Inhaler devices: what remains to be done?

The 1000 Years of Pharmaceutical Aerosols Conference convened posing the question; "what remains to be done?" When applying this question to the topic of inhaler devices, two hugely different perspectives could be taken. On the one hand, it could be argued that because there is an array of delivery systems available and the industry, prescribing physicians and patients alike have considerable choice, why would we believe it necessary to do anything further? On the other hand, as an industry, we are constantly reminded by our "customers" that the inhaler devices available are less than adequate, and in some cases woefully inadequate, that they are not "patient" friendly, not intuitive to use and importantly do nothing to encourage the patient to take the medication as intended and as prescribed. So, taking the second point of view as more reflective of reality--the Voice of the Customer--our starting point must be that there is still much to do in the field of inhaler devices. The purpose of this article is to outline some key basic requirements for inhaler design and perhaps to question some of the entrenched thinking that has pervaded inhaler product design for too many years.     

Pulmonary formulations: what remains to be done?

Significant advances have been made in the last 50 years in developing safe and efficacious aerosol formulations for pulmonary delivery. The key to future innovation may lie at the interface between biology and particle engineering. Improved understanding of biological processes including particle clearance, cellular targeting, intracellular trafficking, and drug absorption are needed to better design formulations that deliver to the "target" with the optimal balance of pharmacodynamic, pharmacokinetic, and safety profiles. More specifically, continued advances are needed in the development of: (1) controlled release formulations; (2) formulations with improved regional targeting within the lungs (e.g., airway versus alveoli and vice versa); (3) formulations containing active targeting moieties; (4) formulation strategies for improving the systemic bioavailability of inhaled macromolecules; (5) formulation strategies for delivering macromolecules, including siRNA and DNA into cells; and (f) formulations with improved dose consistency. It is likely that such innovation will require the development of novel excipients and particle engineering strategies. Future innovation must also take into the account the changing marketplace and the diverse set of customers (patient, healthcare professional, heath authorities, payers, and politicians) who must be satisfied. The pharmacoeconomics of new delivery systems will be closely scrutinized, so it is imperative that cost factors be taken into account. Otherwise, the new technology option may overshoot the evolving inhalation marketplace.     

Why might statins prevent venous thromboembolism: what needs to be done to know more?

Dyslipidaemia may be a risk factor for venous thromboembolism and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) may be protective. The current review outlines the cumulative evidence from both the basic and epidemiologic sciences for why this might be so and offers some directions for future research.     

Colorectal polyps in the elderly: what should be done?

Colorectal cancer is an important cause of morbidity and mortality among Western nations, and is more common in the elderly than in younger individuals. With the general acceptance of the adenoma-carcinoma sequence, the current consideration is that colorectal cancer is preventable if all adenomas are removed before they have the chance to progress to cancer. To that end, physicians should now advocate screening for colorectal cancer and through this effort a large number of patients with adenomatous polyps will be discovered. It is important to understand the strategy in dealing with this growing population of patients with adenomas. After an initial polypectomy, patients with adenomas should be entered into a surveillance program to detect and remove recurrent adenomas. Recommended surveillance intervals are shorter for patients with a family history of colorectal cancer, those with multiple adenomas (>2), large adenomas (> or = 1cm), or those whose adenomas have high-grade dysplasia, villous architecture, or that are cancerous. Effective chemoprevention would be a potential method of lengthening colonoscopic surveillance intervals. Unfortunately, no treatment has been found to be effective enough to alter our current surveillance practice. The only recommendation that can be made at this time for those patients with a history of colonic adenomas is to add 3 g/day of calcium carbonate to their diet, though its effect on adenoma recurrence is modest.     

Facilitating adherence to highly active antiretroviral therapy in children with HIV infection: what are the issues and what can be done?

Treatment of HIV infection with highly active antiretroviral therapy (HAART) requires sustained adherence to treatment to maintain efficacy. In pediatric patients, adherence to HAART represents a significant challenge for treated children and for their caregivers and healthcare providers. Many factors can affect adherence to HAART including: (i) factors related to the patient and his/her family; (ii) factors related to the drug/medication; and (iii) factors related to the healthcare system. Different strategies can be employed to tackle the specific obstacles identified in these three groups, and thus to facilitate adherence. Among the key interventions centered on the patient and his/her family are the tailoring of the HAART regimen to the daily activities of the child and his/her family, and the implementation of an intensive education program on adherence for the child and the caregiver, prior to starting the treatment. Specific medication-related problems (depending on drug pharmacokinetic and pharmacodynamic properties, taste and palatability, food interactions, etc.) exist; such problems can not be solved solely by clinicians or by families. Greater commitment of the pharmaceutical industry is needed, and innovative solutions have to be identified by clinicians in partnership with drug manufacturers. Furthermore, the development of an 'adherence strategy/program' can be recommended to all institutions working in pediatric HIV infection. Most of the necessary interventions to be included in such programs can be easily implemented, but they require trained and committed staff (and institutions), and time to be spent with patients and their caregivers.     

Inadequate pharmacotherapeutic data for drugs used in children: what can be done?

Although infants and children are affected by many acute and chronic diseases, nearly 80% of the drugs approved in the US for use in adults have not been labelled for paediatric use. This leads to the 'off-label' use of drugs which may produce suboptimal efficacy or harmful effects. Recent regulations proposed by the US Food and Drug Administration (FDA) require the industry to conduct paediatric studies in certain situations. However, some incentives will be provided to the industry to seek paediatric labelling. Paediatric practitioners and researchers will play an active role in conducting research and disseminating data about medication use in infants and children. However, increased funding is required for paediatric research. Industry, government, associations, academia and the public should work together to develop an agenda for action, with the goal of improving clinical outcomes and quality of life in infants and children.     

Neurofibromatosis and brainstem implants: what to do?

The histopathological changes in the temporal bones of one donor individual deceased for complications of neurofibromatosis type 2 are studied. The different modalities of presentation of neurofibromatosis and the criteria for the differential diagnosis are presented. The possibilities of the auditory brainstem implants in this pathology are discussed.     

Drugs, heart failure and quality of life: what are we achieving? What should we be trying to achieve?

This article is a review of chronic compensated congestive heart failure (CHF), with special reference to its clinical features and pathophysiology and recent advances in pharmacotherapy, including beta-blockers, loop diuretics, ACE inhibitors and angiotensin II receptor antagonists. Clinical problems related to elderly patients and multifaceted aspects of multidisciplinary approaches of medical care to these particular patients are also discussed with special emphasis on the aspect of improved quality of life associated with reduced mortality. Concepts of CHF have greatly changed over the past decades with regard to its pathophysiology, natural progression, mechanisms, causes of death, arrhythmias and treatment goals. Although the current most frequent aetiologies of CHF include coronary heart disease and dilated cardiomyopathy, hypertension has been revisited in a different way, and has been considered of pivotal importance in most recent trends and possibly in future perspectives. Nowadays, however, with the results of improved survival, alleviation of symptoms, improvement in functional capacity and prevention of associated complications including even left ventricular remodelling through various appropriate pharmacotherapies, patients with CHF are used to being physically and psychosocially more active than ever before. Thus, improvement of patients' quality of life and reduction of mortality have become of prime importance in achieving treatment goals. Another emerging aspect of CHF is aging itself, and special features in the medical care of elderly patients with CHF always have to be taken into consideration in reduction of hospital readmission along with improvement of morbidity and mortality. Despite advances in the treatment of CHF, it remains a common disease with a poor prognosis. Therefore, this review focuses on what we should be trying to achieve in reaching goals to reduce repeated hospital readmission and mortality, and increase social activity and quality of life, especially in elderly patients with CHF. In these clinical settings, educational strategies for patients and their family members should be emphasised. Multidisciplinary interventions by nurses and possibly other contributions from a widely available social support system might be effective in preventing repeated hospital readmissions of elderly patients with CHF. In this regard, special precautions have to be paid in the management of elderly patients to achieve effective treatment goals, and any treatment strategy has to be appropriately determined through a comprehensive assessment of patient clinical profiles. Multidisciplinary approaches to these problems have to be effectively utilised to improve patients' quality of life, while possibly reducing medical expenses.     

Heart regeneration: what cells to use and how?

Coronary artery disease (CAD) is the leading cause of death in modern societies. Recent achievements in the treatment of CAD including statins, ACE inhibitors, beta blockers, and interventional procedure improved the outcome of patients with CAD, but this conventional approach failed to control cardiovascular mortality. Nowadays, cells (stem cells) and their potential role in managing patients with heart disease is a field of intensive research. Various types of cells have been used for transplantation targeting heart regeneration, including bone marrow cells (BMCs), cardiac stem cells (CSCs), endothelial progenitor cells (EPCs), skeletal myoblasts (SMs), adipose stroma tissue cells (ATSCs), mesenchymal cells (MCs), and embryonic stem cells (ESCs). Several routes have been used to deliver these cells to human myocardium or to the coronary circulation such as, intracoronary injection, intravenous infusion, direct injection into the ventricular wall, or transepicardial/transendocardial infusions. Although the results of the recent clinical trials in this area are rather conflicting, these therapeutic approaches seem to be promising for the treatment of ischemic heart disease.