Genetic mutations that cause specific lysosomal protein deficiencies account for more than 45 Lysosomal Storage Diseases (LSDs), mostly pre-adult disorders which are associated with neurological symptoms and mental retardation. Interestingly, such diseases are often characterized by intracellular deposition and protein aggregation, events also found in age-related neurodegenerative diseases. During the past twenty years, different approaches have been introduced for the treatment of these disorders, several of which are now in routine clinical use or clinical trials. Among them, enzyme replacement therapy (ERT) represented a major progress. However, the usefulness of ERT is limited due to the fact that enzyme distribution is insufficient and treatment costs are very high. A further novel therapeutic option for LSDs is based on the use of small molecules, that can either inhibit a key enzyme which is responsible for substrate synthesis (substrate reduction) or act as a chaperone to increase the residual activity of the lysosomal enzyme (pharmacological chaperones). In addition recently various gene therapy approaches have been developed, mostly based on adeno-associated and lentiviral vectors, and strategies based on stem cells administration are beginning their route. This review provides an update of the status of research on LSDs therapeutic approaches, including recent patents in the field.
Neurodegenerative diseases constitute a major public health issue due to an increasingly aged population as a consequence of generally improved medical care and demographic changes. Current drug treatment of Alzheimer's disease (AD), the most prevalent dementia, with cholinesterase inhibitors or NMDA antagonists has demonstrated very modest, symptomatic efficacy, leaving an unmet medical need for new, more effective therapies. Drug development efforts for AD in the last two decades have primarily focused on targets defined by the amyloid cascade hypothesis, so far with disappointing results. In contrast, tau-based strategies have received little attention until recently despite that the presence of extensive tau pathology is central to the disease. The discovery of mutations within the tau gene that cause fronto-temporal dementia demonstrated that tau dysfunction, in the absence of amyloid pathology, was sufficient to cause neuronal loss and clinical dementia. This review focuses on emerging therapeutic strategies aimed at treating the underlying causes of the tau pathology in tauopathies and AD, including some targets with significant potential in the field and which might be on the verge of providing new treatment paradigms within the coming years. Among those strategies, immunotherapy approaches will be mostly discussed. An update on 2010 patents regarding different aspects of tau-based therapeutic strategies is also provided.
Cancers of the brain are intrinsically more complicated to treat than systemic malignancies due to the unique anatomical features of the brain. The blood-brain barrier prevents chemotherapeutic agents from reaching brain neoplasms, and angiogenesis occurs as the metabolic needs of the tumour increase, thus further complicating treatment. The newly formed blood vessels form the blood-tumour barrier and are distinct from the blood-brain barrier in that they are more permeable. Being more permeable, these abnormal blood vessels lead to the formation of peri-tumoural edema, which is the cause of much morbidity and mortality associated with central nervous system neoplasms. While the cause of the increased permeability is unclear, kinins have been implicated in regulating the permeability of normal vasculature. Kinins are also known to exert many inflammatory actions affecting both normal and angiogenic blood vessels, as well as tumour cells. The vasodilatory and vascular permeabilizing effects of kinins, and particularly bradykinin and substance P, have been investigated with regard to delivery of chemotherapeutic agents to neoplastic brain tissue through both vascular barriers. In contrast, kinin receptor antagonists have been found to exert effects on tumour cells that result in decreased angiogenesis, tumour cell motility and growth. Thus, many recent patents describe kinin activity on brain vasculature, which may play an integral role in the development of treatments for malignancies in the central nervous system through amelioration of angiogenesis. In conjunction, patents that discuss the ability of kinins to decrease tumour cell migration and proliferation demonstrate that kinins may offer novel approaches to brain tumour therapy in the future.
The large number of randomized controlled clinical trials on migraine have drawn the attention of some authors to the need to improve the design of such trials. In particular, adequate methodology is a critical issue in their planning and execution, as different methodological approaches can translate into different results. The side-effects observed in both the active medication arm and the placebo arm - considering anti-migraine randomized clinical trials - are often influenced by non specific factors. This issue can be quantified by using a systematic review approach to study the rates of adverse events reported in the placebo arms of clinical trials. Such a study requires increased standardization of the methods used to collect adverse data in clinical trials. This focused review article provides a critical re-analysis of the results obtained, by our group, in a recent systematic review of adverse events reported in the placebo groups of clinical trials for three classes of anti-migraine drugs: NSAIDs, triptans and anticonvulsants [Amanzio et al., 2009]. We consider the need for caution in interpreting side-effect profiles of the different placebo groups. In particular, since the side-effects observed in both the active medication and placebo arms of randomized clinical trials are often influenced by patients and investigators expectations, the nocebo phenomenon may help to understand the occurrence of (adverse) non-specific side effects observed in these groups. We also discuss the importance of evaluating the role of contributing factors in the results obtained, such as the need for the examiner to be blind to the expected side-effects of the drug being evaluated and a better rationalization of informed consent in order to avoid the occurrence of negative expectations in patients, aimed at preventing negative expectation effects among both investigators and patients. Currently, there is one patented design for investigating reductions in the placebo effect in controlled clinical trials. This paper discusses how these ideas may be helpful in the assessment of adverse events in active and placebo groups.
Erection is a neurovascular event characterized by the tumescence of the cavernous bodies that relies upon integration of neural and humoral mechanisms requiring the participation of autonomic and somatic nerves and the integration of numerous spinal and supraspinal sites. Erectile dysfunction (ED) is a highly prevalent problem increasing with age, as well as the major mens sexual concern. Significant advances in the pharmacological treatment of ED have occurred in recent years, most notably after the introduction of sildenafil, the first oral selective phosphodiesterase type 5 inhibitor. Nevertheless, many other oral, local and surgical treatments are available and their efficacy and safety depend on the specific cases. This review provides a comprehensive description of both currently available neurogenic ED treatments and most promising future therapies, including assigned patents.
Alzheimer's disease is the most common form of dementia. Alzheimer's disease will be responsible for an enormous burden on the individual and the society, as with the aging of the population, the incidence and the prevalence will grow. Presently, the drugs used in Alzheimer's disease are only effective symptomatically and improve functioning. They do not halt the progression of the disease. With the recent advances in our understanding of the pathogenesis of this disease, there have been tremendous advances in the clinical trials of compounds that can modify the disease process. Numerous therapeutic interventions and neuroprotective approaches are also in trial phase. It seems that in near future some of these compounds may be found effective and safe for use in this disease there by reducing the incidence of this disease in years to come, thereby lessen the burden due to it. In this article various compounds that can modify the course of the disease are discussed. Some recent patents and inventions for the treatment of Alzheimer's disease have also been discussed.