The fourth issue of volume two of Therapeutics and Clinical Risk Management contains
twelve review articles from international authors that address a broad range of current
and apposite topics within the remit of the journal.
Glaucoma is a multifactorial optic neuropathy that results in progressive vision loss
secondary to optic nerve atrophy and a reduction in retinal ganglion cells (RCGs).
Raised intraocular pressure (IOP) has been identified as a major risk factor in both
the development and progression of the condition. Hence, a primary aim of glaucoma
therapy is to effect a reduction in IOP to attenuate the risk of disease progression
and loss of vision; a strategy whose effectiveness has been demonstrated through recent
randomized, controlled clinical trials (RCTs). Brimonidine is the only selective alpha-adrenergic
receptor agonist currently approved for chronic use in glaucoma and has established
efficacy as mono-, adjunct, and replacement therapy in the treatment of ocular hypertension
and open-angle glaucoma. Louis Cantor opens this issue with a consideration of the
pharmacology, pharmacokinetics, and mechanism of action of topical brimonidine. Cantor's
review continues with an assessment of clinical trials of brimonidine in neuroprotection,
the primary goal of which is the attenuation of neuronal death and preservation of
physiological function; a strategy that enables treatment even in cases of unknown
etiology. In addition, the author discusses the different drug formulations available,
brimonidine's clinical efficacy in IOP reduction, and addresses issues of safety and
tolerability and patient acceptability and compliance.
Asthma is a complex syndrome, characterized by a variable degree of airway obstruction,
with many clinical phenotypes in both adults and children. Despite improvements in
asthma treatment and increased understanding of the underlying pathogenic mechanisms,
the incidence and prevalence of asthma have been rising worldwide. Asthma is now the
most common disease in westernized countries. Although the cause of the increase is
unknown, it is clear that environmental triggers play an important role. The majority
of allergic asthmatic children are sensitive to indoor allergens of which the house
dust mite (HDM) appears to be the most important environmental agent associated with
asthma. There have been many attempts to lessen the impact of asthma by reducing infestation
with HDM. However, several meta-analysis and review studies have suggested that simple
interventions do little to reduce HDM allergen levels. Vallance and colleagues have
reviewed whether HDM avoidance is efficacious in the treatment of asthma. In addition
to a comprehensive and critical review of the literature they also present findings
of their own experience with the association between HDM levels and asthma in Scotland,
which has the highest incidence of adolescent asthma in the world. Modern building
regulations in the UK have resulted in a warmer and more humid domestic environment,
which is the perfect microclimate for the proliferation of HDM. The authors point
out that the many studies designed to reduce the impact of asthma by reducing indoor
allergens, primarily HDM, have proved to be difficult and costly and their efficacy
has been unconvincing. They recommend an intervention strategy that uses the best
evidence-base from the most promising published methods, and to use this to impact
on building regulations to encourage change in the design, construction, and use patterns
of domestic buildings in the UK. Overall, the challenge appears to be to further refine
the interventions to reduce HDM levels so that positive clinical outcomes may be more
easily demonstrated.
Over the past thirty years, an outstanding combination of innovative clinical achievement
coupled with technological advancement and refinement has enabled the fields of fertility
medicine and research to experience significant leaps forward in both basic knowledge
and translational activity. In that time, assisted reproductive technologies (ART)
have resulted in the birth of over 2 million children worldwide and in vitro fertilization
(IVF) techniques have developed to the level of a routine procedure can be performed
in 10 to 15 minutes in a physician's consulting room without the need for hospitalization
or general anesthesia. Wang and Sauer review the rapid and exciting developments in
the field since the pioneering birth of Louise Brown in 1978 under the guidance of
Patrick Steptoe and Robert Edwards at Oldham General Hospital and offer an intriguing
insight into the evolution of modern techniques for addressing the needs of infertile
couples. The authors present an overview of the initial work on IVF during the 1970s
that focused on women who presented with tubal disease. They then move on to discuss
the advancements of the mid-1980s amongst women with natural or premature ovarian
failure and a discussion of the increasing emphasis on women of advanced reproductive
age and the evolving role of embryo cryopreservation. The developments of gamete intrafallopian
transfer (GIFT) and zygote intrafallopian transfer (ZIFT) are considered and compared,
together with the ooctye retrieval technique of transvaginal ultrasound-guided transvaginal
follicle aspiration that rapidly became the procedure of choice following its introduction
in 1987. Until the late-1980s, male infertility remained a rate-limiting factor in
the overall success rate of fertility treatment. The authors highlight the role of
a number of techniques that were developed to address this situation, including partial
zona dissection (PZD) and subzonal insemination (SUZI). They then discuss the later
combined techniques of microepididymal sperm aspiration and intracytoplasmic sperm
injection (MESA-ICSI) and include an assessment of the relative developmental outcomes
of children born via ICSI and standard IVF procedures. An examination of the evolving
role of pre-implantation genetic diagnosis (PGD) includes the transition from polymerase
chain reaction (PCR) techniques to fluorescence in-situ hybridization (FISH) and a
consideration of expanding the role of PGD to disorders other than infertility, including
HLA-typing for stem cell donation and preservation of fertility amongst cancer patients.
The authors conclude with the observation that, in spite of the significant technological
advances of the past three decades, continuing intense enquiry is required in order
to assess the long-term effects of a technique whose eldest beneficiary is only 27
years old.
Rheumatoid arthritis (RA) is a prevalent condition whose clinical sequelae can result
in significant reductions in functional capacity and quality of life with considerable
attendant debilitating impact upon psychological health. Although there have been
recent therapeutic advances, a number of challenges remain: only a percentage of patients
will respond to the disease-modifying anti-rheumatic drugs (DMARDs); toxicity and/or
resistance dictate that another sub-group requires combinations of DMARDs and the
anti-tumor necrosis factor-α (TNF-α) agents; and further subgroups gain no worthwhile
benefit from any of the existing therapies. There is a growing body of evidence to
support the role of T-cell activation in the development and progression of RA. Abatacept
is a soluble fusion protein that comprises the extracellular domain of human CTLA4
and a fragment of the Fc portion of human immunoglobulin G1 (IgG1) that targets T-cell
activation. Edward Vital and Paul Emery review abatacept's mechanism of action and
studies examining its efficacy and safety. The authors present an overview of the
rationale for co-stimulation blockade in RA, pharmacokinetic data from in vitro studies
and a Phase I dose-finding clinical trial, and immunological activity and immunogenicity.
A review of efficacy studies includes a discussion of relevant outcome measures including
the American College of Rheumatology response rates, the Disease Activity Score 28
(DAS28), and the Modified Stanford Health Assessment Questionnaire (mHAQ). They further
discuss studies in patients who do not respond to DMARDs, analyse findings relating
to disease activity and structural change, and functional capacity and quality of
life. In considering studies in patients who did not respond to anti-TNF-α agents,
the authors discuss the Phase III ATTAIN trial including primary and secondary end-points
for disease activity and function and their correlations with patients’ own perceived
improvements. Considerable data from Phase III trials indicate that abatacept is both
safe and effective and support its use in the management of RA, in particular amongst
patients who do not respond to DMARDs and TNF-α agents. There is a brief discussion
of abatacept's safety either as monotherapy or when administered in combination with
other RA therapies (the ASSURE trial) and the authors conclude with the opinion that
abatacept therapy in RA will represent the primary clinical application of co-stimulation
blockade with the potential to demonstrate a role in the treatment of a broad range
of immunological disorders.
The myelodysplastic syndromes (MDS) constitute a group of acquired disorders of the
bone marrow caused by defective clonal stem cells. Together with chronic lymphocytic
leukemia, they represent the most frequently occurring hematological malignancy, with
an incidence of 15 to 50 new cases/100 000/year. MDS are characterized by advancing
bone marrow failure, increased risk of life-threatening infection, and myeloid cell
abnormalities. Although the natural history of MDS is variable, approximately 30%
of cases transform into acute myeloblastic leukemia and there are high rates of morbidity
and mortality secondary most commonly to bleeding and infection. MDS present as a
variety of sub-types, the number of which is dependent upon the classification system:
the French American British (FAB) system identifies five morphological sub-groups
with prognostic importance; the World Health Organization system includes seven subgroups;
and the International Prognostic Scoring System identifies those patients at enhanced
risk of transformation. Allogenic stem cell transplantation represents the only curative
therapy but is only suitable in a minority of cases, the remainder of patients being
managed conservatively through combinations of infection prophylaxis, blood and platelet
transfusions, and growth factors such as erythropoietin and granulocyte-colony stimulating
factor. Emerging candidate therapies include the methyltransferase inhibitors (MTI)
such as azacytidine, a chemically synthesized nucleoside analogue that has the potential
to reverse gene methylation and is currently the only drug in this class with US Food
and Drug Administration approval for use in all subtypes of MDS. Raj and Mufti outline
and review the role of and clinical evidence for azacytidine in MDS. They begin with
an introduction to classification procedure and the role of epigenetics in assessing
disease progression and risk. They then move onto a discussion of the rationale for
azacytidine in MDS, and its chemical structure and pharmacokinetics. An analysis of
the three successive cancer and Leukemia Group B (CALGB) studies includes discussion
of the Phase III randomized controlled trial that demonstrated azacytidine's effectiveness
relative to the best model of supportive care. The authors also summarize the clinical
response, relapses and toxicity, the drug's mechanism of action in MDS, and duration
of therapy. They conclude with a brief discussion of other MTI's in MDS, the role
of combination therapy, and future directions in the management of this group of hematological
conditions.
Psoriatic arthritis (PsA) is a progressive, unpleasant and potentially debilitating
inflammatory arthritis characterized by joint pain and swelling, fatigue and moderate-to-severe
skin lesions. The condition can result in severe joint erosion and attendant significant
reduction in functional capacity and quality of life. It is frequently misdiagnosed
and, together with a lack of disease classification guidelines and consensus-led diagnostic
criteria, this hampers accurate estimates of prevalence and incidence. Although the
etiological and pathophysiological factors that contribute to development of PsA remain
to be fully elucidated, the condition seems to arise from a complex interaction between
genes, environment, and the immune system. In particular, developing insights into
the fundamental immunological mechanisms of the disease highlighted the role of TNF-α
in mediating the pathogenesis of PsA and led to the development of a number of anti-TNF-α
drugs for PsA therapy. Philip Mease reviews the role of infliximab, a chimeric, human–mouse
IgG1 monoclonal antibody, in the treatment of PsA. He discusses its clinical presentation
and sub-types together with the etiology and pathophysiology of the condition before
moving onto current treatment approaches. He outlines the traditional role of the
non-steroidal anti-inflammatory drugs (NSAIDS) and DMARDs and notes that both classes
of drugs are hampered by inadequate control, failure to halt disease progression and
poor compliance rates due to side-effects and lack of efficacy. His discussion of
infliximab includes thorough discussions of the IMPACT and IMPACT II trials and the
subsequent multi-centre, randomized, double-blind, placebo-controlled Phase III studies,
SPIRIT in the US and EXPRESS in Europe. The author concludes with a consideration
of other TNF-α agents and the newer T-cell-directed agents for PsA treatment.
Skin and soft tissue infections (SSTIs) are one of the most frequent sites of bacterial
infection and concomitantly, in the US, rate as one of the most common reasons for
both institution of antibiotic therapy and admission to hospital. Complicated SSTIs
(cSSTIs) are by definition more inherently serious. They represent a significant clinical
challenge, not only as they frequently present with associated bacteremia and sepsis
but also because the underlying pathologies that predispose to their development –
such as host immunosuppression, surgery, diabetes mellitus, and peripheral vascular
disease – may mean they are less sensitive to standard antibiotic therapy and require
in-patient surgical intervention and parenterally administered drug regimens. Management
of cSSTIs is further complicated by the range of bacterial pathogens and constantly
evolving resistance to available antibiotics. Meropenem is a broad-spectrum antibiotic
of the carbapenem class that demonstrates excellent therapeutic activity across a
range of pathogens commonly associated with cSSTIs. In the first of two reviews of
the treatment of cSSTIs, Douglas Fish presents a comprehensive review of meropenem
and its use in these conditions. He begins with an overview of the clinical characteristics
of cSSTIs, their associated bacterial etiology and the considerations underpinning
appropriate therapeutic interventions. The author provides a thorough review of meopenem
including a consideration of its antibacterial activity and pharmacokinetics and pharmacodynamics
before moving onto a discussion of the clinical data in which he provides an in-depth
critique of the largest and most recent study. In discussing its role in cSSTIs, he
highlights its excellent activity against the bacteria most commonly associated with
these conditions; proven clinical efficacy; low toxicity; competitive wholesale pricing;
and possible advantages relative to other available therapeutic agents; and concludes
with a personal recommendation regarding an appropriate dosing regimen.
In the second review of antibiotic therapy in the treatment of SSTIs, David Guay addresses
the role of moxifloxacin, one of the newer members of the fluoroquinone class of antimicrobials.
He comprehensively reviews the in vitro antimicrobial activity of moxifloxacin and
underscores the fact that it demonstrates significantly greater in vitro activity
against potential Gram-positive and Gram-negative aerobic pathogens in SSSIs, relative
to earlier quinolones such as ciprofloxacin. From a pharmacokinetic perspective, moxifloxacin
demonstrates good penetration of muscle, subcutaneous adipose tissue, and inflammatory
blister fluid and the author provides a table of comparative pharmacokinetic parameters
in healthy adult volunteers. The results of clinical trials are presented in light
of the limitations intrinsic to their interpretation: the problems inherent in designing
trials of SSTIs that are both rigorous and reproducible; the majority of studies were
underpowered to avoid Type II statistical errors; and the consequent lack of generalization
of results. In addition, the author addresses issues of safety and potential drug–drug
interactions. Of these, the sole pharmacodynamic interaction with potential clinical
relevance is the additive electrophysiological effects of moxifloxacin when combined
with other drugs with the ability to prolong the QTc interval. However, a lack of
rigorous epidemiological and multi-dose studies at present precludes an assessment
of the clinical relevance of this potential effect.
Pancreatic cancer is a highly aggressive malignancy that is, for the most part, chemo-refractory
and has a five-year survival rate of approximately 2%; most patients present with
unresectable disease and survive for less than one year after diagnosis. Gemcitabine
monotherapy was adopted worldwide as a standard of care in the therapy of advanced
pancreatic cancer following a randomized controlled trial in which it showed significantly
enhanced clinical benefit and a modest increase in median survival relative to 5-fluorouracil.
However, continuing poor prognosis coupled with conflicting data from trials of combination
therapy clearly indicate the need to continue the search for new and more effective
therapeutic strategies. The last ten years have seen a considerable accrual of knowledge
in the molecular pathogenesis of pancreatic cancer and the identification and development
of novel potential therapies has arisen from our enhanced understanding of the tumor/stroma/host
axis and the interface with genetics and epigenetics. Anomalies in signal transduction
via the epidermal growth factor receptor (EGFR) exert influence at several key stages
of tumor development including proliferation, susceptibility to apoptosis, invasion,
angiongensis, and metastasis. Exploitation of this pathway is showing promise in the
treatment of advanced pancreatic cancer, primarily through the use of monoclonal antibodies
against the extracellular domain and small molecule tyrosine kinase inhibitors (TKIs)
that compete at the ATP binding site of the tyrosine kinase domain.
Erlotinib is a quinazoline-based small molecule TKI with high selectivity against
the EGFR. Naureen Starling and colleagues introduce the role of EGFR signaling in
pancreatic cancer and give an overview of the pre-clinical evaluation of erlotinib
in which they discuss the elucidation of the pharmacology and preliminary pharmacokinetics
of erlotinib through early phase studies. Combination therapy offers considerable
benefit in the management of cancer through the modulation of resistance, synergistic
effects of combined drugs, and attendant potential for an enhanced effectiveness.
The authors review the clinical development of erlotinib/gemcitabine combination therapy
for the management of pancreatic cancer. They discuss the results of the National
Canadian Institute of Cancer international, multi-centre, randomised, placebo-controlled
Phase III trial and the conflicting data from the TRIBUTE and TALENT studies, noting
that the latter studies' failure to select for potential responders to EGFR TKIs attenuated
erlotinib's therapeutic effect. Two ongoing studies, TARGET and SWOG, are mentioned
briefly together with potential erlotinib-associated toxicity and the importance of
careful evidence-based patient selection. The authors conclude with the observation
that recent findings, although small, represent important progress and, notwithstanding
pharmacoeconomic and quality of life considerations, form the basis for future multi-targeted
approaches to a disease that is both aggressive and difficult to treat.
Pain is a frequent outcome of cancer and its treatment. Its prevalence and severity
are in part dependent upon the disease stage and the site of primary tumor and metastases,
with prevalence rates estimated at 30% amongst those patients who are being actively
treated for metastatic spread and 60% to 90% of patients with advanced disease. However,
in spite of the existence of incremental, validated, consensus-based guidelines for
analgesia, pain control in cancer is frequently sub-optimally managed. This appears
to be a result of a number of factors including concerns regarding tolerance, side
effects, and out-of-date knowledge amongst both health professionals and patients.
Opiates represent the preferred treatment strategy for palliation of severe pain amongst
cancer patients and their use is guided by the World Health Organization three-step
analgesia ladder, a flexible framework developed to assist in the appropriate application
of analgesic drugs. Mandala and colleagues address the question of how to optimize
the use of opiates in the palliation of cancer pain by focusing on four separate aspects
of therapy. Firstly, they consider how best to implement the use of opioids and make
two suggestions: (1) the necessity of appropriate assessment by an inter-disciplinary
team who can deliver a holistic approach to pain control; and (2) the introduction
of straightforward protocols or guidelines to further assist in management of symptoms.
Secondly, they consider approaches to optimize the use of morphine, which in spite
of being the most widely used and cost-effective opioid, is limited by poor systemic
availability of the orally administered drug that results in inter-individual variability
in the dose-response. The authors discuss thoroughly the dose-titration approach to
administration and give a brief overview of the role of spinal morphine. Thirdly,
they address the major clinical challenge of management of side effects (including
gastrointestinal and central nervous system) and suggest a four-step approach including
dose reduction, toxicity management, opioid rotation, and alternative routes of administration.
Lastly, they consider the role of other potent opioids including methadone, oxycodone,
and transdermal fentanyl.
The increase in antibiotic resistant strains of microorganisms worldwide continues
to be a major concern that highlights the necessity for the development of new and
more effective treatments. While the contribution of multi-resistant Gram-positive
pathogens continue to be a major problem in the hospital setting, the growing tendency
towards progressive shortening of hospitalization has led to community-acquired infections
involving Gram-positive cocci becoming more common. It is therefore of note that Roberto
Manfredi has provided a comprehensive review of the role of multi-antibiotic resistant
Gram-positive pathogens in both the hospital and community setting. The review considers
current guidelines for the management of these infections, particularly in compromised
individuals. Their effective management is hampered by the spectrum of available antimicrobial
compounds being significantly impaired in selection and clinical efficacy by the spread
of methicillin-resistant and more recently glycopeptide-resistant Gram-positive microbial
strains. In this regard the potential contribution of linezolid a novel oxazolidinone
derivative is described in terms of microbiological properties, clinical indications
and effectiveness together with tolerability, safety issues and pharmacoeconomic assessments.
Other important issues are also discussed including the usefulness of linezolid in
pediatric populations, the presence of Gram-negative pathogens necessitating the use
of combination therapy and the degree to which linezolid-resistance pathogens may
in time prove problematic.
Restless leg syndrome (RLS), also known as Ekbom's syndrome, is a prevalent sensorimotor
and sleep disorder characterized by sensations of discomfort deep within the legs
that can only be relieved by repetitive leg movements. The pathogenesis of RLS, is
probably a function of the interaction between a lack of systemic or brain iron and
inadequate subcortical dopaminergic neurotransmission. The condition has been clearly
defined since the mid-1940s; however, in spite of this it remains poorly recognized
and is notable for its frequent misdiagnosis and inadequate treatment. Cotter and
O’Keefe examine the factors that contribute to the condition being so frequently overlooked
(and that can result in a delay of over a decade for an accurate diagnosis); outline
contemporary approaches to its pathogenesis and treatment; and enumerate the benefits
to the patient of adequate diagnosis and management. In laying the groundwork for
our understanding of RLS, the authors elaborate upon the current diagnostic criteria,
including essential criteria and supportive and associated clinical features; address
a number of myths and misconceptions underlying the condition; and discuss why a diagnosis
of RLS should be considered important and managed accordingly. They also present a
succinct discussion of the therapeutic regimens available for the management of both
primary and secondary RLS and conclude with a brief summary of treatment options.