Optimal management strategies for chronic iron overload

Iron overload is characterised by excessive iron deposition and consequent injury and dysfunction of target organs, especially the heart, liver, anterior pituitary, pancreas and joints. Iron overload disorders are common worldwide and occur in most major race/ethnicity groups. Physiological mechanisms to excrete iron are very limited. Thus, all patients with iron overload need safe and effective treatment that is compatible with their co-existing medical conditions. Treatments for iron overload include phlebotomy and erythrocytapheresis that remove iron predominantly as haemoglobin, and chelation therapy with drugs that bind excess iron selectively and increase its excretion. The most important potential benefits of therapy are preventing deaths due to cardiac siderosis and hepatic cirrhosis. Preventing iron-related injury to endocrine organs is critical in children. Successful treatment or prevention of iron overload increases quality of life and survival in many patients. This article characterises the major categories of iron overload disorders, tabulates methods to evaluate and treat iron overload, and describes treatment options for iron overload disorders. Research needed to advance knowledge about treatment of iron overload is proposed.     

Anthracycline-induced cardiotoxicity in children with cancer: strategies for prevention and management

The fact that anthracyclines are cardiotoxic seriously narrows their therapeutic index in cancer therapy. The cardiotoxic risk increases with the cumulative dose and may lead to congestive heart failure (CHF) and dilated cardiomyopathy in adults and in children. The prevention of anthracycline-induced cardiotoxicity is particularly important in children who can be expected to survive for decades after being cured of their malignancy. Attempts to reduce anthracycline cardiotoxicity have been directed towards: (i) decreasing myocardial concentrations of anthracyclines and their metabolites by dose limitation and schedule modification; (ii) developing less cardio-toxic analogs; and (iii) concurrently administering cardioprotective agents to attenuate the effects of anthracyclines on the heart. As regards schedule modification, avoidance of anthracycline peak levels may reduce the pathologic and clinical cardiotoxicity, although this has not always been observed. The analogs of doxorubicin, such as idarubicin and epirubicin, have similar cardiotoxicity to that of doxorubicin when given in amounts of equivalent myelotoxicity. Liposomal anthracyclines are a new class of agents that may permit more specific organ targeting, thereby producing less systemic and cardiac toxicity, but more studies are required to assess the advantages, if any, of these preparations over classical anthracyclines. The cardioprotective agent, dexrazoxane, an iron chelator, is highly effective and provides short-term cardioprotection to most patients receiving even the most intensive doxorubicin-containing regimens. Its long-term benefits remain to be determined. In addition, data remain insufficient to make specific recommendations regarding current use of dexrazoxane in children. It is thought that subtle abnormalities, related to anthracycline treatment in childhood, can develop into more permanent myocardial disease resulting in cardiomyopathy, which may progress to CHF. As regards the therapy of patients with anthracycline cardiotoxicity, two different situations have, therefore, to be considered: (i) if the patient presents with cardiac abnormalities, such as a reduction in fractional shortening at echocardiogram, without cardiac symptoms; and (ii) if the patient has CHF. In the presence of CHF, recovery with digitalis-diuretic therapy alone seldom occurs, and in patients who have refractory hemodynamic decompensation, heart transplantation is indicated. In patients with CHF, therapy with ACE inhibitors induces improvement in left ventricular structure and function, but this improvement is transient. Randomized clinical trials are, therefore, necessary to determine the effects of ACE inhibitors in mild-to-moderate left ventricular dysfunction. The beneficial effects of beta-adrenoceptor antagonists (beta-blockers) on cardiac function in heart failure due to anthracyclines seem comparable with those observed in other forms of heart failure with systolic dysfunction. Many drugs are available to treat children with CHF due to anthracycline treatment, but they are only palliative.     

Allergic rhinitis in children : diagnosis and management strategies

The incidence of allergic rhinitis has been increasing for the last few decades, in keeping with the rising incidence of atopy worldwide. Allergic rhinitis has a prevalence of up to 40% in children, although it frequently goes unrecognized and untreated. This can have enormous negative consequences, particularly in children, since it is associated with numerous complications and comorbidities that have a significant health impact on quality of life. In fact, allergic rhinitis is considered to be a risk factor for asthma. There are numerous signs of allergic rhinitis, particularly in children, that can alert an observant clinician to its presence. Children with severe allergic rhinitis often have facial manifestations of itching and obstructed breathing, including a gaping mouth, chapped lips, evidence of sleep deprivation, a long face, dental malloclusions, and the allergic shiner, allergic salute, or allergic crease. The medical history is extremely important as it can reveal information regarding a family history of atopy and the progression of atopy in the child. It is also important to identify the specific triggers of allergic rhinitis, because one of the keys to successful management is the avoidance of triggers. A tripartite treatment strategy that embraces environmental control, immunotherapy, and pharmacologic treatment is the most comprehensive approach. Immunotherapy has come to be viewed as potentially prophylactic, capable of altering the course of allergic rhinitis. The most recent guidelines for the management of allergic rhinitis issued by the WHO recommend a tiered approach that integrates diagnosis and treatment, in which allergic rhinitis is subclassified both by frequency, as either intermittent or persistent, and by severity, as either mild or moderate to severe. Oral or topical antihistamines and intranasal corticosteroids are the mainstay of pharmacologic therapy for allergic rhinitis, depending upon its severity, and several agents have been approved for use in children aged 5 years old and younger.     

Insulin resistance syndrome in children : pathophysiology and potential management strategies

The simultaneous presence of various cardiovascular risk factors in the same individual is not rare, even in the pediatric age group. The clustering of risk factors can be termed insulin resistance syndrome (IRS) because of the putative central role of tissue insulin insensitivity in the background of the inter-related metabolic disturbances. Fasting hyperinsulinemia, impaired glucose tolerance, dyslipidemia, and hypertension are considered to represent the basic abnormalities of IRS. The most prevalent related disturbances are increased plasma levels of plasminogen activator inhibitor-1, fibrinogen, uric acid, homocysteine, and C-reactive protein, as well as visceral adiposity, microalbuminuria, disturbed essential fatty acid metabolism, low availability of lipid-soluble antioxidant vitamins, and enhanced expression of tumor necrosis factor-alpha in adipose tissues. Certain genetic abnormalities have been associated with IRS, but explain only a small part of the variability in insulin resistance. The exact prevalence of IRS in children remains to be defined; it was found to be 9% in one survey among children with obesity seeking medical attention. Modification of lifestyle, i.e. reduction of energy intake and enhancement of physical activity, are unquestionable prerequisites for long-term success in the management of IRS. In at least two randomized controlled studies, metformin proved to be clinically effective in increasing insulin sensitivity in hyperinsulinemic, nondiabetic adolescents. Thiazolidinediones have been successfully tested for the treatment of insulin resistance in adults, but not in children as yet. Prevention of the development of IRS in children is obviously of great significance for the health status of the community. However, the efficacy of various preventive approaches should be investigated further in carefully designed controlled trials.     

Type 1 diabetes in children and adolescents--new strategies in management and treatment

Type 1 diabetes (T1D) is the most common metabolic disease in childhood with an increasing incidence of about 3 to 5% per year, particularly in preschool children. Despite substantial progresses in diabetes research concerning its pathogenesis and etiology in the last decades, there is no strategy for primary prevention in subjects with subclinical signs of diabetes. Nowadays, it is well-known that T1D is caused by partial or total destruction of pancreatic islet cells, resulting in progressive incapacity to produce insulin. This inflammation is of an autoimmune nature, resulting both from environmental and genetic influences. Children with T1D usually have a several day history of typical symptoms such as frequent urination, excessive thirst and weight loss, which appear when about 80% of the pancreatic beta cells are already destroyed. If those symptoms are misinterpreted, the continuing hyperglycaemic metabolism leads to a potential life-threatening condition the diabetic ketoacidosis. Patients with T1D require daily subcutaneous injections of insulin, with the overall aim to mimic the physiological release of insulin during meal-associated and fasting periods (intensive insulin therapy). The most important parameters to evaluate the effectiveness of insulin treatment are blood glucose monitoring and HbA1c. The increased availability of systems for continuous glucose monitoring may help patients to have a better insight into their metabolic conditions. Sensor-based insulin treatment is likely to have a significant impact on paediatric diabetes therapy and education in the future.     

Combination strategies for pain management

At least two factors relating to pain management using oral analgesics suggest that combination strategies merit consideration: many pains arise from more than one physiological cause and current analgesics have adverse effect profiles that might be reduced by combination with another agent in smaller doses or with less frequent dosing. In addition to increased convenience, combinations sometimes also result in the unexpected benefit of synergy. But not all pains, clinical settings or combinations merit the extra expense or other potential negative features of fixed-ratio products. This review examines the multiple basic science, clinical and pharmacoeconomic issues relating to analgesic combinations and the methodologies available for assessing these issues.     

Combination strategies for pain management

At least two factors relating to pain management using oral analgesics suggest that combination strategies merit consideration: many pains arise from more than one physiological cause and current analgesics have adverse effect profiles that might be reduced by combination with another agent in smaller doses or with less frequent dosing. In addition to increased convenience, combinations sometimes also result in the unexpected benefit of synergy. But not all pains, clinical settings or combinations merit the extra expense or other potential negative features of fixed-ratio products. This review examines the multiple basic science, clinical and pharmacoeconomic issues relating to analgesic combinations and the methodologies available for assessing these issues.     

Optimal management of asthma in elderly patients: strategies to improve adherence to recommended interventions

Adherence to asthma medications presents a problem in all age groups, and older people with chronic illnesses such as asthma also have multiple co-morbidities and consequently complex healthcare needs. It has been suggested that older people are also less likely to adhere to medication and treatment than younger people. Although the prevalence of asthma in older people is similar to that of the general population, over two-thirds of those who die from asthma are >50 years of age and there is strong evidence for under-diagnosis. Clinicians therefore face specific challenges in providing healthcare with respect to both asthma diagnosis and treatment in older age groups. Non-adherence to medication can be defined as either 'intentional' or 'unintentional'. Unintentional non-adherence is more likely to be associated with sociodemographic or physical barriers to the use of medication. Intentional non-adherence results from the balance of individual reasoning of risks versus the benefits of taking medication and acceptance of asthma diagnosis. Intentional non-adherence can be addressed through strategies that influence health beliefs and concerns about the adverse effects of medicine. Unintentional adherence can be addressed by assessing and educating the patient in relation to device use and providing education and clear written instructions about medication requirements. However, some barriers to medication use, such as financial ones, may be systematic. Most studies of medication use, efficacy, adverse effects and adherence in patients with asthma primarily involve younger people. Studies of strategies to improve asthma adherence outcomes specifically in older people are urgently needed.     

Current management strategies for intraocular retinoblastoma

Survival rates for retinoblastoma patients have increased dramatically over the last century, with documented 5-year survival figures reaching 87-99% in developed countries. During the last decade, there has been a dramatic paradigm shift in the treatment approach for intraocular retinoblastoma, emphasising chemoreduction protocols and minimising the use of external beam radiation. The recognition of the increased risk for second non-ocular cancers with external beam radiation contributed to the growing emergence of chemotherapy. Although chemoreduction protocols vary slightly between institutions, many centres are currently treating intraocular retinoblastoma with carboplatin, vincristine and etoposide as a three-drug regimen given in two to six cycles. Clinical studies have demonstrated that systemic chemotherapy must be combined with other modalities, such as laser treatment and cryotherapy, for adequate tumour control and many eyes with advanced intraocular disease require salvage therapy with radiation or enucleation. Therefore, modern centres treating retinoblastoma continue to manage patients with a variety of modalities, individualising the therapy according to the patient's presentation and clinical course.     

Tick-borne infections in children: epidemiology, clinical manifestations, and optimal management strategies

Ticks can transmit bacterial, protozoal, and viral infections to humans. Specific therapy is available for several of these infections. Doxycycline is the antimicrobial treatment of choice for all patients, regardless of age, with Rocky Mountain spotted fever, human monocytic ehrlichiosis, or human granulocytic ehrlichiosis. Chloramphenicol has been used to treat these infections in children but is demonstrably inferior to doxycycline. In patients with Mediterranean spotted fever, doxycycline, chloramphenicol, and newer macrolides all appear to be effective therapies. Therapy of Lyme disease depends on the age of the child and stage of the disease. For early localized disease, amoxicillin (for those aged <8 years) or doxycycline (for those aged >/=8 years) is effective. Doxycycline, penicillin V (phenoxymethylpenicillin) or penicillin G (benzylpenicillin) preparations, and erythromycin are all effective treatments for tick-borne relapsing fever. Hospitalized patients with tularemia should receive gentamicin or streptomycin. Doxycycline and ciprofloxacin have each been investigated for the treatment of tularemia in outpatients; however, these agents do not yet have established roles in the treatment of this disease in children. Combination therapy with clindamycin and quinine is preferred for children with babesiosis; the combination of azithromycin and atovaquone also appears promising. Ribavirin has been recently shown to markedly improve survival in patients with Crimean-Congo hemorrhagic fever. The role of antiviral therapy in the treatment of other tick-borne viral infections, including other hemorrhagic fevers and tick-borne encephalitis, is not yet defined.     

Cost-assessment of alternative management strategies for achalasia

Achalasia is a primary oesophageal motor disorder characterised by the abnormal relaxation of the lower oesophageal sphincter (LES) and absent oesophageal peristalsis. It is a rare disease, with an estimated incidence of ～ 1/100,000 and a prevalence close to 10/100,000 [1]. Its exact aetiology remains unknown. Autoimmune, infectious, degenerative and hereditary processes have all been proposed as factors that lead to a chronic inflammatory response in the myenteric plexus, thus resulting in selective loss of inhibitory neurons [2] and failure of the LES to relax and aperistalsis in the body of the oesophagus. The most common symptoms of achalasia are dysphagia for solids and liquids, regurgitation, chest pain, weight loss and heartburn in > 90 ～ 75, 40 – 50, ～ 60, ～ 40%, respectively [3,4]. The diagnosis is based on symptoms, barium swallow and manometry. A barium oesophagram typically shows a dilated oesophagus that tapers into a ‘bird-beak’ at the gastro-oesophageal junction with lack of normal peristalsis on fluoroscopic evaluation. The characteristic manometric features of achalasia are abnormal LES relaxation and aperistalsis; additionally, the LES pressure is frequently high, but can also be normal. Current practice of medicine is faced with rising healthcare costs and limited budgets [5]. We are therefore confronted with an increasing demand to justify the value of our therapeutic interventions, not only from the risk/benefit standpoint but also from the cost perspective [6,7].     

儿童术后呕吐的预防性干预策略

目的研究并比较阿扎司琼、昂丹司琼、托烷司琼、地塞米松和胃复安预防儿童术后呕吐（POV）的效果。方法 600例择期行腹股沟斜疝疝囊高扎术患儿,随机分为6组（n=100）,分别在术毕时静注阿扎司琼（A组）、昂丹司琼（B组）、托烷司琼（C组）、地塞米松（D组）、胃复安（E组）和空白生理盐水（F组）。观察并比较患儿术后24h POV发生情况。结果 A、B、C、D、E组POV的发生率（1%、3%、4%、8%、17%）均明显低于F组（29%,P〈0.05）;A、B、C和D组组间比较差异无统计学意义,但A、B、C和D组POV发生率均明显低于E组（P〈0.05）。结论阿扎司琼、昂丹司琼、托烷司琼、地塞米松和胃复安均能有效预防儿童POV的发生,但5-HT3受体拮抗剂为儿童首选预防药。     

Pharmacotherapy and management strategies for coeliac disease

Introduction: Coeliac disease is a common disease that affects approximately 1% of Northern European and American populations. Evidence suggests it is caused by an inappropriate immune response in genetically susceptible patients to dietary gluten found in wheat, rye, barley and, in a small minority of patients, oats. Treatment involves a lifelong gluten-free diet. This diet limits nutritional variety and is costly and difficult to maintain.

Areas covered: This review covers the current treatment options available and discusses novel emerging therapies for coeliac disease.

Expert opinion: Novel therapies are still in early stages of development and therefore, at present, a gluten-free diet remains the treatment of choice in coeliac disease due to its low side-effect profile. A replacement for a gluten-free diet would be superior to an adjunct; in this case dietary modification of gluten may well have the least side effects, be tolerated by a wider group of coeliac patients and therefore be accepted.

Search terms used: Pubmed, Medline and clinicaltrials.gov were searched with ‘celiac disease’ and ‘therapy’ as MESH terms. Patent database was searched using the term ‘celiac disease’. Conference attendance at DDW Chicago 2011 and Columbia 2010 was also used to gain further information from conference abstracts.     

Pharmacotherapy and management strategies for coeliac disease

INTRODUCTION: Coeliac disease is a common disease that affects approximately 1% of Northern European and American populations. Evidence suggests it is caused by an inappropriate immune response in genetically susceptible patients to dietary gluten found in wheat, rye, barley and, in a small minority of patients, oats. Treatment involves a lifelong gluten-free diet. This diet limits nutritional variety and is costly and difficult to maintain. AREAS COVERED: This review covers the current treatment options available and discusses novel emerging therapies for coeliac disease. EXPERT OPINION: Novel therapies are still in early stages of development and therefore, at present, a gluten-free diet remains the treatment of choice in coeliac disease due to its low side-effect profile. A replacement for a gluten-free diet would be superior to an adjunct; in this case dietary modification of gluten may well have the least side effects, be tolerated by a wider group of coeliac patients and therefore be accepted. Search terms used: Pubmed, Medline and clinicaltrials.gov were searched with 'celiac disease' and 'therapy' as MESH terms. Patent database was searched using the term 'celiac disease'. Conference attendance at DDW Chicago 2011 and Columbia 2010 was also used to gain further information from conference abstracts.     

Cost-assessment of alternative management strategies for achalasia

Achalasia is a primary oesophageal motor disorder characterised by the abnormal relaxation of the lower oesophageal sphincter (LES) and absent oesophageal peristalsis. It is a rare disease, with an estimated incidence of approximately 1/100,000 and a prevalence close to 10/100,000 [1]. Its exact aetiology remains unknown. Autoimmune, infectious, degenerative and hereditary processes have all been proposed as factors that lead to a chronic inflammatory response in the myenteric plexus, thus resulting in selective loss of inhibitory neurons [2] and failure of the LES to relax and aperistalsis in the body of the oesophagus. The most common symptoms of achalasia are dysphagia for solids and liquids, regurgitation, chest pain, weight loss and heartburn in > 90 approximately 75, 40 - 50, approximately 60, approximately 40%, respectively [3,4]. The diagnosis is based on symptoms, barium swallow and manometry. A barium oesophagram typically shows a dilated oesophagus that tapers into a 'bird-beak' at the gastro-oesophageal junction with lack of normal peristalsis on fluoroscopic evaluation. The characteristic manometric features of achalasia are abnormal LES relaxation and aperistalsis; additionally, the LES pressure is frequently high, but can also be normal. Current practice of medicine is faced with rising healthcare costs and limited budgets [5]. We are therefore confronted with an increasing demand to justify the value of our therapeutic interventions, not only from the risk/benefit standpoint but also from the cost perspective [6,7].     

Management strategies for hepatitis C virus infection in children

Chronic hepatitis C virus (HCV) infection is a major cause of morbidity and mortality worldwide. Progression to cirrhosis and hepatocellular carcinoma occurs in 20% of infected adults. The natural history following childhood infection is less well defined, although cirrhosis in children is described. Since blood product screening for HCV infection was introduced in 1990, most children who acquire HCV do so by vertical transmission from an infected mother. Transmission to offspring occurs in approximately 5%. Most children with HCV infection are asymptomatic. Diagnosis is made by testing those at risk for HCV RNA by polymerase chain reaction (PCR) and HCV antibody (anti-HCV) by enzyme immunoassay (EIA). The clinical impact of HCV infection is assessed by monitoring symptoms and signs, blood testing of liver enzymes, ultrasound imaging, and by liver biopsy. Improved efficacy and tolerability of treatment strategies in adults have had a significant impact on the management of children with HCV infection. The emphasis is now on promoting awareness, early diagnosis, and treatment. Treatment strategies have evolved from monotherapy with interferon alfa (IFNalpha), to combination therapy with ribavirin. Pegylated IFNalpha is superior to conventional IFNalpha, and forms the basis of current recommendations. The genotype of HCV influences treatment efficacy. Treatment is generally well tolerated in children, although adverse effects are common. Preparation and support throughout treatment for the whole family is needed. A proportion of children with HCV infection have co-morbidity, including viral co-infection or hematologic disease. Although treatment may be contraindicated, risks and benefits must be considered before denying treatment. Anemia is more common in those with HIV co-infection, renal insufficiency, thalassemia, or cirrhosis, and may be aggravated by treatment. Children with thalassemia may have iron overload, and transfusion requirements may increase during treatment. Further refinements of combination therapy and development of new drugs are in progress. Vaccine candidates are undergoing phase I and II treatment trials.     

Optimal therapeutic strategies for resectable oesophageal or oesophagogastric junction cancer

Oesophageal cancer is the eighth most common cancer diagnosed worldwide, with almost half a million new cases diagnosed each year. Despite improvements in surgical and radiotherapy techniques and refinements of chemotherapeutic regimens, long-term survival, even from localized oesophageal cancer, remains poor. Surgical resection alone remains the standard approach for very early stage disease (stage I), but whilst surgery remains fundamental to the treatment of stage II-III resectable adenocarcinoma, multimodality therapy with chemotherapy or chemoradiation (CRT) is internationally accepted as the standard of care. Data from two large, randomized phase III trials support the use of perioperative combination chemotherapy in lower oesophageal and oesophagogastric junction adenocarcinomas, but the contribution of the adjuvant therapy is uncertain. There are conflicting data from randomized studies of a purely neoadjuvant approach; however, recent meta-analyses have demonstrated that chemotherapy or CRT given prior to radical surgery improves survival in patients with adenocarcinoma of the oesophagus. Neoadjuvant CRT but not chemotherapy alone is also beneficial for patients with squamous cell carcinoma. Definitive CRT has emerged as a useful option for the treatment of resectable squamous cell carcinoma of the oesophagus, avoiding potential surgical morbidity and mortality for most patients, with salvage surgery reserved for those with persistent disease. In this review, we focus on the pharmacotherapy of resectable oesophageal and oesophagogastric junction cancers and how clinical trials and meta-analyses inform current clinical practice.     

Immunosuppressive strategies and management

<正>Advances in immunosuppressive therapy have significantly improved short-term allograft and patient survival.However,chronic allograft failure,antibody mediated rejection,recurrent diseases and immunosuppressive drug associated adverse effects remain serious barriers to long-term survival and quality of life.New immunosuppressive agents and protocols are being evaluated to combat these problems.Importantly, clinicians must work to manage post-transplant complications and avoid complex medication regimens,which will potentiate drug interactions and non-compliance.     

Crisis management strategies.

This paper discusses the different facets of crisis as experienced within the pharmaceutical industry but which are also prevalent throughout other industries. It highlights the importance of early identification and management of crises and issues, which in return are strongly intertwined with a fundamental positive internal corporate climate. A corporate philosophy should always embrace crisis management with the attitude of 'when' and not 'if'; therefore, a company should act today and not tomorrow once a crisis is on its doorstep. Preparation is of utmost importance and there are several items that can be addressed even before a crisis has arisen. Further, this paper also provides guidance on how to deal with the media, what to do and what not to do, and how to appoint the appropriate spokesperson. In this era of fast exchange of information, crisis, which previously may have stayed behind corporate doors, may not do so any longer. Image is very important and should therefore not be risked. Crisis and issue management should therefore be integrated in every company's philosophy and standard operating procedures.