Treatment of psychosis in Parkinson's disease.

Psychotic symptoms, including hallucinations, delusions, delirium,sleep-wake disturbances, are a common problem in Parkinson's disease and often lead to a significant decline in the patient's overall function. Treatment of these symptoms is a dilemma in patients with parkinsonism because traditional antipsychotics that are usually effective in older people will often worsen motor symptoms and counteract the effect of antiparkinsonian medications. Several new atypical antipsychotics and other drugs have now been tested in clinical trials and are much more effective in the alleviation of psychotic symptoms without worsening Parkinson symptoms. We have performed an extensive literature review of this topic and present detailed information on medications currently available for the treatment of psychosis in Parkinson's disease as well as some promising drugs that may be available in the future.

Fibrin: mediator of in vivo and in vitro injury and inflammation.

We examined the role that fibrin deposition and fibrin-associated factors (FAF) play in acute anterior segment inflammatory responses in the rabbit eye. It was demonstrated by immunofluorescence that fibrin represented a major component of the exudative meshwork deposited within the anterior chamber and on leukocyte surfaces therein. Using our in vivo model of endocular inflammation we next demonstrated that fibrin and fibrinogen-derived peptides, but not thrombin, induced inflammatory responses characterized by both leukocyte influx and endothelial cell injury. Fibrin formation within the anterior chamber induced a leukocyte influx consisting primarily of PMN's. Fibrinogen-derived peptides induced primarily a monocyte influx. This dichotomy suggests that multiple inflammatory mediators are elaborated or released during endocular fibrinogenesis and fibrinolysis. To investigate direct effects of fibrin deposition on the corneal endothelial cells (CEC) an in vitro "corneal cup" organ culture model was next developed. Studies comparing various types of mediators demonstrated that only fibrin- derived preparations directly induced CEC injury. Fibrin deposition may thus play multiple roles in endocular inflammation, including the modulation of leukocyte influx, and the direct mediation of corneal endothelial cell injury.

Fibrin-mediated vascular injury. Identification of fibrin peptides that mediate endothelial cell retraction.

The deposition of fibrin, a ubiquitous component of acute and chronic inflammatory reactions, has been implicated by a number of recent studies as playing an active role in inflammation. In particular, fibrin deposition has been implicated in the development of tissue edema. As the "gateway" through which intravascular-to-extravascular movement of fluid, nutrients, and cells must pass, the vascular endothelial cells play a crucial regulatory role in this process. In support of this concept, recent studies in this laboratory have demonstrated that endothelial cells retract not only in the presence of fibrin but also in the presence of low molecular weight cleavage products of fibrinogen. It was further shown that this reaction was 1) specific for both vascular and corneal endothelial cells, 2) nontoxic, and 3) completely reversible. The present work examined the physiochemical nature of these endothelial-cell reactive factors. It was demonstrated by the use of enzymatically derived and synthetic fibrinogen peptides, that the active soluble fibrinogen-derived factor was associated with the amino-terminal end of the B chain of fibrinogen. The active factor has been tentatively identified as the B beta peptides, which is a primary plasmin cleavage product of fibrinogen and contains the thrombin-generated fibrinopeptide B. It is thus suggested that soluble, endothelial-cell-reactive peptides are released during both fibrinogenesis and fibrinolysis and, as such, modulate endothelial cell functions in vivo.

Fibrin-mediated vascular injury: demonstration of vascular endothelial cell retraction in response to soluble fibrin-associated factors.

Until recently, fibrin deposition has been generally viewed as a ubiquitous, but passive, characteristic of both acute and chronic inflammatory processes. An increasing number of studies, however, suggest that fibrin deposition and fibrin degradation products may play an active role in these reactions, especially in the development of tissue edema. As the intravascular-to-extravascular "gateway" for movement of fluids, solutes, and cells must pass, the vascular endothelial cells may play a crucial regulatory role in this process. Recent evidence suggests that the interaction of whole fibrin with endothelial cells may lead to endothelial cell injury. This work examines the role of fibrin and fibrinogen-associated factors (FAF) in the injury of cultured vascular endothelial cells (VEC). It was demonstrated that endothelial cell injury, evidenced by retraction of the cells, was induced not only by whole fibrin, but also by soluble thrombin-cleaved products of fibrinogen. This reaction was shown to be specific for endothelial cells, nontoxic, and completely reversible. The general biological importance of this reaction was further underscored in that active factors could be generated from fibrinogen obtained from a number of species. Reproducible, quantitative assays of cultured endothelial cell retraction were developed to aid in the characterization of the endothelial cell-specific FAFs.

Demonstration of inflammatory mediator-induced inflammation and endothelial cell damage in the anterior segment of the eye.

Although some investigations have demonstrated the ability of inflammatory mediators, including vasopermeability and chemotactic factors, to induce acute inflammatory reactions in vivo, little is known about the response of various elements of the anterior segment to the direct effects of inflammatory mediators. These studies were initiated to develop models for the investigation of inflammatory responses in this region of the eye. Acute inflammatory reactions were induced within the rabbit anterior chamber by intracameral injection of 50 microliters of various inflammatory mediators and were evaluated by clinical grade, leukocyte influx into the aqueous humor, and morphologic changes in the corneal endothelium. Peak responses were recorded following injection of 10(-4) M formyl-methionyl-leucyl-phenylalanine (fMLP); 5 ED50 C5fr; 0.5 mg/ml C5; undiluted anti-red blood cell (RBC) serum; and 10(-5) M histamine. The number of leukocytes per milliliter of aqueous humor induced by each mediator was quantitated by comparison with the number of leukocytes induced by buffer instillation into a separate group of rabbits (mediator-induced influx/buffer-induced influx). Comparisons were made 24 hours after instillation of mediators. The results of these studies were as follows: buffer alone, 1.0; fMLP, 3.1 C5fr, 61.0; C5, 8.7; anti-RBC, 91.0; and histamine, 24.0. Clinical grades correlated well with these ratios. In addition, differences were noted when the time kinetics of acute responses induced by two different mediators (10(-4) M fMLP, a synthetic preformed chemotactic factor; and a 1:5 dilution of anti-RBC, which binds to vascular and corneal endothelial cells) were directly compared over 48 hours. Responses induced with fMLP peaked between 5 and 8 hours and resolved rapidly, whereas anti-RBC-induced responses peaked between 8 and 12 hours and resolved very slowly. Histopathologic analysis indicated that both fMLP and anti-RBC induced a similar sequence of changes in the corneal endothelium. Within 2-3 hours after instillation of either mediator, the endothelial cells exhibited prominent vacuolization/retraction phenomena. At the peak of leukocyte influx PMNs filled these vacuoles, then migrated back into the aqueous humor within several hours. Normal morphologic features were recovered following clearance of leukocytes from the anterior chamber. We believe that these models will be useful in identifying the roles of individual mediators in acute and chronic endocular inflammation and in the injury of corneal endothelium.

Inhibitory effects of tunicamycin on procollagen biosynthesis and secretion.

Chick embryo cells were briefly exposed to the antibiotic, tunicamycin. Pre-exposed cells, compared to control cultures, showed a severe, progressive inhibition of the incorporation of glucosamine and mannose into total cellular macromolecules. Inhibition of the incorporation of glycine, leucine and proline was also progressive but not as marked as for the carbohydrates. Cellular secretion of all macromolecules was severely impaired. while comparison of the procollagens showed no difference in their subunit size or in their degree of glycosylation; the intracellular content of procollagen polypeptides was similar for both types of cells. In vitro studies showed that tunicamycin selectively inhibited glucosamine, but not mannose, incorporation into macromolecules. The composite results indicate that tunicamycin effectively inhibits protein synthesis, protein glycosylation and protein secretion in chick embryo cells.