease prednisone 10 mg. Ramig L, Countryman S, O’Brien C, Hoehn M, Thompson L. Intensive speech treatment for patients with Parkinson’s disease: short and long term comparison of two techniques. Early cognitive changes and nondementing behavioral abnormalities in Parkinson’s disease. National Family Care- givers Association (NFCA), 2000. Stacy Barrow Neurological Institute, Phoenix, Arizona, U. INTRODUCTION Dopamine agonists (DA) have been used to treat symptoms of Parkinson’s disease (PD) since the late 1970s (1). These agents were initially introduced to supplement the beneﬁcial effect and possibly reduce the incidence of long- term complications of levodopa. In the last 30 years, methodical investigations of DA have demonstrated therapeutic beneﬁt in all stages of PD both in combination with levodopa and as monotherapy. More recently, positron emission tomography (PET) and single photon emission computed tomography (SPECT) imaging have demonstrated possible beneﬁt in patients randomized to a DA when compared to subjects receiving levodopa (2–4). Increasingly, clinical, animal model, and cellular data suggest not only a levodopa-sparing effect and a delay in the incidence of motor ﬂuctuations, but also a potential neuroprotective effect (5). A number of hypotheses regarding this phenomenon have been proposed. These include reduction of free radical formation by limiting levodopa exposure or increase in the activity of radical-scavenging systems, perhaps by changing mitochondrial membrane potential. In addition, some investigators suggest that DA may enhance neurotrophic activity. This chapter will review the history of DA usage in the treatment of PD and provide a summary of data concerning efﬁcacy, treatment approaches, and comparison between commonly prescribed DA. In addition, data suggesting long-term favorability when compared to levodopa will be reviewed. Lastly, similarly designed clinical trials will be discussed with direct comparative trials in an effort to better deﬁne the relative efﬁcacy of these agents. DOPAMINE AGONISTS AND DOPAMINE RECEPTORS The DA most often used in treating symptoms of PD include apomorphine, bromocriptine, cabergoline, lisuride, pergolide, pramipexole, and ropinirole. All of these agents activate D2 receptors, while pergolide has been shown to be a mild D1 agonist, and pramipexole may have higher afﬁnity for D3 (Table 1). Five subtypes of DA receptors have been identiﬁed and may be classiﬁed into striatal (D1 and D2) receptors or cortical (D3,D,4 and D5) receptors. The D3–5 receptors are present in the limbic system and other dopaminergic pathways. Although the different roles of D1 and D2 receptors in regulation of striatal function are more fully outlined elsewhere in this volume, the D1 receptor (D1,5) family is associated with activation of adenylate cyclase, and dopamine and DA activate the D2 receptor family (D2–4) (6). Postmortem examination of brains of subjects with PD reveal upregulation of striatal D2 and downregulation of the D1 receptors. It is postulated that these changes lead to alteration of the indirect D2-mediated pathway and disinhibition of the subthalamic nucleus. Intracortical inhibition studies comparing apomorphine, a rapid-acting DA, to deep brain stimulation found comparable changes in Uniﬁed Parkinson’s Disease Rating Scale (UPDRS) and intracortical inhibition with bilateral sub- thalamic nuclei or globus pallidus stimulation or with apomorphine infusion, suggesting a connection between the nigral dopaminergic pathway and the thalamo-cortical motor pathway (7). Apomorphine Because of the powerful emetic action of apomorphine, clinical usage of this compound in treating PD has been avoided (8). More recently, this short- acting DA has been developed as injectable and sublingual forms to be used in ‘‘rescuing’’ PD patients from unpredictable off-periods. This therapy may Copyright 2003 by Marcel Dekker, Inc. TABLE 1 Dopamine Agonists in Parkinson’s Disease Dopamine agonist D1 D2 D3 D4 D5 5-HT NE ACh Dopamine þ þþ þþþ þþ þþþ Bromocriptine 0 Pergolide þ þþþ þþþ þþþ þ 0 þ 0 Pramipexole 0 þþþ þþþ þþ 0 Ropinirole 0 þþþ þþþ D¼dopamine; 5-HT¼5 hydroxytryptamine; NE¼norepinephrine; ACh¼acetylcholine. This agent has been demonstrated to be effective as a subcutaneously administered agent in 30 patients for up to 5 years of therapy (10), and some follow-up studies of up to 8 years have demonstrated long-term persistence of apomorphine efﬁcacy. In a subset of patients who could no longer tolerate subcutaneous injections, an intravenous (IV) preparation is being evaluated.
Measurement of the dopaminergic degeneration in Parkinson’s disease with [123I] beta-CIT and SPECT cheap 40mg prednisone with visa. Correlation with clinical ﬁndings and comparison with multiple system atrophy and progressive supranuclear palsy buy prednisone 20 mg on line. D Brooks, V Ibanez, G Sawle, E Playford, N Quinn, C Mathias, A Lees, C Marsden, R Bannister, R Frackowiak. Differing patterns of striatal 18F- DOPA uptake in Parkinson’s disease, multiple system atrophy and progressive supranuclear palsy. A Varrone, KL Marek, D Jennings, RB Innis, JP Seibyl. Can imaging distinguish PSP from other neurodegenerative disorders? A Antonini, K Kazumata, A Feigin, F Mandel, V Dhawan, C Margouleff, D Eidelberg. Differential diagnosis of parkinsonism with [18F]ﬂuorodeoxyglu- cose and PET. Effects of tocopherol and deprenyl on the progression of disability in early Parkinson’s disease. Pramipexole vs levodopa as initial therapy for Parkinson’s disease. O Rascol, D Brooks, A Korczyn, P De Deyn, C Clarke, A Lang. A ﬁve-year study of the incidence of dyskinesia in patients with early Parkinson’s disease who were treated with ropinirole or levodopa. RA Hauser, WC Koller, JP Hubble, T Malapira, K Busenbark, CW Olanow. Time course of loss of clinical beneﬁt following withdrawal of levodopa/ carbidopa and bromocriptine in early Parkinson’s disease. Parkinson disease, the effect of levodopa, and the ELLDOPA trial. K Marek, R Innis, C van Dyck, B Fussell, M Early, S Eberly, D Oakes, J Seibyl. Measuring the rate of progression and estimating the preclinical period of Parkinson’s disease with [18F]dopa PET. E Nurmi, H Ruottinen, V Kaasinen, J Bergman, M Haaparanta, O Solin, J Rinne. Progression in parkinson’s disease: a positron emission tomography study with a dopamine transporter ligand [18F]CFT. E Nurmi, H Ruottinen, J Bergman, M Haaparanta, O Solin, P Sonninen, J Rinne. Rate of progression in Parkinson’s disease: A 6-[18F]ﬂuoro-L-dopa PET study. W Pirker, S Djamshidian, S Asenbaum, W Gerschlager, G Tribl, M Hoffman, T Bruecke. Progression of dopaminergic degeneration in Parkinson’s disease and atypical parkinsonism: a longitudinal b-CIT SPECT study. The role of positron emission tomography in the asesment of human transplantation. T Nakamura, V Dhawan, T Chaly, M Fukuda, Y Ma, R Breeze, P Greene, S Fahn, C Freed, D Eidelberg. Blinded positron emission tomography study of dopamine cell implantation for Parkinson’s disease. Fetal nigral transplantation as a therapy for Parkinson’s disease. Monitoring neuroprotection and restorative therapies in Parkinson’s disease with PET. VG De Gruttola, P Clax, DL DeMets, GJ Downing, SS Ellenberg, L Friedman, MH Gail, R Prentice, J Wittes, SL Zeger.