Late-stage Complications Research Articles

Therapy for Acute Retinal Necrosis

Acute retinal necrosis is a progressive necrotizing retinopathy caused by herpes simplex virus (HSV) or varicella zoster virus (VZV). The mainstay of its treatment is antiviral therapy against these pathogenic organisms, such as intravenous acyclovir or oral valacyclovir. Systemic and topical corticosteroids together with antiviral therapy are used as an anti-inflammatory treatment to minimize damages to the optic nerve and retinal blood vessels. Because the majority of severe cases of the disease show occlusive retinal vasculitis, a low dosage of aspirin is used as anti-thrombotic treatment. Vitreo-retinal surgery is useful to repair rhegmatogenous retinal detachment, one of the main late-stage complications. Moreover, recent articles have reported some encouraging results of prophylactic vitrectomy before rhegmatogenous retinal detachment occurs. The efficacy of laser photocoagulation to prevent the development or extension of rhegmatogenous retinal detachment is controversial. Despite these treatments, the visual prognosis of acute retinal necrosis is still poor, in particular VZV-induced acute retinal necrosis.

Influence of tetrahydrocurcumin on tail tendon collagen contents and its properties in rats with streptozotocin–nicotinamide‐induced type 2 diabetes

Changes in the structural and functional properties of collagen caused by advanced glycation might be of importance for the etiology of late-stage complications in diabetics. Curcumin is the most active component of turmeric. It is believed that curcumin is a potent antioxidant and anti-inflammatory agent. Tetrahydrocurcumin (THC) is one of the major metabolites of curcumin, exhibiting many of the same physiological and pharmacological activities of curcumin and in some systems may exert greater antioxidant activity than curcumin. In diabetic rats, hydroxyproline and collagen content as well as its degree of cross-linking were increased, as shown by increased extent of glycation, collagen-linked fluorescence, neutral salt collagen, and decreased acid and pepsin solubility. Administration of THC for 45 days to diabetic rats significantly reduced the accumulation and cross-linking of collagen. The effects of THC were comparable with those of curcumin. In conclusion, administration of THC had a positive influence on the content of collagen and its properties in streptozotocin- and nicotinamide-induced diabetic rats. THC was found to be more effective than curcumin.

The emerging role of molecular imaging and targeted therapeutics in peritoneal carcinomatosis

Peritoneal carcinomatosis is a common and often fatal late-stage complication of many gastrointestinal and gynecologic malignancies. This review discusses the ongoing evolution of diagnostic and treatment strategies for peritoneal carcinomatosis and the role that molecular imaging and radioimmunotherapy may play in improving patient survival. An overview of recent developments in targeted imaging and therapeutics for peritoneal carcinomatosis, as well as the authors’ opinions as to future developments in this field is also provided.

Modeling the effect of levothyroxine therapy on bone mass density in postmenopausal women: a different approach leads to new inference.

BackgroundThe diagnosis, treatment and prevention of osteoporosis is a national health emergency. Osteoporosis quietly progresses without symptoms until late stage complications occur. Older patients are more commonly at risk of fractures due to osteoporosis. The fracture risk increases when suppressive doses of levothyroxine are administered especially in postmenopausal women. The question is; "When should bone mass density be tested in postmenopausal women after the initiation of suppressive levothyroxine therapy?". Standard guidelines for the prevention of osteoporosis suggest that follow-up be done in 1 to 2 years. We were interested in predicting the level of bone mass density in postmenopausal women after the initiation of suppressive levothyroxine therapy with a novel approach.MethodsThe study used data from the literature on the influence of exogenous thyroid hormones on bone mass density. Four cubic polynomial equations were obtained by curve fitting for Ward's triangle, trochanter, spine and femoral neck. The behaviors of the models were investigated by statistical and mathematical analyses.ResultsThere are four points of inflexion on the graphs of the first derivatives of the equations with respect to time at about 6, 5, 7 and 5 months. In other words, there is a maximum speed of bone loss around the 6th month after the start of suppressive L-thyroxine therapy in post-menopausal women.ConclusionIt seems reasonable to check bone mass density at the 6th month of therapy. More research is needed to explain the cause and to confirm the clinical application of this phenomenon for osteoporosis, but such an approach can be used as a guide to future experimentation. The investigation of change over time may lead to more sophisticated decision making in a wide variety of clinical problems.

HAART to Heart

More than one million Americans have been diagnosed with human immunodeficiency virus (HIV). Advances in prevention and treatment of HIV have led to an increased life expectancy for patients with HIV infection. Due to their increased life span, HIV+ patients are now presenting to hospitals with an increased number of diverse late-stage complications, such as cardiomyopathy and other cardiovascular conditions. These complications are as a direct or indirect result of HIV disease, HIV treatment modalities, comorbid conditions, dietary and lifestyle factors, and unknown etiologies. Cardiac complications, particularly HIV-related dilated cardiomyopathy, are potentially life-threatening diagnoses, with symptoms that may be minimized with appropriate cardiac-specific assessments and treatments, patient teaching, and collaboration among nurses caring for the HIV-positive client with cardiac disease.

ARTERIAL RECONSTRUCTIONS ASSOCIATED WITH THE RESECTION OF MALIGNANT TUMORS.

When trunk arteries are affected by malignant neoplasia, and surgical treatment involving tumor and arterial resection is used, the vascular reconstruction must be performed immediately to avoid ischemia in the brain and large tissue masses. The objective of this study was to analyze the results obtained with the treatment of patients with malignant neoplasia who underwent tumor and vascular resection associated with arterial reconstruction. The primary patency of reconstructions, the occurrence arterial complications, and patient survival were assessed. Thirty-six patients with cervical, abdominal, or lower limb neoplasias were followed up. These patients underwent elective operations at Hospital do Câncer A.C. Camargo, São Paulo, between September 1997 and September 2004. They were divided into 3 groups according to tumor location: Cervical (14), lower limbs (13), and Abdomen (9). Thirty-eight arterial reconstructions were performed in these 36 patients. There were 5 arterial complications: 2 early- and 3 late-stage. The early complications consisted of 1 symptomatic carotid occlusion with sequelae and 1 femoral graft rupture without sequelae. The late-stage complications consisted of 1 symptomatic carotid occlusion, 1 occlusion of an axillary-carotid graft, and 1 occlusion of a branch of the aortobifemoral graft, all without sequelae. There was no difference between the primary arterial patency rates. All the deaths (22) resulted from progression of neoplasic disease. Arterial reconstructions associated with resection of malignant neoplasia in cervical, abdominal, or lower limbs can be carried out with low rates of morbidity and mortality. There was no difference in the primary arterial patency rates among the groups studied.

Isolated pulmonary hypertension in scleroderma

Isolated pulmonary hypertension (PHT) is now the most frequent cause of disease-related death in limited cutaneous scleroderma, the commonest disease variant of this disabling connective tissue disorder. Endothelin-1 receptor antagonists provide symptomatic benefit but to date have not been shown to prolong survival. To determine the frequency, disease characteristics and survival of symptomatic patients with isolated PHT in our cohort of scleroderma patients. Systematic review of the clinical course of all patients registered on the South Australian Scleroderma Register, a population-based register of 374 living and 234 deceased patients with scleroderma. Thirty-four patients were identified with isolated PHT, the majority with limited scleroderma. From our deceased register, we estimate that >11% of patients with this limited variant will develop this complication. Isolated PHT occurs as a late-stage complication approximately 20 years after the first symptoms of scleroderma. Patients with isolated PHT were characterized by the presence of multiple telangiectasia, reduced nailfold capillary density, digital ulceration, gross reduction of diffusing capacity for carbon monoxide and echocardiographic evidence of elevated pulmonary artery pressure. Survival was significantly shortened as compared with those patients without this complication (P=0.002), with a mean survival of 2.5 years from symptomatic onset of PHT. Isolated PHT occurs as a late-stage complication in > or =11% of patients with limited cutaneous scleroderma and leads to rapid death from right heart failure. The early use of endothelin-1 receptor antagonists may change the natural history of this fatal complication.

RSK4 and PAK5 Are Novel Candidate Genes in Diabetic Rat Kidney and Brain

The orphan hepatic nuclear factor (HNF) HNF4alpha is of pivotal importance for liver development and hepatocellular differentiation and plays an essential role in a regulatory circuitry to control a wide range of metabolic processes. It also targets genes in other organs, including pancreas, kidney, intestine, and colon; promotes expression of an epithelial phenotype; triggers de novo formation of functional tight junctions; and contributes to epithelial cell polarity. In particular, HNF4alpha dysfunction leads to metabolic disorders, including diabetes. We used the chromatin immunoprecipitation (ChIP) cloning procedure and a bioinformatic approach to search for candidate genes associated with impaired liver, pancreas, and kidney function. We identified two novel targets regulated by HNF4alpha, which participate in the control, at least in part, in cell-cycle regulation and are members of the mitogen-activated kinase pathway. In multiple ChIP assays, ribosomal S6 kinase 4 (RSK4) and p21-activated kinase 5 (PAK5) were confirmed, and in vitro binding of HNF4alpha was evidenced by electrophoretic mobility shift assays (EMSA) using oligonucleotides, which harbor novel binding sites. We also used EMSA to probe for binding sites in promoters of HNF1alpha, apolipoprotein B, alpha1-antitrypsin, and angiotensinogen. We further studied RSK4 and PAK5 kinase expression in streptozotocin-induced diabetic rat kidney and brain and observed significant repression of HNF4alpha, RSK4, and PAK5 as determined by quantitative real-time reverse transcriptase-polymerase chain reaction. RSK4 and PAK5 may provide a molecular rationale for late-stage complications in disease, and further studies are warranted to explore these targets for the treatment of diabetic nephro- and neuropathy, frequently seen in patients with HNF4alpha dysfunction.

Parapelvic kidney cysts: A distinguishing feature with high prevalence in Fabry disease

Fabry disease is an X-linked generalized progressive debilitating lysosomal storage disorder. The disease usually manifests in childhood, but the diagnosis is often made following the occurrence of late-stage complications such as progressive kidney failure. In order to identify key novel renal diagnostic imaging features of Fabry disease, we conducted a cross sectional case-control study of kidney involvement in patients with Fabry disease. Twenty-four patients (mean age 36.1 +/- 8.1 years, median 37 years, range 20 to 48 years) with chronic neuropathic pain who were enrolled in an enzyme replacement trial underwent prospective renal imaging evaluation with magnetic resonance imaging (MRI) and computed tomography (CT) at the National Institutes of Health, Bethesda, Maryland. We concurrently enrolled 19 age-matched healthy controls (mean age 34.6 +/- 12.0 years, median 33 years, range 18 to 61 years). The presence and localization of kidney cysts as well as the ratio of the signal intensity between medulla and cortex were determined. Fifty percent of the Fabry disease patients had renal sinus cysts, compared to one individual (7%) in the control group. The ratio of the signal intensity between medulla and cortex on T2-weighted scans in Fabry disease patients with sinus cysts was elevated compared with Fabry disease patients without cysts (P= 0.0083), and elevated in Fabry disease patients without cysts compared with normal controls without cysts (P= 0.0173). The finding of multiple renal sinus cysts in the workup of a patient with kidney disease patient should strongly suggest the consideration of Fabry disease in the differential diagnosis. The cause of such cysts in Fabry disease remains to be elaborated.

Totally implantable femoral vein catheters in cancer patients

Introduction. Totally implantable devices are increasingly being utilized for chemotherapy treatment of oncological patients. When it is impossible to implant the reservoir on the anterior wall of the thorax, or when there is an obstruction of the superior vena cava system, alternative access routes must be sought. Of these, the femoral vein is the most utilized. Few studies have been performed to analyse the results obtained from the implantation and utilization of such catheters in the femoral vein. The goal of this work was to prospectively study the results obtained from the implantation of 20 TIC in femoral veins in a large-sized cancer hospital with its own dedicated vascular clinical team. Material and methods. Twenty femoral TIC were inserted in 20 patients out of a group of 560 cancer patients submitted to TIC implantation for chemotherapy. Evaluations were made of the early and late-stage complications and patient evolution until removal of the device, death or the end of the treatment. Results. The prospective analysis showed a mean duration of 215 days for the catheters. There were 16 patients with no complications. There were no early complications. Among the late complications, three were infections, representing 0.69/1000 days of catheter use, and one was a deep vein thrombosis (0.23/1000 days of catheter use). One catheter was removed due to primary bacteremia and one due to subcutaneous pocket infection. Fourteen patients died while the catheter was functioning and four patients are still making use of the catheter. Conclusion. The low rate of complications implying catheter loss in this study confirms the safety and convenience of the use of femoral TIC in patients who cannot be submitted to implantation in the superior vena cava system.

Totally implantable venous catheters for chemotherapy: experience in 500 patients

Totally implantable devices are increasingly being utilized for chemotherapy treatment of oncological patients, although few studies have been done in our environment to analyze the results obtained from the implantation and utilization of such catheters. To study the results obtained from the implantation of totally implantable catheters in patients submitted to chemotherapy. Prospective. Hospital do Cancer A.C. Camargo, Sao Paulo, Brazil. 519 totally implantable catheters were placed in 500 patients submitted to chemotherapy, with preference for the use of the right external jugular vein. Evaluations were made of the early and late-stage complications and patient evolution until removal of the device, death or the end of the treatment. The prospective analysis showed an average duration of 353 days for the catheters. There were 427 (82.2%) catheters with no complications. Among the early complications observed, there were 15 pathway hematomas, 8 cases of thrombophlebitis of the distal stump of the external jugular vein and one case of pocket infection. Among the late-stage complications observed, there were 43 infectious complications (0.23/1000 days of catheter use), 11 obstructions (0.06/1000 days of catheter use) and 14 cases of deep vein thrombosis (0.07/1000 days of catheter use). Removal of 101 catheters was performed: 35 due to complications and 66 upon terminating the treatment. A total of 240 patients died while the catheter was functioning and 178 patients are still making use of the catheter. The low rate of complications obtained in this study confirms the safety and convenience of the use of totally implantable accesses in patients undergoing prolonged chemotherapy regimes.

Prediabetes mellitus and its links to atherosclerosis.

Type 2 diabetes mellitus is a chronic insidious process contributing to an overwhelming amount of morbidity and mortality, much of which is related to atherosclerosis, which often accompanies and complicates the natural history of diabetes. Although considerable attention has focused on new insights into diabetic mechanisms and emerging treatments, perhaps one of the greatest opportunities for decreasing the toll of diabetes and its late-stage complications may be intervening earlier in the disease process. Such notions redirect attention toward the concept of prediabetes mellitus as a potentially discrete syndrome, which may be identifiable in clinical practice. This article seeks to offer support for this hypothesis by considering the data surrounding prediabetes mellitus, with particular attention on the mechanistic and clinical links to atherosclerosis.

Endothelial dysfunction in the pathogenesis of atherosclerosis.

Healthy endothelium plays a central role in cardiovascular control. Therefore, endothelial dysfunction (ED), which is characterized by an imbalance between relaxing and contracting factors, procoagulant and anticoagulant substances, and between proinflammatory and antiinflammatory mediators, may play a particularly significant role in the pathogenesis of atherosclerosis. Endothelial dysfunction is closely related to different risk factors of atherosclerosis, and to their intensity and duration. The involvement of risk factors in ED is also supported by results of interventions studies that showed regression of ED with treatment of risk factors. Because risk factors are commonly accompanied by decreased bioavailability of nitric oxide, the common denominator whereby different risk factors cause ED is most probably increased oxidative stress. Endothelial dysfunction may promote atherogenesis through different mechanisms such as increased adherence of monocytes, macrophages, and enhanced permeability of the endothelial layer. Further, ED probably plays an important role in the growth of atherosclerotic lesions and in the development of thrombotic complications in late stages of the disease. Because ED is a key underlying factor in the atherosclerotic process, markers of endothelial abnormalities have been sought. Detection of ED is based on tests of endothelium-dependent vasomotion (dilation capability of peripheral and coronary arteries) and on circulating markers of endothelial function (endothelin-1, von Willebrand factor, tissue plasminogen activator, plasminogen activator inhibitor, and adhesion molecules). Using these tests it is possible to follow the dose response of harmful effects of risk factors, and the effects of preventive procedures on vessel wall function.

Health-related quality of life and healthcare utilisation in patients with Parkinson's disease: impact of motor fluctuations and dyskinesias.

Idiopathic Parkinson's disease (PD) is a common chronic progressive neuro-degenerative disorder associated with the progressive loss of dopaminergic neurons in the substantia nigra. The natural course of the disease may lead to severe disability despite a variety of pharmacological and surgical treatment options. Levodopa is still the most effective symptomatic treatment for PD; however, long term use can cause a number of adverse effects including motor complications, nausea and vomiting, postural hypotension and changes in mental status. The onset of motor complications marks a crucial point in the management of PD. They may present as changes between akinetic and mobile phases (motor fluctuations) or as abnormal involuntary movements (dyskinesias). After levodopa treatment for 3 to 5 years, motor complications occur in approximately 50% of patients, and after 10 years in >80% of patients. Treatment options have recently expanded as new drugs have been licensed and surgical procedures refined. Patients with motor complications present a demanding task in disease management, and often multiple drugs and high dosages are necessary to achieve only suboptimal control, resulting in increased healthcare utilisation. Costs increase considerably in patients with motor fluctuations and dyskinesias compared with patients without these symptoms. In a French study, 6-month direct medical costs per patient increased from 1648 euros (EUR) to EUR3028 in patients without and with motor fluctuations, respectively. In a recent French study a significant difference in monthly direct medical costs was found in patients with and without dyskinesias (EUR560 vs 170). Unfortunately, no data are available on the effect of motor complications on indirect costs. Several studies have shown that health-related quality of life (HR-QOL) is reduced when motor fluctuations occur. This may also be true of dyskinesias, but because of the limited number of studies a definite conclusion is not yet possible. Recently, surgical treatment options have been used to deal with advanced PD and late stage complications. Although their effect on motor complications and HR-QOL is well documented, they result in increased costs (total medical cost: EUR28920) compared with drug treatment alone and are increasingly restricted by healthcare providers. The purpose of this article is to review the available data from pharmacotherapeutic. surgical and economic studies on HR-QOL and healthcare expenditure in patients with PD, with a major focus on the impact of motor fluctuations and dyskinesias.

Amantadine infusion in treatment of motor fluctuations and dyskinesias in Parkinson's disease

Efficiency and safety of amantadine sulfate (AMS) infusions were investigated in late stage complications of Parkinson's disease (PD). In an open-label study, 21 PD patients suffering from motor fluctuations and/or dyskinesias were administered AMS infusions (PK-Merz, 400 mg per day) during seven days. Oral AMS treatment followed. Significant improvement of UPDRS motor scores was observed between day 0 and day 7, remaining improved until day 21. Based on patients' diary notes, both severity and occurrence of hypokinetic "off" state significantly decreased (from 6.6 to 3.1 hours, p < 0.001, average "off" time per day) as well as dopaminergic-induced dyskinesias (from 2.5 to 1.3 hours, p < 0.05, average duration of dyskinesias per day). AMS infusions followed by oral administration appeared as a safe method for improvement of both motor fluctuations and dyskinesias in advanced PD. In advantage to simple oral therapy, AMS infusions allowed fast introduction of a profound and durable treatment effect.

Incidence of and risk factors for proliferative retinopathy and its association with blindness among diabetes clinic attenders

BACKGROUND: Proliferative diabetic retinopathy (PDR), a prevalent late-stage complication of diabetes, is associated with severe visual loss. The objectives of this report were to estimate the incidence of and risk factors for PDR using routinely collected data from a clinical information system at University Hospital Nottingham for insulin- and non-insulin-dependent (insulin-treated and non-insulin-treated) diabetes separately. We also attempted to assess the risk of blindness in these diabetes clinic attenders. METHODS: During a mean (standard deviation (SD)) follow-up period of 5.1 (2.9) (range 0.5-12.4) years, 3482 diabetic patients (1915 male and 1567 female) from three outpatient clinics at University Hospital, Nottingham were examined. The mean (SD) age of the participants was 49.3 (17.9) years with a mean duration of diabetes of 7.1 (8.7) years at registration. RESULTS: Among the 3482 patients who attended the clinic at least twice in the period 1979-1992, and who were free of PDR at registration, the overall incidence of PDR was 16.2 per 1000 person-years, based on 17,618 person-years of follow-up. The incidence rate of PDR was nearly three times as high among patients with non-proliferative diabetic retinopathy (NPDR) as in those without any retinopathy (42.1 vs. 15.0 per 1000 person-years). Based on a Cox's Proportional Hazards Model, significant independent predictors of PDR recorded at baseline were glycosylated haemoglobin (HbA1), systolic blood pressure, and longer duration of diabetes for patients without PDR or any retinopathy among insulin-dependent patients. Longer duration of diabetes was the only independent predictor of PDR for patients without PDR or any retinopathy in both insulin- and non-insulin-treated non-insulin-dependent patients. These clinic-based data clearly indicate the higher risk of PDR in non-insulin-dependent patients. Gender, age, BMI, creatinine, proteinuria and cigarette smoking, had no significant independent association with PDR when other covariates were considered in all groups. The risk of blindness was greater among those with PDR than those with NPDR in all three types of diabetes, but was substantial even for those without retinopathy. CONCLUSION: These data are of value in identifying those diabetes clinic attenders who may be most at risk.

The need for perspective in evidence-based medicine.

Research advances are generating a growing body of clinical trial and other data on the effects of tests and treatments on outcomes, but there is no information resource within the health care system that systematically puts that information in perspective. Policy makers, clinicians, and individuals lack a ready means to compare the relative effectiveness of various interventions in prolonging survival or preventing the occurrence or complications of a disease: information that is critical in setting priorities. A crude analysis of preventable deaths suggests that evidence-based primary prevention (getting the population to stop smoking, exercise, lower cholesterol levels, and control blood pressure) would prevent considerably more deaths per year than would various evidence-based treatments for cardiovascular disease. Examining evidence from this perspective calls attention to mismatched priorities-most health care expenditures in the United States go toward treatment of diseases and their late-stage complications and relatively few resources are devoted to primary prevention and health promotion. Similar analyses at the individual level can help patients put personal options in perspective. This article proposes a bibliographic evidence-collection center and simulation modeling program to estimate potential benefits and harms of competing interventions for populations and individuals. Such evidence-based projections would enable policy makers, clinicians, and patients to judge whether they give due priority to the interventions most likely to improve health. With the steady growth in research data, the need for a system that enables society and individuals to put evidence in perspective will become progressively more urgent.

Preventing disseminated Mycobacterium avium complex disease in patients infected with human immunodeficiency virus.

Disseminated Mycobacterium avium complex (MAC) infection is an important late-stage complication of infection with the human immunodeficiency virus. Since MAC is widely dispersed in the environment, the source of infection for patients with disseminated MAC generally cannot be determined. Therefore, specific recommendations for avoiding exposure are not supported at this time. Routine screening of stools and sputum to detect MAC colonization as a means of targeting prophylaxis for disseminated disease is also not recommended at present. Two randomized, placebo-controlled trials have demonstrated that prophylactic use of rifabutin in persons with low CD4 lymphocyte counts results in a 50% decrease in MAC bacteremia as well as a reduction in some signs, symptoms, and laboratory abnormalities associated with MAC disease. Thus a prophylactic daily dose of rifabutin (300 mg) should be considered for adults who have had a previous AIDS-defining opportunistic illness and who have a CD4 lymphocyte count of < 75/microL. Many experts would consider prophylaxis appropriate only when the CD4 lymphocyte count is < 50/microL, particularly when there has not been a previous AIDS-defining opportunistic infection. Clinicians should be aware of drug interactions and potential adverse effects associated with the use of rifabutin. Preliminary reports of randomized, placebo-controlled trials suggest that chemoprophylaxis with clarithromycin is also effective in the prevention of disseminated MAC disease, and evaluation of other agents is under way. Prophylaxis for disseminated MAC infection in children has not been evaluated but is presumed to be as effective as that in adults. Decisions regarding initiation of MAC chemoprophylaxis should be individualized.

Nitrosamine Excretion in Patients with Continent Ileal Reservoirs for Urinary Diversion

Adenocarcinomas are a recognized complication following ureterosigmoidostomy for which the endogenous formation of N-nitroso compounds may be a risk factor. As an alternative means of urinary diversion, the continent ileal reservoir has recently been developed. Microbiological and chemical investigations on the urine of patients with an ileal reservoir showed the presence of bacteria, nitrate, nitrite and N-nitrosamines formed endogenously in the ileal pouch. The role of nitrosamines in carcinogenesis in these patients as a late stage complication resulting from the use of a continent ileal reservoir is discussed.

Prevention and Management of Late Stage Complications in Parkinson’s Disease

The major complications of therapy in PD are motor, autonomic and psychiatric. Motor complications may be associated with altered striatal bioavailability of levodopa, and may in part respond to changes in timing of drug administration, redistribution of dietary protein and the use of controlled-release preparations. Since long-term complications seem to be associated with higher cumulative doses of levodopa, the early use of adjunctive agents such as deprenyl and/or dopamine agonists is encouraged. Autonomic effects include impaired bladder and bowel function, impotence and postural hypotension. If conservative measures are ineffective, pharmacotherapy with domperidone, fludrocortisone, indomethacin or adrenergic agents may be required. Depression in PD is associated with decreased levels of noradrenaline and 5-HT and responds to tricyclic antidepressants. Drug-induced psychosis reflects stimulation of mesolimbic-cortical dopamine receptors. Alternatives include reduction of medication, the use of atypical neuroleptics (which may act at novel subtypes of the dopamine receptor) and electroconvulsive therapy.