Efficacy and safety of itraconazole pulse therapy: Brazilian multicentric study on toenail onychomycosis caused by dermatophytes

Background Itraconazole is a large spectrum triazole with known efficacy in both continuous and pulse therapy for various mycoses.Objectives Evaluate the efficacy and tolerability of itraconazole pulse therapy for onychomycosis of the toenails due to dermatophytes, in a prospective, open, non-comparative and multicentric investigation.Patients and methods the trial was completed by 72 patients of an initial total of 89. Treatment consisted of four cycles of itraconazole, 200 mg twice a day, for seven consecutive days each month. Patients were evaluated clinically, mycologically and biochemically before, during and at the end of the investigation, and were divided into two groups according to the measure of normal portion of the most affected nail (target nail), as follows: Group 1. 0-5.9 mm; and Group 2: more than 6 mm.Results Improvement was satisfactory and progressive. Results were statistically significant, when comparing the three moments of the study: pre-treatment, end of therapy (fourth month) and follow-up (ninth month) in both groups.Conclusions Itraconazole pulse therapy was efficient and safe for the treatment of onychomycosis caused by dermatophytes, although a much higher daily dosage than the known continuous administration was used. Group 1, with nails initially more extensively affected, had a more evident improvement, by the mean variation in millimeters of normal portion of the target nail. This group showed a very satisfactory response, although not reaching total cure, thus demonstrating the great importance of early treatment of this disease. A residual therapeutic effect is maintained even after suspension of the drug. Group 2 obtained better total cure rates, and four pulses were, in general, sufficient, whereas more cycles would have been beneficial for the Group 1 patients with more extensive involvement. (C) 1998 Elsevier B.V. B.V. All rights reserved.

High-dose intravenous immunoglobulin pulse therapy in patients with progressive immunoglobulin A nephropathy: a long-term follow-up

In progressive immunoglobulin A nephropathy (IgAN), intravenous immunoglobulin (IVIg) treatment has been used to delay disease progression, but the long-term efficacy is largely unknown. We report the clinical outcomes after IVIg therapy in six male patients with progressive IgAN [median glomerular filtration rate (GFR) 31 ml/min per 1.73 m(2)] followed for a median observation period of 8 years. In this single-arm, non-randomized study, IVIg was given monthly at a dose of 2 g/kg body weight for 6 months. The course of renal function was assessed by linear regression analysis of GFR and proteinuria, and was compared to eight patients with IgAN (median GFR 29 ml/min per 1.73 m(2)) without IVIg as a contemporaneous control group. IgAN disease progression was delayed after IVIg therapy on average for 3 years. The mean loss of renal function decreased from -1.05 ml/min per month to -0.15 ml/min per month (P = 0.024) and proteinuria decreased from 2.4 g/l to 1.0 g/l (P = 0.015). The primary end-point (GFR < 10 ml/min or relapse) occurred 5.2 years (median; range 0.4-8.8) after the first IVIg pulse, and after 1.3 years (median; range 0.8-2.4) in the control group (P = 0.043). In Kaplan-Meier analysis, the median renal survival time with IVIg was prolonged by 3.5 years (IVIg 4.7 years versus control 1.2 years; P = 0.006). IVIg pulse therapy may be considered as a treatment option to reduce the loss of renal function and improve proteinuria in patients with progressive IgAN.

High-dose intravenous corticosteroid pulse therapy in alopecia areata: own experience compared with the literature

BACKGROUND: Seven prospective studies including 193 patients have been published on high-dose intravenous corticosteroid pulse therapy in alopecia areata (AA).We compare these data with a retrospective analysis of our own consecutive patients. PATIENTS AND METHODS: Between 1998 and 2002,25 patients with severe AA were treated at the Department of Dermatology, University of Bern, with infusions of 500 mg methylprednisolone on 3 consecutive days.In addition to the inpatient records, in 2004 all patients were followed up by a questionnaire. RESULTS: Four of 10 patients with multifocal AA and 3 of 9 patients with ophiasis-type AA had full re-growth of hair, whereas all 6 patients with AA totalis/universalis failed to respond. CONCLUSION: Intravenous corticosteroid pulse therapy may be helpful in the treatment of multifocal and ophiasis-type AA. Patients with an initial episode of short duration have better chances for success.

Sequential immunosuppressive therapy in progressive IgA nephropathy

BACKGROUNDS: Cyclophosphamide and high-dose steroids have been used as limited induction therapy in progressive IgA nephropathy (IgAN) to reduce the loss of renal function and proteinuria. We evaluated the effect of cyclophosphamide pulses (CyP) and mycophenolic acid (MPA) as sequential therapy on renal function in patients with progressive IgAN. METHODS: Twenty patients with progressive IgAN and advanced renal failure (median GFR 22 ml/min per 1.73 m2) and further disease activity (triangle downGFR -0.8 ml/min per month) after cyclophosphamide (CyP; n = 18) or steroid pulse therapy (n = 2) were treated with mycophenolate mofetil 1 g per day for a median of 27 months. RESULTS: The monthly loss of renal function was significantly reduced in linear regression analysis from -2.4 ml/min before CyP to -0.12 ml/min with CyP/MPA (p = 0.0009). Estimated renal survival time was significantly prolonged by a median of 65 months (p = 0.0014). Proteinuria decreased significantly from 1.7 to 0.4 g/l during MPA treatment (p = 0.015). In Cox regression analysis, only proteinuria >1.0 g/l was an independent risk factor for doubling of creatinine during CyP/MPA treatment (p = 0.03). CONCLUSION: A sequential therapy with CyP/MPA may arrest or slow down the loss of renal function and reduces proteinuria even in patients who passed the so called 'point of no return' with progressive IgAN.

Interferon Alpha-2B and liver resection to treat multifocal hepatic epithelioid hemangioendothelioma: A relevant approach to avoid liver transplantation

Background. Hepatic epithelioid hemangioendothelioma is a rare malignant tumor of vascular origin with frequent multifocal appearance. Liver resection may cause tumor spread. Liver transplantation has been indicated for unresectable nodules. We hypothesized that adjuvant interferon treatment is effective to prevent metastasis after liver resection. We report a case of multifocal hepatic epithelioid hemangioendothelioma successfully treated with interferon pulse therapy and bilobar hepatic resection.Methodology. CT scan and magnetic resonance imaging diagnosed three nodules in the liver (segments IV, VI and VII). Histopathology and specific immunostaining of a percutaneous nodule biopsy confirmed the diagnosis of hepatic epithelioid hemangioendothelioma. The treatment protocol included daily interferon alpha 2b 9 weeks before and 1 week after resection of liver segments IV, VI and VII.Results. The postoperative outcome was complicated by a self-limited biliary fistula. The patient remains tumor free at 3 years after liver resection and currently enjoys excellent health.Conclusion. Interferon pulse therapy and hepatic resection was a good option to treat multifocal bilobar hepatic epithelioid hemangioendothelioma; it may prevent metastasis dissemination.

Eficácia das terapias convencionais (Pentoxifilina e Nicotinamida/Alopurinol) comparadas a metilprednisolona intravenosa no tratamento da oftalmopatia de Graves

Pós-graduação em Fisiopatologia em Clínica Médica - FMB

Stroke as the First Clinical Manifestation of Takayasu's Arteritis

Takayasu's arteritis is a chronic inflammatory disease, and neurological symptoms occur in 50% of cases, most commonly including headache, dizziness, visual disturbances, convulsive crisis, transient ischemic attack, stroke and posterior reversible encephalopathy syndrome. The aim of this study was to report the case of a young Brazilian female with a focal neurological deficit. She presented with asymmetry of brachial and radial pulses, aphasia, dysarthria and right hemiplegia. Stroke was investigated extensively in this young patient. Only nonspecific inflammatory markers such as velocity of hemosedimentation and C-reactive protein were elevated. During hospitalization, clinical treatment was performed with pulse therapy showing improvement in neurological recuperation on subsequent days. In the chronic phase, the patient was submitted to medicated angioplasty of the brachiocephalic trunk with paclitaxel, with significant improvement of the stenosis. At the 6-month follow-up, the neurological exam presented mild dysarthria, faciobrachial predominant disproportionate hemiparesis, an NIHSS score of 4 and a modified Rankin Scale score of 3 (moderate incapacity). In conclusion, Takayasu's arteritis must be recognized as a potential cause of ischemic stroke in young females.

Fluktuierende Kopfschmerzen und Wesensveränderung bei einem 63-jährigen Patienten

We present a 63 year old man with new onset of fluctuating headache and behavioural changes showing marked inhibition and disorientation. After non invasive and invasive diagnostics an isolated cerebral vasculitis was found. Key results have been found in cerebral MRI and cerebral digital subtraction angiography with irregularities of vessel calibre of the intracerebral arteries. During treatment with high-dose corticosteroid therapy and Cyclophosphamid pulse therapy qualitative disorders and headache rapidly regressed. We discuss differential diagnosis of secondary headache, etiology of cerebral vasculitides, diagnostic challenge and therapy in isolated cerebral vasculitis.

Treatment of optic neuritis with erythropoietin (TONE): a randomised, double-blind, placebo-controlled trial-study protocol.

INTRODUCTION Optic neuritis leads to degeneration of retinal ganglion cells whose axons form the optic nerve. The standard treatment is a methylprednisolone pulse therapy. This treatment slightly shortens the time of recovery but does not prevent neurodegeneration and persistent visual impairment. In a phase II trial performed in preparation of this study, we have shown that erythropoietin protects global retinal nerve fibre layer thickness (RNFLT-G) in acute optic neuritis; however, the preparatory trial was not powered to show effects on visual function. METHODS AND ANALYSIS Treatment of Optic Neuritis with Erythropoietin (TONE) is a national, randomised, double-blind, placebo-controlled, multicentre trial with two parallel arms. The primary objective is to determine the efficacy of erythropoietin compared to placebo given add-on to methylprednisolone as assessed by measurements of RNFLT-G and low-contrast visual acuity in the affected eye 6 months after randomisation. Inclusion criteria are a first episode of optic neuritis with decreased visual acuity to ≤0.5 (decimal system) and an onset of symptoms within 10 days prior to inclusion. The most important exclusion criteria are history of optic neuritis or multiple sclerosis or any ocular disease (affected or non-affected eye), significant hyperopia, myopia or astigmatism, elevated blood pressure, thrombotic events or malignancy. After randomisation, patients either receive 33 000 international units human recombinant erythropoietin intravenously for 3 consecutive days or placebo (0.9% saline) administered intravenously. With an estimated power of 80%, the calculated sample size is 100 patients. The trial started in September 2014 with a planned recruitment period of 30 months. ETHICS AND DISSEMINATION TONE has been approved by the Central Ethics Commission in Freiburg (194/14) and the German Federal Institute for Drugs and Medical Devices (61-3910-4039831). It complies with the Declaration of Helsinki, local laws and ICH-GCP. TRIAL REGISTRATION NUMBER NCT01962571.

Determinants of CD4 cell count decline after treatment interruption

Patients who had started HAART (Highly Active Anti-Retroviral Treatment) under previous aggressive DHHS guidelines (1997) underwent a life-long continuous HAART that was associated with many short term as well as long term complications. Many interventions attempted to reduce those complications including intermittent treatment also called pulse therapy. Many studies were done to study the determinants of rate of fall in CD4 count after interruption as this data would help guide treatment interruptions. The data set used here was a part of a cohort study taking place at the Johns Hopkins AIDS service since January 1984, in which the data were collected both prospectively and retrospectively. The patients in this data set consisted of 47 patients receiving via pulse therapy with the aim of reducing the long-term complications. ^ The aim of this project was to study the impact of virologic and immunologic factors on the rate of CD4 loss after treatment interruption. The exposure variables under investigation included CD4 cell count and viral load at treatment initiation. The rates of change of CD4 cell count after treatment interruption was estimated from observed data using advanced longitudinal data analysis methods (i.e., linear mixed model). Using random effects accounted for repeated measures of CD4 per person after treatment interruption. The regression coefficient estimates from the model was then used to produce subject specific rates of CD4 change accounting for group trends in change. The exposure variables of interest were age, race, and gender, CD4 cell counts and HIV RNA levels at HAART initiation. ^ The rate of fall of CD4 count did not depend on CD4 cell count or viral load at initiation of treatment. Thus these factors may not be used to determine who can have a chance of successful treatment interruption. CD4 and viral load were again studied by t-tests and ANOVA test after grouping based on medians and quartiles to see any difference in means of rate of CD4 fall after interruption. There was no significant difference between the groups suggesting that there was no association between rate of fall of CD4 after treatment interruption and above mentioned exposure variables. ^

Kawasaki Disease and Peripheral Gangrene in Infancy

Introduction: Early diagnosis and treatment of Kawasaki disease as the most common cause of acquired heart disease in childhood, may significantly improve the prognosis. Diagnosing infantile Kawasaki (younger than a year) is difficult because of obscure symptoms; at the same time they are at the higher risk of coronary abnormalities. Case Presentation: We report three infants with prolonged (more than 5 days) fever and peripheral gangrene without any other clinical manifestations of Kawasaki disease. Kawasaki was diagnosed due to dilation of coronary artery and other aortic branches, thrombocytosis, and rising of ESR and CRP. All patients were treated with high dose aspirin, IVIG and pulse therapy with methylprednisolone. Additionally, cytotoxic drugs or infliximab were used for two of them because of severe aneurysms in the aortic branches. All 3 patients received aspirin with anti-platelet aggregation dose and 2 patients heparin as an anti-coagulant agent for longtime. After adequate treatment, peripheral gangrene, arterial dilations and aneurysms improved, but during 12 months follow-up coronary aneurysms did not improve completely. Conclusions: Peripheral gangrene must be regarded as an important sign of infantile Kawasaki disease early treatment of which can prevent severe permanent coronary involvements and sequels.

Postmenopausal hot flushes, vascular health and hormone therapy

Vasomotor hot flushes are complained of by approximately 75% of postmenopausal women, but their frequency and severity show great individual variation. Hot flushes have been present in women attending observational studies showing cardiovascular benefit associated with hormone therapy use, whereas they have been absent or very mild in randomized hormone therapy trials showing cardiovascular harm. Therefore, if hot flushes are a factor connected with vascular health, they could perhaps be one explanation for the divergence of cardiovascular data in observational versus randomized studies. For the present study 150 healthy, recently postmenopausal women showing a large variation in hot flushes were studied in regard to cardiovascular health by way of pulse wave analysis, ambulatory blood pressure and several biochemical vascular markers. In addition, the possible impact of hot flushes on outcomes of hormone therapy was studied. This study shows that women with severe hot flushes exhibit a greater vasodilatory reactivity as assessed by pulse wave analysis than do women without vasomotor symptoms. This can be seen as a hot flush-related vascular benefit. Although severe night-time hot flushes seem to be accompanied by transient increases in blood pressure and heart rate, the diurnal blood pressure and heart rate profiles show no significant differences between women without and with mild, moderate or severe hot flushes. The levels of vascular markers, such as lipids, lipoproteins, C-reactive protein and sex hormone-binding globulin show no association with hot flush status. In the 6-month hormone therapy trial the women were classified as having either tolerable or intolerable hot flushes. These groups were treated in a randomized order with transdermal estradiol gel, oral estradiol alone or in combination with medroxyprogesterone acetate, or with placebo. In women with only tolerable hot flushes, oral estradiol leads to a reduced vasodilatory response and increases in 24-hour and daytime blood pressures as compared to women with intolerable hot flushes receiving the same therapy. No such effects were observed with the other treatment regimes or in women with intolerable hot flushes. The responses of vascular biomarkers to hormone therapy are unaffected by hot flush status. In conclusion, hot flush status contributes to cardiovascular health before and during hormone therapy. Severe hot flushes are associated with an increased vasodilatory, and thus, a beneficial vascular status. Oral estradiol leads to vasoconstrictive changes and increases in blood pressure, and thus to possible vascular harm, but only in women whose hot flushes are so mild that they would probably not lead to the initiation of hormone therapy in clinical practice. Healthy, recently postmenopausal women with moderate to severe hot flushes should be given the opportunity to use hormone therapy alleviate hot flushes, and if estrogen is prescribed for indications other than for the control of hot flushes, transdermal route of administration should be favored.

Combination antiretroviral therapy -associated lipodystrophy : insights into pathogenesis and treatment

Introduction: Combination antiretroviral therapy (cART) has decreased morbidity and mortality of individuals infected with human immunodeficiency virus type 1 (HIV-1). Its use, however, is associated with adverse effects which increase the patients risk of conditions such as diabetes and coronary heart disease. Perhaps the most stigmatizing side effect is lipodystrophy, i.e., the loss of subcutaneous adipose tissue (SAT) in the face, limbs and trunk while fat accumulates intra-abdominally and dorsocervically. The pathogenesis of cART-associated lipodystrophy is obscure. Nucleoside reverse transcriptase inhibitors (NRTI) have been implicated to cause lipoatrophy via mitochondrial toxicity. There is no known effective treatment for cART-associated lipodystrophy during unchanged antiretroviral regimen in humans, but in vitro data have shown uridine to abrogate NRTI-induced toxicity in adipocytes. Aims: To investigate whether i) cART or lipodystrophy associated with its use affect arterial stiffness; ii) lipoatrophic SAT is inflamed compared to non-lipoatrophic SAT; iii) abdominal SAT from patients with compared to those without cART-associated lipoatrophy differs with respect to mitochondrial DNA (mtDNA) content, adipose tissue inflammation and gene expression, and if NRTIs stavudine and zidovudine are associated with different degree of changes; iv) lipoatrophic abdominal SAT differs from preserved dorsocervical SAT with respect to mtDNA content, adipose tissue inflammation and gene expression in patients with cART-associated lipodystrophy and v) whether uridine can revert lipoatrophy and the associated metabolic disturbances in patients on stavudine or zidovudine based cART. Subjects and methods: 64 cART-treated patients with (n=45) and without lipodystrophy/-atrophy (n=19) were compared cross-sectionally. A marker of arterial stiffness, heart rate corrected augmentation index (AgIHR), was measured by pulse wave analysis. Body composition was measured by magnetic resonance imaging and dual-energy X-ray absorptiometry, and liver fat content by proton magnetic resonance spectroscopy. Gene expression and mtDNA content in SAT were assessed by real-time polymerase chain reaction and microarray. Adipose tissue composition and inflammation were assessed by histology and immunohistochemistry. Dorsocervical and abdominal SAT were studied. The efficacy and safety of uridine for the treatment of cART-associated lipoatrophy were evaluated in a randomized, double-blind, placebo-controlled 3-month trial in 20 lipoatrophic cART-treated patients. Results: Duration of antiretroviral treatment and cumulative exposure to NRTIs and protease inhibitors, but not the presence of cART-associated lipodystrophy, predicted AgIHR independent of age and blood pressure. Gene expression of inflammatory markers was increased in SAT of lipodystrophic as compared to non-lipodystrophic patients. Expression of genes involved in adipogenesis, triglyceride synthesis and glucose disposal was lower and of those involved in mitochondrial biogenesis, apoptosis and oxidative stress higher in SAT of patients with than without cART-associated lipoatrophy. Most changes were more pronounced in stavudine-treated than in zidovudine-treated individuals. Lipoatrophic SAT had lower mtDNA than SAT of non-lipoatrophic patients. Expression of inflammatory genes was lower in dorsocervical than in abdominal SAT. Neither depot had characteristics of brown adipose tissue. Despite being spared from lipoatrophy, dorsocervical SAT of lipodystrophic patients had lower mtDNA than the phenotypically similar corresponding depot of non-lipodystrophic patients. The greatest difference in gene expression between dorsocervical and abdominal SAT, irrespective of lipodystrophy status, was in expression of homeobox genes that regulate transcription and regionalization of organs during embryonal development. Uridine increased limb fat and its proportion of total fat, but had no effect on liver fat content and markers of insulin resistance. Conclusions: Long-term cART is associated with increased arterial stiffness and, thus, with higher cardiovascular risk. Lipoatrophic abdominal SAT is characterized by inflammation, apoptosis and mtDNA depletion. As mtDNA is depleted even in non-lipoatrophic dorsocervical SAT, lipoatrophy is unlikely to be caused directly by mtDNA depletion. Preserved dorsocervical SAT of patients with cART-associated lipodystrophy is less inflamed than their lipoatrophic abdominal SAT, and does not resemble brown adipose tissue. The greatest difference in gene expression between dorsocervical and abdominal SAT is in expression of transcriptional regulators, homeobox genes, which might explain the differential susceptibility of these adipose tissue depots to cART-induced toxicity. Uridine is able to increase peripheral SAT in lipoatrophic patients during unchanged cART.

Intermolecular Multiple Quantum Coherences Enable Accurate Thermal Imaging of Red Bone Marrow During Thermal Therapy of Bone Metastases

Prostate and breast cancers are two of the most common types of cancer in the United States, and those cancers metastasize to bone in more than two thirds of patients. Recent evidence suggests that thermal therapy is effective at treating metastatic bone cancer. For example, thermal therapy enables targeted drug delivery to bone, ablation of cancer cells in bone marrow, and palliation of bone pain. Thermal therapy of bone metastases would be greatly improved if it were possible to image the temperature of the tissue surrounding the disease, which is usually red bone marrow (RBM). Unfortunately, current thermal imaging techniques are inaccurate in RBM.

This dissertation shows that many of the difficulties with thermal imaging of RBM can be overcome using a magnetic resonance phenomenon called an intermolecular multiple quantum coherence (iMQC). Herein, iMQCs are detected with a magnetic resonance imaging (MRI) pulse sequence called multi-spin-echo HOMOGENIZED with off resonance transfer (MSE-HOT). Compared to traditional methods, MSE-HOT provided ten-fold more accurate images of temperature change. Furthermore, MSE-HOT was translated to a human MRI scanner, which enabled imaging of RBM temperature during heating with a clinical focused ultrasound applicator. In summary, this dissertation develops a MRI technique that enables thermal imaging of RBM during thermal therapy of bone metastases.