Health-Related Quality of Life Impact of a Triple Combination of Olmesartan Medoxomil, Amlodipine Besylate and Hydrochlorotiazide in Subjects with Hypertension

BACKGROUND: A post-hoc analysis was performed on the data from a 54 weeks phase III study (ClinicalTrials.gov identifier: NCT00923091) to measure changes in the health-related quality of life (HRQoL) of 2,690 patients aged ≥18 with moderate-to-severe hypertension who received one of six doses of olmesartan/amlodipine/hydrochlorothiazide (OLM/AML/HCTZ), using the MINICHAL and EQ-5D instruments. METHODS: Descriptive statistics were used to assess blood pressure and HRQoL scores over the study period. Analysis of covariance (ANCOVA) was used to identify those factors that could possibly have influenced HRQoL. Linear regression was used to assess the relationship between changes in blood pressure and HRQoL scores. RESULTS: Patients' baseline MINICHAL mood and somatic domains scores were 5.5 and 2.6. Over the study period HRQoL improved as both MINICHAL scores decreased by 31-33%. Patients' baseline EQ-5D index and VAS scores were 0.9 and 73.4 respectively, increasing by 6% and 12% over the study period. Patients' QALY gain over the 54 weeks study period was estimated to be 0.029 QALYs. The ANCOVA showed that changes in patients' HRQoL was likely to have been influenced by patients' achievement of blood pressure control, the amount of concomitant medication and patients' last used dosage strength of antihypertensive. Linear regression showed that blood pressure improvement may have been associated with improved HRQoL. CONCLUSIONS: This study showed that OLM/AML/HCTZ reduced blood pressure and significantly increased blood pressure control whilst improving patients' HRQoL. Achieving blood pressure control, amount of concomitant medication and dosage strength of antihypertensive impacted on patients' HRQoL.

Drug Provocation Tests to Betalactam Antibiotics: Experience in a Paediatric Setting

Background: Few studies have been performed in children withs uspected betalactam allergy.We aimed to assess the role of the drug provocation test(DPT)with betalactams in a paediatric setting and to study the association between allergy to betalactam antibiotics and other allergic diseases. Methods:We included all the patients under 15 years old who were consecutively referred to the Immunoallergy Department, Dona Estefânia Hospital,Portugal(January 2002 to April 2008)for a compatible history of allergic reaction to betalactam. All were submitted to a DPT.Children were proposed to performs kintests(ST)to betalactam antibiotics followed by DPT. If they decline ST,a DPT with the culprit drug was performed. Results: We studied 161 children,60%were boys,with a median age of 5years old at the time of the DPT.Thirty-three patients(20.5%)had an immediate reaction and 33(20.5%)a non-immediate reaction. These verity of there porte dreactions was low in most cases. Skin tests to betalactams were performed in 47 children and were positive in 8.DPT was positive inonlyone(3.4%)of the patients skin tested and in 11(13.4%)of those not skin tested. These verity of the DPT reaction was low.Asthma and food allergy were associated with a positive DPT in the later group. Conclusions: DPT seems a safe procedure even in the absence of ST in non-severe cases. This could be a practical optionin infants and pre-school children,where ST are painful and difficult to perform.Additional caution should be taken in children with asthma and food allergy.

Sirolimus-Induced Drug Fever in a Renal Transplant Patient: a Case Report

Herein we have described the case of a male renal transplant recipient who developed drug fever apparently related to sirolimus. He had been stable under an immunosuppressive regimen of tacrolimus and mycophenolate mofetil, but developed acute cellular rejection at 5 years after transplantation due to noncompliance. Renal biopsy showed marked interstitial fibrosis, and immunosuppression was switched from mycophenolate to sirolimus, maintaining low tacrolimus levels. One month later he was admitted to our hospital for investigation of intermittently high fever, fatigue, myalgias, and diarrhea. Physical examination was unremarkable and drug levels were not increased. Lactic dehydrogenase and C-reactive protein were increased. The blood cell count and chest radiographic findings were normal. After extensive cultures, he was started on broad-spectrum antibiotics. Inflammatory markers and fever worsened, but diarrhea resolved. All serologic and imaging tests excluded infection, immune-mediated diseases, and malignancy. After 12 days antibiotics were stopped as no clinical improvement was achieved. Drug fever was suspected; sirolimus was replaced by mycophenolate mofetil. Fever and other symptoms disappeared after 24 hours; inflammatory markers normalized in a few days. After 1 month the patient was in good health with stable renal function. Although infrequent, the recognition of drug fever as a potential side effect of sirolimus may avoid unnecessary invasive diagnostic procedures. Nevertheless, exclusion of other common causes of fever is essential.

Osteoporosis in Paediatric Patients with Spina Bifida

The prevalence andmorbidity associated with osteoporosis and fractures in patients with spina bifida (SB) highlight the importance of osteoporosis prevention and treatment in early childhood; however, the issue has received little attention. The method for the selection of appropriate patients for drug treatment has not been clarified. Objective: To review the literature concerning fracture risks and low bone density in paediatric patients with SB. We looked for studies describing state-of-the-art treatments and for prevention of secondary osteoporosis. Methods: Articles were identified through a search in the electronic database (PUBMED) supplemented with reviews of the reference lists of selected papers. The main outcome measures were incidence of fractures and risk factors for fracture, an association between bone mineral density (BMD) and occurrence of fracture, risk factors of low BMD, and effects of pharmacological and non-pharmacological treatments on BMD and on the incidence of fractures. We considered as a secondary outcome the occurrence of fractures in relation to the mechanism of injury. Results: Results indicated that patients with SB are at increased risk for fractures and low BMD. Risk factors that may predispose patients to fractures include higher levels of neurological involvement, non-ambulatory status, physical inactivity, hypercalciuria, higher body fat levels, contractures, and a previous spontaneous fracture. Limitations were observed in the number and quality of studies concerning osteoporosis prevention and treatment in paediatric patients with SB. The safety and efficiency of drugs to treat osteoporosis in adults have not been evaluated satisfactorily in children with SB.

The Risks of Self - Medication: Case Report of Familial Misuse of AM3 (Immunoferon®)

Over the last decades extended medical knowledge has been an important health care benefit in terms of disease prevention and management. However, probably with no exception, most pharmaceutical products are not devoid of adverse consequences. Immunomodulators are commonly considered a “benign” drug whose advantages bypass consequences. The immunomodulator AM3 (Immunoferon®) is a clinically used, orally administered compound whose active principle is stabilised in an inorganic matrix of calcium. We report the misuse of AM3 in three members of a family; father and two children. The drug was prescribed to the father who subsequently administered it to the children without seeking medical advice. Two months later, all subjects developed abdominal and/or flank colicky pain. Hypercalciuria was diagnosed in the children with different degrees of severity. It is likely that the calcium content of the inorganic matrix played an important role in the onset of symptoms. No adverse side effects related to the inorganic matrix of calcium of immunoferon® have been documented so far. This family case report calls attention to the risks of self -medication in a susceptible family. Paediatric patients are vulnerable as they rely on adults for the supply of medications. Concerning the use of drugs in family, especially nonprescription drugs, the quality of health care provided to the children depends on the health literacy of their parents.

Anti-Tumor Necrosis Factor Alpha-Induced Drug Eruptions: One Patient, More Than a Pattern

Background: Tumor necrosis factor alpha (TNFα) antagonists are effective in treating several immune-inflammatory diseases, including psoriasis and inflammatory bowel disease. The paradoxical and unpredictable induction of psoriasis and psoriasiform skin lesions is a recognized adverse event, although of unclear aetiology. However, histological analysis of these eruptions remains insufficient, yet suggesting that some might constitute a new pattern of adverse drug reaction, rather than true psoriasis. Case report: The authors report the case of a 43-year-old woman with severe recalcitrant Crohn disease who started treatment with infliximab. There was also a personal history of mild plaque psoriasis without clinical expression for the past eight years. She developed a heterogeneous cutaneous eruption of psoriasiform morphology with pustules and crusts after the third infliximab infusion. The histopathological diagnosis was of a Sweet-like dermatosis. The patient was successfully treated with cyclosporine in association with both topical corticosteroid and vitamin D3 analogue. Three weeks after switching to adalimumab a new psoriasiform eruption was observed, histologically compatible with a psoriasiform drug eruption. Despite this, and considering the beneficial effect on the inflammatory bowel disease, it was decided to maintain treatment with adalimumab and to treat through with topicals, with progressive control of skin disease. Discussion: Not much is known about the pathogenesis of psoriasiform eruptions induced by biological therapies, but genetic predisposition and Koebner phenomenon may contribute to it. Histopathology can add new facets to the comprehension of psoriasiform reactions. In fact, histopathologic patterns of such skin lesions appear to be varied, in a clear asymmetry with clinical findings. Conclusion: The sequential identification in the same patient of two clinical and histopathologic patterns of drug reaction to TNFα antagonists is rare. Additionally, to the authors’ knowledge, there is only one other description in literature of a TNFα antagonist-induced Sweet-like dermatosis, emphasizing the singularity of this case report.

Genomic Signatures and Antiviral Drug Susceptibility Profile of A(H1N1)pdm09

Background: Genetic changes in influenza surface and internal genes can alter viral fitness and virulence. Mutation trend analysis and antiviral drug susceptibility profiling of A(H1N1)pdm09 viruses is essential for risk assessment of emergent strains and disease management. Objective: To profile genomic signatures and antiviral drug resistance of A(H1N1)pdm09 viruses and to discuss the potential role of mutated residues in human host adaptation and virulence. Study design: A(H1N1)pdm09 viruses circulating in Portugal during pandemic and post-pandemic periods and 2009/2010 season. Viruses were isolated in MDCK-SIAT1 cell culture and subjected to mutation analysis of surface and internal proteins, and to antiviral drug susceptibility profiling. Results: The A(H1N1)pdm09 strains circulating during the epidemic period in Portugal were resistant to amantadine. The majority of the strains were found to be susceptible to oseltamivir and zanamivir, with five outliers to neuraminidase inhibitors (NAIs) identified. Specific mutation patterns were detected within the functional domains of internal proteins PB2, PB1, PA, NP, NS1, M1 and NS2/NEP, which were common to all isolates and also some cluster-specific. Discussion: Modification of viral genome transcription, replication and apoptosis kinetics, changes in antigenicity and antiviral drug susceptibility are known determinants of virulence. We report several point mutations with putative roles in viral fitness and virulence, and discuss their potential to result in more virulent phenotypes. Monitoring of specific mutations and genetic patterns in influenza viral genes is essential for risk assessing emergent strains, disease epidemiology and public health implications.

Health-Related Quality of Life of Pediatric Intensive Care Survivors

Objetivo: Avaliar a qualidade de vida relacionada à saúde (QVRS)de crianças sobreviventes à alta da terapia intensiva pediátrica. Métodos: Foi realizada uma avaliação prospectiva da QVRS na admissão e após 6 meses em crianças com idade igual ou superior a 6 anos, internadas em três unidades de terapia intensiva pediátricas (UTIPs) terciárias de maio de 2002 a junho de 2004. A QVRS foi avaliada com o questionário Health Utilities Index Mark 3 (HUI3), aplicado a um representante da criança. Resultados: Das 517 admissões elegíveis, 44 crianças faleceram na UTIP (8,5%) e 320 casos foram avaliados na admissão; entre eles, foi possível realizar o seguimento de 252 casos. Não foram encontradas diferenças estatisticamente significativas entre os escores globais do HUI3 antes da admissão e no seguimento [medianas (intervalo interquartil) de 0,86 (0,42-1,00) e 0,83 (0,45-1,00); p = 0,674, respectivamente]. No âmbito individual, 21% das crianças não apresentaram mudanças na QVRS, foi observada melhora em 40% e agravamento em 38% dos casos. Deficiência grave antes da admissão (escore global do HUI3 < 0,70)esteve presente em 36% dos casos, com melhora no seguimento aos 6 meses em 60% deles. Entre aqueles que apresentaram agravamento da QVRS no seguimento, 45% eram vítimas de trauma. Conclusões: Embora a QVRS seja globalmente semelhante nas duas avaliações, foram encontradas várias diferenças no âmbito individual. As crianças com baixa QVRS antes da admissão (deficiência grave) podem se beneficiar da terapia intensiva pediátrica, visto que muitas dessas crianças melhoraram a QVRS, em comparação com seu estado pré-admissão.

Effect of Efavirenz on High-Density Lipoprotein Antioxidant Properties in HIV-Infected Patients

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: * In previous work, we showed a long-term and concentration-dependent beneficial effect of the non-nucleoside reverse transcriptase inhibitor efavirenz (EFV) on high-density lipoproteins (HDL) in human immunodeficiency virus (HIV)-infected patients. * Furthermore, it has been suggested that instead of the current practice of only measuring HDL-chelesterol values, the evaluation of HDL function, namely its antioxidant properties, might be an improved tool for identifying subjects at increased risk for cardiovascular events. * Paraoxonase-1 (PON-1) is an enzyme associated with HDL that is responsible for HDL antioxidant function. WHAT THIS STUDY ADDS: * In the present work, we studied the effect of EFV on the activity of PON-1 and showed, for the first time, that EFV-based antiretroviral therapy is associated with a better antioxidant function, i.e. with a higher PON-1 activity. AIMS: A long-term and concentration-dependent beneficial effect of efavirenz (EFV) on cholesterol associated with high-density lipoprotein (HDL-c) in human immunodeficiency virus (HIV)-infected patients has been documented. Furthermore, it has been suggested that, instead of the current practice of only measuring HDL-c values, the evaluation of HDL quality might be an improved tool for identifying subjects at increased risk of cardiovascular events. Paraoxonase-1 (PON-1) is an enzyme associated with HDL that is involved in the onset of cardiovascular disease and responsible for HDL antioxidant function. The aim of the present study was to investigate the effect of EFV on the circulating activity of PON-1 in HIV-infected patients. METHODS: The patients included were adults with a documented HIV-1 infection, nontreated or treated with antiretroviral regimens including EFV 600 mg once daily as first therapeutic regimen for at least 3 months. The influence of treatment with EFV, HDL-c and CD4 cell count on PON-1 activity was analysed. RESULTS: HIV-infected White patients treated with EFV had higher PON-1 activity [77.35 U l(-1) (65.66, 89.04)] (P < 0.05) and higher PON-1 activity : HDL-c ratio [1.88 (1.49, 2.28)] (P < 0.01) than untreated patients. PON-1 activity was higher in Black patients (P < 0.001) and in patients with a CD4 cell count >500 cells ml(-1) (P= 0.0120). CONCLUSIONS: EFV-based antiretroviral regimens are associated with HDL particles with a better antioxidant function, i.e. with a higher PON-1 activity. The PON-1 activity of Black patients is higher than that found in Whites regardless of treatment. Ethnicity should be taken into consideration when studying drug effects on PON-1 activity.

Investigation and Control of a Large Outbreak of Multi-Drug Resistant Tuberculosis at a Central Lisbon Hospital

An increase in the number of new cases of tuberculosis (TB) combined with poor clinical outcome was identified among HIV-infected injecting drug users attending a large HIV unit in central Lisbon. A retrospective epidemiological and laboratory study was conducted to review all newly diagnosed cases of TB from 1995 to 1996 in the HIV unit. Results showed that from 1995 to 1996, 63% (109/173) of the Mycobacterium tuberculosis isolates from HIV-infected patients were resistant to one or more anti-tuberculosis drugs; 89% (95) of these were multidrug-resistant, i.e., resistant to at least isoniazid and rifampicin. Eighty percent of the multidrug-resistant strains (MDR) available for restriction fragment length polymorphism (RFLP) DNA fingerprinting clustered into one of two large clusters. Epidemiological data support the conclusion that the transmission of MDR-TB occurred among HIV-infected injecting drug users exposed to infectious TB cases on open wards in the HIV unit. Improved infection control measures on the HIV unit and the use of empirical therapy with six drugs once patients were suspected to have TB, reduced the incidence of MDR-TB from 42% of TB cases in 1996 to 11% in 1999.

Locally Advanced and Metastatic Prostate Cancer Treated with Intermittent Androgen Monotherapy or Maximal Androgen Blockade: Results from a Randomised Phase 3 Study by the South European Uroncological Group

BACKGROUND: Few randomised studies have compared antiandrogen intermittent hormonal therapy (IHT) with continuous maximal androgen blockade (MAB) therapy for advanced prostate cancer (PCa). OBJECTIVE: To determine whether overall survival (OS) on IHT (cyproterone acetate; CPA) is noninferior to OS on continuous MAB. DESIGN, SETTING, AND PARTICIPANTS: This phase 3 randomised trial compared IHT and continuous MAB in patients with locally advanced or metastatic PCa. INTERVENTION: During induction, patients received CPA 200 mg/d for 2 wk and then monthly depot injections of a luteinising hormone-releasing hormone (LHRH; triptoreline 11.25 mg) analogue plus CPA 200 mg/d. Patients whose prostate-specific antigen (PSA) was <4 ng/ml after 3 mo of induction treatment were randomised to the IHT arm (stopped treatment and restarted on CPA 300 mg/d monotherapy if PSA rose to ≥20 ng/ml or they were symptomatic) or the continuous arm (CPA 200 mg/d plus monthly LHRH analogue). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Primary outcome measurement was OS. Secondary outcomes included cause-specific survival, time to subjective or objective progression, and quality of life. Time off therapy in the intermittent arm was recorded. RESULTS AND LIMITATIONS: We recruited 1045 patients, of which 918 responded to induction therapy and were randomised (462 to IHT and 456 to continuous MAB). OS was similar between groups (p=0.25), and noninferiority of IHT was demonstrated (hazard ratio [HR]: 0.90; 95% confidence interval [CI], 0.76-1.07). There was a trend for an interaction between PSA and treatment (p=0.05), favouring IHT over continuous therapy in patients with PSA ≤1 ng/ml (HR: 0.79; 95% CI, 0.61-1.02). Men treated with IHT reported better sexual function. Among the 462 patients on IHT, 50% and 28% of patients were off therapy for ≥2.5 yr or >5 yr, respectively, after randomisation. The main limitation is that the length of time for the trial to mature means that other therapies are now available. A second limitation is that T3 patients may now profit from watchful waiting instead of androgen-deprivation therapy. CONCLUSIONS: Noninferiority of IHT in terms of survival and its association with better sexual activity than continuous therapy suggest that IHT should be considered for use in routine clinical practice.

Economic Evaluation of Ticagrelor for Secondary Prevention Following Acute Coronary Syndromes

INTRODUCTION AND OBJECTIVES: To estimate the cost-effectiveness and cost-utility of ticagrelor in the treatment of patients with acute coronary syndromes (unstable angina or myocardial infarction with or without ST-segment elevation), including patients treated medically and those undergoing percutaneous coronary intervention or coronary artery bypass grafting. METHODS: A short-term decision tree and a long-term Markov model were used to simulate the evolution of patients' life-cycles. Clinical effectiveness data were collected from the PLATO trial and resource use data were obtained from the Hospital de Santa Marta database, disease-related group legislation and the literature. RESULTS: Ticagrelor provides increases of 0.1276 life years and 0.1106 quality-adjusted life years (QALYs) per patient. From a societal perspective these clinical gains entail an increase in expenditure of €610. Thus the incremental cost per life year saved is €4780 and the incremental cost per QALY is €5517. CONCLUSIONS: The simulation results show that ticagrelor reduces events compared to clopidogrel. The costs of ticagrelor are partially offset by lower costs arising from events prevented. The use of ticagrelor in clinical practice is therefore cost-effective compared to generic clopidogrel.