Current Drug Therapy - Volume 5, Issue 1, 2010

The cost of health care is ever increasing and absorbing larger portions of national budgets. This issue has recently come into sharp focus in the United States with the debates on health care reform. Other countries are not immune from this issue. Those that have comprehensive health care systems are struggling with ever increasing cost, and many countries with more limited resources are trying to find ways to deliver even basic health care. There are many reasons for the escalating costs of health care, and if solutions are to be found, they will likely take many forms. One “problem” with health care is that many of the drugs we use are intended for wide patient populations, with the thought that if it does not work; physicians and patients will switch to something else. For patients who respond, this approach works well, but for those who do not, it leads to delay in therapy, adverse reactions without benefit, and a waste of money. One of the potential “ solutions” to this predicament is targeted therapy. This is not a new concept, and was certainly a goal of pharmaceutical development long before the current debate on healthcare. In almost every disease and therapy, there are some patients who respond, and some who do not; some patients who tolerate the therapy, and others not. The goal is to identify patients who are most likely to benefit with the lowest risk of adverse drug reactions. In some areas, especially chemotherapy, there have been marked successes in getting the right drug to the right patient. In other areas, success has been more limited, largely because understanding of the pathophysiology of disease is more limited, or it is not clear how and why patients differ in their responses. The reasons for these differences in response and tolerability appear to be largely related to genetics, although environmental and cultural factors may also play a role. As we understand more about the interplay between genetic variability in health and disease, we will be in a better position to target drugs to disorders in specific patients, rather than entire populations. What does this have to do with Current Drug Therapy? Even in this issue and we can expect more and more in the future, we will see articles describing therapies for selected groups of patients and individuals with clearly defined characteristics, thus delivering the right drug to the right patient.

Chordomas are relatively rare, slowly growing primary tumors of bone that arise from embryonic remnants of the notochord. These neoplasms typically occur in the axial skeleton mainly in the skull base (about 35%) and sacral region (about 50%) and have an overall peak distribution in patients aged 55-65 years. Chordomas are divided into conventional (the most common type), chondroid, and dedifferentiated types. Aggressive initial therapy, based on radical-maximal surgery followed by post-operative irradiation, improves overall outcome. Patients who relapse locally have a poor prognosis but both radiation and surgery can be used as salvage therapy. Radiation therapy alone may also be used in order to treat some patients with advanced, inoperable lesions or local recurrence. Proton beam irradiation has been reported as a very active form of irradiation for its peculiar physical properties. Chordomas are reported as tumors non sensitive to chemotherapy, even though anecdotal reports have been shown some sensitivity to molecularly targeted therapies.

Retigabine is a new anticonvulsant in clinical development, which activates neuronal M-current by opening voltage-gated potassium channels (KCNQ2/3 and KCNQ3/5). Retigabine had demonstrated potent anticonvulsant activity in various animal models of epileptic seizures including partial and generalized seizure models as well as status epilepticus model. Up to date, three pivotal clinical studies had been completed in patients with partial seizures as an adjunctive therapy. These studies showed that retigabine doses of 600-1200 mg/day (200-400 mg three times daily) were associated with significant reduction in seizure frequency when compared with placebo. Retigabine was generally well tolerated and most commonly reported adverse events were CNS-related (i.e. dizziness and confusion) in clinical trials. This article reviewed retigabine's primary mechanism of action, pharmacokinetics, and preclinical data as well as its efficacy and safety in patients with epilepsy.

Systemic chemotherapy for cancer of the urothelial tract is used according to two main strategies. Neoadjuvant or adjuvant treatment combined with surgery and/or radiotherapy is aimed at cure of localised disease whilst treatment for advanced incurable disease allows for improved survival and palliation of symptoms. Cisplatin based combination regimens represent the standard of care in both of these settings and incorporation of gemcitabine has allowed for improvements in tolerability over older drugs. However, despite high objective response rates, impact on survival is modest. Targeted agents are now being incorporated into early phase clinical trials. These exciting new strategies hold promise for improved efficacy but with new challenges regarding toxicity profiles. This review will describe current evidence for the use of systemic chemotherapy for urothelial cancer and the state of the research evidence for use of the newer targeted agents.

In the past few years accumulating evidence involved chromosomal instability and the subsequent aneuploidy that it generates in tumor formation. Moreover, the misregulation of most of the proteins involved in the mitotic checkpoint as well as kinetochore assembly has proven to have tumorigenic potential in vivo. Thus, the overexpression of Ndc80/Hec1, an outer kinetochore protein involved in spindle assembly checkpoint (SAC) recruitment, has been shown to induce tumor formation in different organs. Since Ndc80/Hec1 is a protein “ highly expressed in cancer” , it is an attractive target that can be used for cancer therapy. In this direction, several strategies aiming to in vivo block this complex structure and activity are being developed, and some of them have demonstrated to have tumor growth inhibition potential. These therapies represent a potential interesting approach for the treatment of malignancies where Ndc80/Hec1 expression is upregulated. Here we will discuss different aspects of Ndc80/Hec1 biology, its role in kinetochore assembly and spindle checkpoint, and its importance as a potential therapeutical target.

The heart and vascular system represent major targets of the thyroid hormone action, and marked changes occur in cardiac electro-mechanical function of patients with hyper-hypothyroidism. Thyroid hormones exert their effects through both genomic (nuclear) and nongenomic (extranuclear) mechanisms. Understanding the cellular mechanisms of thyroid hormone action on the heart and cardiovascular system is the basis to explain the changes in cardiac output, cardiac contractility, blood pressure, vascular resistance, and rhythm abnormalities secondary to thyroid dysfunction. Not only overt, but also subclinical thyroid diseases have been associated with systolic and diastolic cardiac abnormalities, and with alterations of well known cardiovascular risk factors. Moreover, the early diagnosis and treatment of thyroid diseases restore to normal most of the cardiovascular changes. Nowadays, it is becoming increasingly evident that, like a vicious circle, acute and chronic cardiovascular diseases may influence thyroid hormone metabolism, which, in turn, can contribute to cardiovascular impairment progression.

As the indications for recombinant human growth hormone (r-hGH) treatment have expanded, the number of patients receiving r-hGH has increased and injectable delivery of r-hGH is likely to be required for the foreseeable future. Continued innovations in the ease of use, safety and reliability of r-hGH devices have already gone some way to making GH treatment less stressful for patients, both physically and psychologically. Adherence with r-hGH remains a problem, which may be alleviated by offering free patient choice. In addition development of electronic auto-injectors now also provides the potential for monitoring adherence both for healthcare professionals, and also aiding patients in administering and monitoring their own GH injections.

Critical illness is a pathophysiological stress response that typically requires mechanical ventilation and hemodynamic support in an intensive care unit (ICU). Allostatic mechanisms tailor the critically ill state and eventually downregulate the stress response. Failure to downregulate the stress response can lead to increased morbidity and mortality. In general, ICU care focuses on component organ system physiology and prioritizes cardiopulmonary function. However, vast knowledge gaps exist in understanding why some patients simply fail to recover from a prolonged critical illness condition. In this review, we present an integrative physiology approach to the metabolic care in critical illness with an emphasis on skeletal allostasis. In particular, we discuss the different allostatic responses and their effects on bone in acute, prolonged, and chronic critical illness, currently available clinical interventions targeting skeletal remodeling, and emergent biological therapies with skeletal effects. It is hoped that by shifting the paradigm to a systems approach, some of the significant knowledge gaps can be closed and critical illness outcomes can be improved.

Introduction: Little is known about the effectiveness of various interferon regimes in patients with chronic hepatitis C in every day clinical practice. Therefore, we conducted a retrospective evaluation and analysis of all therapy results from patients treated with interferon in our general care hospital during the last 12 years. Patients and methods: 108 patients (66 men, 42 women) with bioptically confirmed hepatitis C and HCV-RNA positivity received and completed interferon therapy. Therapy consisted of interferon-α (IFN-α, for 48 weeks; group A, n=22), IFN-α plus ribavirin (for 48 weeks; group B, n=32) or pegylated IFN-α (PEG-IFN-α) plus ribavirin (for 24 weeks for genotypes 2 and 3, and 48 weeks for genotypes 1 and 4; group C, n=54). Virological response (HCV negativity) at end the of treatment as well as after follow-up of 24 weeks were analyzed. Results: In group A (100 % genotype 1), virological response at the end of treatment was 36.4 %, while in group B (100 % genotypes 2 and 3) it was 59.4 % and in group C (57.4 % genotype 1) 77.8 % (p≤ 0.05). In group A (IFN-α), SVR was 10.5 %, in group B (IFN-α/R) 45.0 %, and the overall SVR in group C (PEG-IFN-α/R) was 63.3 % (p≤ 0.05). Regarding SVR for genotype 1, PEG-IFN-α/R outmatched monotherapy with IFN-α (10.5 % vs. 50.0 %; p≤ 0.05), and for genotype 2 and 3, therapy with IFN-α/R (45.0 vs. 77.8 % p≤ 0.05). Conclusion: For group A (IFN-α) and group C (PEG-IFN-α/R), our therapy results were comparable to the findings of randomized controlled studies, whereas results from group B (IFN-α/R) were significantly lower compared to the virological response rates of these studies. Nevertheless, in patients with chronic hepatitis C, good treatment results may be achieved in every day clinical practice outside randomized controlled studies.

Breakthrough pain (BP) is a common problem in patients with cancer and is associated with significant morbidity in this group of patients. BP has been defined as a transitory increase in pain intensity that occurs either spontaneously, or in relation to a specific predictable or unpredictable trigger, despite relatively stable and adequately controlled background pain. A well understood subtype of BP is incident pain, which is due to movement and commonly associated with bone metastases or fractures. These episodes are associated with a functional impairment on measures of mood and anxiety, and on scales of pain interferences with function. A comprehensive pain assessment is recommended including frequency and duration of each episode, intensity, precipitating factors, previous and current pain treatments for baseline (persistent) pain, and their effectiveness. Onset and peak intensity, location, quality and predictability, and factors that precipitated them or provided relief once they occurred, or able to prevent them should also be recorded (by the patient). Given that different subtypes of BP exist, different therapeutic approaches are individually required, optimizing or assembling pre-emptive drugs for the prevention of the events. The availability of supplemental doses of oral opioids in addition to the continuous analgesic medication is the main treatment suggested to manage pain flares. An oral dose form can take a longer time to relieve pain, with peak concentrations achieved within 30-45 minutes. As pain relief is usually required urgently, therefore, routes of administration designed to deliver drugs rapidly are often chosen. Studies of oral transmucosal fentanyl citrate (OTFC) have shown that this approach produces a faster onset of relief and a greater degree of pain relief than the oral morphine, at 15, 30, and 60 min. The choice of the opioid dose to be prescribed as needed remains controversial. New delivery systems have been developed, including the effervescent technology to provide faster pain relief. Sublingual and intranasal administration of fentanyl will soon be introduced in the market to provide fast delivery of fentanyl.

Extrapulmonary tuberculosis refers to disease other than the lungs. The recent pandemic of Human Immunodeficiency Virus (HIV) and Acquired Immunodeficiency Syndrome (AIDS) has changed the epidemiology of tuberculosis and has once again brought extrapulmonary tuberculosis into the limelight. Over the last two decades the incidence of extrapulmonary tuberculosis has increased at a faster rate than that of pulmonary tuberculosis. The clinical manifestations of extrapulmonary tuberculosis are mostly nonspecific and insidious, resulting in delay of the diagnosis. Extrapulmonary tuberculosis is usually paucibacillary and any treatment regimen that is effective for treating pulmonary tuberculosis is also likely to be effective for the treatment of extrapulmonary tuberculosis. Short-course therapy is mostly suitable for most patients with extrapulmonary tuberculosis, but patients having HIV infection require longer treatment. Extrapulmonary tuberculosis is a persistent problem around the world and is becoming more prevalent as the number of AIDS patients is increased. A high index of suspicion is require for diagnosis and treatment of extrapulmonary tuberculosis, since extrapulmonary tuberculosis can involve any organ system. In this review an attempt has been made to provide a critical overview of the management and control of more commonly encountered forms of extrapulmonary tuberculosis.