Severe Hypotony Maculopathy in Anterior Uveitis Associated with Hodgkin Lymphoma.

Purpose: To describe the clinical course and management of anterior uveitis complicated by ocular hypotony associated with Hodgkin lymphoma.Design: Case report.Methods: Chart and multimodal imaging review, including ultrasound biomicroscopy, widefield fundus pictures, fundus autofluorescence, fluorescein angiography, and indocyanine green angiography.Results: A 44-year-old female with progressive visual deterioration and history of low-grade fever developed bilateral granulomatous anterior uveitis complicated by severe hypotony maculopathy, not improving with systemic and topical steroids. After starting ibopamine 2% eye drops, ocular hypotony progressively resolved with visual recovery. Histologic examination of a biopsied enlarged lymph node of the neck revealed the presence of Hodgkin lymphoma, for which the patient underwent systemic chemotherapy.Conclusion: Severe hypotony maculopathy complicating anterior uveitis can be associated with Hodgkin lymphoma. Topical ipobamine 2% was safe and effective in the treatment of ocular hypotony in this case.

Treatment with a novel oleic-acid-dihydroxyamphetamine conjugation ameliorates non-alcoholic fatty liver disease in obese Zucker rats.

Fatty liver disease is one of the main hepatic complications associated with obesity. To date, there are no effective treatments for this pathology apart from the use of classical fibrates. In this study, we have characterized the in vivo effects of a novel conjugation of oleic acid with an amphetamine derivative (OLHHA) in an animal model of genetic obesity. Lean and obese Zucker rats received a daily intraperitoneal administration of OLHHA (5 mg kg(-1)) for 15 days. Plasma and liver samples were collected for the biochemical and molecular biological analyses, including both immunohistochemical and histological studies. The expression of key enzymes and proteins that are involved in lipid metabolism and energy homeostasis was evaluated in the liver samples. The potential of OLHHA to produce adverse drug reactions or toxicity was also evaluated through the monitoring of interactions with hERG channel and liver cytochrome. We found that OLHHA is a drug with a safe pharmacological profile. Treatment for 15 days with OLHHA reduced the liver fat content and plasma triglyceride levels, and this was accompanied by a general improvement in the profile of plasma parameters related to liver damage in the obese rats. A decrease in fat accumulation in the liver was confirmed using histological staining. Additionally, OLHHA was observed to exert anti-apoptotic effects. This hepatoprotective activity in obese rats was associated with an increase in the mRNA and protein expression of the cannabinoid type 1 receptor and a decrease in the expression of the lipogenic enzymes FAS and HMGCR primarily. However, changes in the mRNA expression of certain proteins were not associated with changes in the protein expression (i.e. L-FABP and INSIG2). The present results demonstrate that OLHHA is a potential anti-steatotic drug that ameliorates the obesity-associated fatty liver and suggest the potential use of this new drug for the treatment of non-alcoholic fatty liver disease.

Six months treatment with ibopamine in patients with hypotony after vitreoretinal surgery for retinal detachment, uveitis or penetrating trauma.

PURPOSE: To evaluate the effectiveness of 6 months treatment with ibopamine eye drops in raising the intraocular pressure in patients with therapy-resistant hypotony after vitreoretinal surgery for proliferative vitreoretinopathy secondary to rhegmatogenous retinal detachment or penetrating trauma. METHODS: A 2% ibopamine eye drop was topically administered 3 times daily during 24 weeks. RESULTS: Seventeen patients were included. Nine patients were able to continue their treatment up to 24 weeks; their mean intraocular pressure increase was 2.11 mmHg (SE, 0.56; 95% confidence interval, 0.96 to 3.23; P < 0.0005) in comparison with baseline values. Eight patients stopped using ibopamine before 24 weeks because of complains of follicular conjunctivitis or irritation without clinically observable conjunctivitis. In these patients a comparable increase in intraocular pressure was observed up to treatment discontinuation. CONCLUSION: This study confirms that the use of topical ibopamine may result in a sustained increase in intraocular pressure of >2 mmHg in the majority of patients, but was only well tolerated in half of them. There may only be a few patients, however, who will clinically benefit from this rise in intraocular pressure. A better formulation or method of administration would be needed.

Low pulse pressure is an independent predictor of mortality and morbidity in non ischaemic, but not in ischaemic advanced heart failure patients.

UNLABELLED: In patients with atherosclerotic disease, a high pulse pressure is an important predictor of cardiovascular events. However, in patients with chronic heart failure (CHF) a low pulse pressure is related to worse outcome, although no distinction was made between ischaemic and non ischaemic heart failure. We therefore aimed to compare the prognostic value of pulse pressure (PP) between those with ischaemic and non ischaemic advanced heart failure. METHOD AND RESULTS: Pulse pressure was analysed for its effect on mortality, adjusting for other modifiers of risk, using Cox proportional hazards regression analysis of data collected from 1901 patients with NYHA class III or IV heart failure (mean age 65 years, mean ejection fraction 26%). In ischaemic heart failure (n=1118), low mean arterial pressure (MAP) was an independent predictor of overall mortality (Hazard Ratio (HR) 0.88 per 10 mm Hg; p=0.04), while pulse pressure was not. In contrast, in non ischaemic heart failure (n=783), a low pulse pressure was an independent predictor of overall mortality (HR 0.84 per 10 mm Hg; p=0.036), while mean arterial pressure was not. In addition, higher NYHA class and lower pulse pressure (HR 0.87 per 10 mm Hg; p=0.002) were the only independent predictors for first heart failure hospitalisation in both ischaemic and non ischaemic patients. CONCLUSION: Low pulse pressure is a readily obtainable risk marker of death in advanced non ischaemic heart failure. Mean arterial pressure remains an important component of blood pressure in predicting mortality, especially in those with heart failure of an ischaemic aetiology. It is postulated that pulse pressure may reflect a deleterious haemodynamic state, in non-atherosclerotic heart failure patients.

Topical ibopamine in the treatment of chronic ocular hypotony attributable to vitreoretinal surgery, uveitis, or penetrating trauma.

PURPOSE: To study whether topical ibopamine effectively increases the intraocular pressure in patients with ocular hypotony after vitreoretinal surgery, uveitis, or penetrating trauma. DESIGN: A prospective randomized, double-blind, placebo controlled, crossover study. METHODS: In ten patients with ocular hypotony, an ibopamine 2% solution or placebo eyedrop was administered at 8 am and frequent applanation tonometry was performed during 10 hours on 2 days, 2 weeks apart. RESULTS: The mean IOP integral after administration of ibopamine was 2.4 mm Hg higher (95% CI for median difference in AUC over 480 minutes [P = .010]) compared with placebo. CONCLUSIONS: The results of the study show that an ibopamine 2% eyedrop twice a day may increase the IOP for a period of over 8 hours in patients with hypotony.

The underreporting of results and possible mechanisms of 'negative' drug trials in patients with chronic heart failure.

Large drug trials have become very important to determine which drugs should be used in the treatment of patients with chronic heart failure (CHF). When these trials showed "positive" results, publication of the data soon followed, leading to a substantial impact on prescription patterns. In the case of "negative" results, many times they were not published, or were reported as an abstract or as short paper disclosing only the main findings. In this article we will discuss some of these trials that were conducted in the last 10 years, since we believe they may provide insight into the pathophysiology and treatment options in CHF.

Confounding by contraindication in a nationwide cohort study of risk for death in patients taking ibopamine.

BACKGROUND: Outcomes may differ in treated and untreated patients because of a contraindication for treatment in the latter that is independently associated with the outcome of interest. OBJECTIVE: To evaluate the effects of confounding by contraindication on risk factors for death in patients taking ibopamine after its use was restricted in early September 1995. DESIGN: Retrospective cohort study. SETTING: The Netherlands. PATIENTS: 1146 patients with congestive heart failure who were prescribed ibopamine at least once and for whom medication history and medical data were available. MEASUREMENTS: Cardiovascular risk factors, clinical characteristics, and medication use. Each patient was assigned an index date (the date of death, or a random date for patients still alive at the end of the study). RESULTS: In univariate analyses comparing patients with an index date before and those with an index date after 8 September 1995, the relative risk for death associated with current use of ibopamine was 3.02 (95% CI, 2.12 to 4.30) compared with 0.71 (CI, 0.53 to 0.96), respectively. In multivariate analyses, the risk for death was 2.62 (CI, 1.76 to 3.90) and 0.93 (CI, 0.84 to 1.02), respectively. CONCLUSION: The marked inversion of the relative risk estimate can be considered a practical example of confounding by contraindication.

Treatment of severe ocular hypotony in AIDS patients with cytomegalovirus retinitis and cidofovir-associated uveitis.

OBJECTIVE: To describe the medical treatment of severe ocular hypotony in HIV-seropositive patients with cytomegalovirus retinitis and cidofovir-associated uveitis. PATIENTS AND METHODS: Two HIV-seropositive patients with cytomegalovirus retinitis and cidofovir-associated uveitis complicated by severe ocular hypotony were unresponsive to conventional therapy after treatment with cidofovir was stopped. They were subsequently treated successfully with ibopamine 2% eyedrops and dexamethasone 0.1% eyedrops. RESULTS: In both cases, an increase in intraocular pressure to normal values was observed on average 18.5 days after starting treatment. Intraocular pressure remained stable while on therapy for a mean follow-up of 9.5 months. During the follow-up period, any attempt to stop treatment was followed by an intraocular pressure decrease; conversely, restoration of therapy increased intraocular pressure to normal values. No reactivation of cidofovir-associated uveitis or cytomegalovirus retinitis was observed during the follow-up period. CONCLUSIONS: Ibopamine 2% eyedrops in combination with dexamethasone 0.1% eyedrops is a satisfactory therapy for severe ocular hypotony in patients with cytomegalovirus retinitis and cidofovir-associated uveitis.

Dopamine in heart failure and critical care.

Dopamine is widely used in critical care to prevent renal function loss. Nevertheless sufficient evidence is still lacking of reduction in end points like mortality or renal replacement therapy. Dopaminergic treatment in chronic heart failure (CHF) has provided an example of unexpected adverse outcome. Pharmacoepidemiological data. Provide additional evidence, finding excess mortality in current ibopamine users (relative risk 2.03 in NYHA I-II CHF, 1.37 in NYHA III-IV), while no relation was found with antiarrhythmic use. In critical care, studies after infrarenal aortic surgery or during septic shock, respectively, failed to find, expected specific renal effects of dopamine. Effects on splanchnic flow mainly depend on baseline flow levels. The implications of recently documented unwanted effects of dopamine, like reduced ventilation and oxygenation during hypoxia, are discussed. In conclusion, controlled clinical trials remain mandatory to assess the overall clinical effects of dopamine in critical care.

Ibopamine treatment in chronic hypotony secondary to long-lasting uveitis. A case report.

PURPOSE: To assess the clinical efficacy of ibopamine eye drops in severe hypotony secondary to chronic progressive uveitis. METHODS: Case report. A 47-year-old man with a 37-year history of diffuse uveitis and severe refractory hypotony was treated with topical 2% ibopamine (Trazyl) six times a day. Intraocular pressure, visual acuity, visual field and side effects were recorded during 15 months of follow-up. RESULTS: IOP, visual acuity and visual field increased after four days of therapy and lasted for two months when the drug was suspended because of the onset of filamentous keratopathy. A new course of treatment with 2% ibopamine eye drops in a different solvent (BSS) resulted in a stable increase in IOP, VA and visual field, with no side effects in a follow-up of 13 months. CONCLUSIONS: Ibopamine 2% eye drops in BSS solvent seem effective in the treatment of uveitis-related hypotony.

Achieving appropriate endpoints in heart failure trials: the PRIME-II protocol. The Second Perspective Randomised study of Ibopamine on Mortality and Efficacy.

Many clinical trials unintentionally include patients with a low risk of the trial endpoints. PRIME II (The Second Perspective Randomised study of Ibopamine on Mortality and Efficacy) was a large international randomised double blind trial comparing the addition of ibopamine or placebo to the therapy of patients with advanced heart failure. The trial was stopped prematurely because ibopamine was associated with an increased fatality rate, but the protocol achieved its objective of including high-risk patients. Here we describe the protocol details that enabled patients with the desired degree of risk to be included. We also amplify our definition of mode of death. The PRIME II protocol was designed with the intention that patients in the placebo group would have an annual fatality rate of 20%. Since the study was to be conducted in some 200 centres in 13 European countries, the inclusion criteria had to be simple and flexible, allowing for different clinical practice. The inclusion criteria, together with the use of simple investigations (which did not have to include angiographic or radionuclide ventriculography) are described. The annual fatality rate in the placebo group was just over 20%. Six categories of mode of death were used, but while they were reasonably easy to apply they did not reveal the reason for the unexpected adverse effect of ibopamine. The inclusion and exclusion criteria used for PRIME II, and the definitions of mode of death, were effective. The PRIME II protocol can be used as a model for future heart failure studies.

Amplified amplitudes of circadian rhythms and nighttime hypotension in patients with chronic fatigue syndrome: improvement by inopamil but not by melatonin.

Fatigue is an important symptom of a disturbed circadian rhythm. To date, no studies of circadian rhythms in patients with chronic fatigue syndrome (CFS) have been published. The objectives of the study were to study rhythms of heart rate and systolic and diastolic blood pressure in patients with chronic fatigue syndrome compared with age-matched normotensive controls and to study the effects of melatonin and inopamil on such rhythms. Ambulatory blood pressure (ABP) measurements (Space Lab, Inc, validated) of 18 patients with CFS were made according to the 1987 U.S. Center for Disease Control Criteria, and measurements of 12 age-matched normotensive controls were used in a cosinor analysis of the two groups. The effects of melatonin and inopamil on ABP were studied subsequently in four patients in an 8-week open-label evaluation. One patient was hypertensive (diastolic blood pressure > 90 mm Hg at least once every 4 hours), and was, therefore, excluded. The data of the remaining 17 patients (15 women, 2 men) revealed a significant 12-hour rhythm in heart rate and 24-hour rhythm in systolic and diastolic blood pressure with 95% confidence intervals not significantly different from sinusoidal patterns. Although these rhythms were synchronous with the control group rhythms, their amplitudes were not and showed, respectively, 2.8, 2.8, and 9.0 times the size of the control group rhythms (p < 0.001, p < 0.001, and p < 0.0001, respectively). Systolic blood pressures in the patients with CFS were consistently below 100 mm Hg during the nighttime. In a subsequent pilot study of four patients from the study population treated with melatonin 4 mg daily and inopamil 200 mg daily for 4 weeks, inopamil reduced nighttime hypotension (p < 0.05), whereas melatonin increased nighttime hypotension (p < 0.02). Patients with CFS have increased amplitudes of circadian rhythms and systolic blood pressures consistently below 100 mm Hg during the nighttime. Positive inotropic compounds may be beneficial in such patients, but melatonin may not be.

Evaluation of ibopamine plus prazosin in congestive heart failure.

STUDY OBJECTIVE: To determine the acute haemodynamic response of a single dose co-administration of ibopamine plus prazosin in patients with congestive heart failure. DESIGN: A double-blind, placebo-controlled randomised crossover study followed by a 2-week, open safety evaluation. SETTING: Wentworth Hospital, Durban. PATIENTS: 12 patients with congestive heart failure who were in functional class (NYHA) II-III. INTERVENTIONS: All patients underwent right heart catheterisation. On days 1 and 2 they received study drug or placebo plus prazosin and underwent haemodynamic recordings for 4 hours. RESULTS: Single-dose (200 mg) ibopamine plus prazosin augmented cardiac output (and index) and an early (0-60 minute) phasic response in the pulmonary capillary wedge pressure (PCWP) that did not appear to be influenced by the presence of prazosin. The increase in cardiac output was accompanied by a moderate decline in systemic vascular resistance (P = NS) without a change in heart rate. In the open evaluation, 8/14 patients reported adverse events. Six events were considered to be related to study medication of which one (dizziness) occurred in the haemodynamic phase. CONCLUSION: This study shows that ibopamine has beneficial haemodynamic effects in patients with moderate to severe heart failure. The increase in cardiac output was mild and sustained but with little change in systemic vascular resistance. The early rise in PCWP is not mediated by the alpha-agonistic vasoconstrictor effects of ibopamine.

Comparison of captopril and ibopamine in mild to moderate heart failure.

OBJECTIVE: To determine the effects of ibopamine 100 mg three times daily compared with captopril 25 mg three times daily on exercise capacity in patients with chronic heart failure. DESIGN: A randomised, double blind, parallel group comparison of the addition of ibopamine versus captopril during a period of 24 weeks. SETTING: 26 outpatient cardiology clinics in seven European countries. PATIENTS: 266 patients, with mild to moderate chronic heart failure (New York Heart Association (NYHA) functional class II, 81% and III, 19%) and evidence of an enlarged left ventricle. Patients received concomitant treatment with diuretics and/or digitalis. MAIN OUTCOME MEASURE: Exercise duration after 24 weeks of treatment, compared with baseline. RESULTS: Mean (SD) ejection fraction was 29 (8)% and the baseline exercise duration in the captopril and ibopamine groups 665 (160) and 675 (174) seconds, respectively. At the end of the study, exercise duration had improved in both groups, by 29 seconds in the ibopamine group (P < 0.01), and by 24 seconds in the captopril group (P < 0.05). There was no difference between groups (P = 0.69, 95% confidence interval -22 to 33). NYHA class, signs and symptoms score, and dyspnoea and fatigue index improved equally in both groups. The total number of adverse events was the same in both treatment groups, but gastrointestinal complaints occurred more often in the ibopamine group. The number of patients with premature withdrawals was no different. CONCLUSIONS: No difference was detected between the effect of captopril and ibopamine on exercise time in patients with mild to moderate heart failure during a treatment period of 24 weeks.