Contents

  • 1. Pharmacogenetics

  • 2. Cancer

  • 3. Cardiovascular Disorders

  • 4. CNS Disorders

  • 5. Dermatologic and Autoimmune Disorders

  • 6. Infectious Diseases

  • 7. Transplantation

  • 8. News from Other Sources

1. Pharmacogenetics

Polymorphism of Human Cytochrome P450 2D6 and Its Clinical Significance: Part I

Cytochrome P450 (CYP) 2D6 is one of the most investigated CYPs in relation to genetic polymorphism but accounts for only a small percentage of all hepatic CYPs (~2–4%). There is a large interindividual variation in the enzyme activity of CYP2D6. The enzyme is largely non-inducible and metabolizes ~25% of current drugs. Typical substrates for CYP2D6 are largely lipophilic bases and include some antidepressants, anti-psychotics, antiarrhythmics, antiemetics, β-adrenoceptor antagonists (β-blockers), and opioids. The CYP2D6 activity ranges considerably within a population and includes ultrarapid metabolizers (UMs), extensive metabolizers (EMs), intermediate metabolizers (IMs), and poor metabolizers (PMs). There is a considerable variability in the CYP2D6 allele distribution among different ethnic groups, resulting in variable percentages of PMs, IMs, Ems, and UMs in a given population.

To date, 74 allelic variants and a series of subvariants of the CYP2D6 gene have been reported, and the number of alleles is still growing. Among these are fully functional alleles, alleles with reduced function, and null (non-functional) alleles, which convey a wide range of enzyme activity, from no activity to ultrarapid metabolism of substrates. As a consequence, drug adverse effects or lack of drug effect may occur if standard doses are applied. The alleles *10, *17, *36, and *41 give rise to substrate-dependent decreased activity. Null alleles of CYP2D6 do not encode a functional protein, and there is no detectable residual enzymatic activity. It is clear that alleles *3, *4, *5, *6, *7, *8, *11, *12, *13, *14, *15, *16, *18, *19, *20, *21, *38, *40, *42, *44, *56, and *62 have no enzyme activity. They are responsible for the PM phenotype when present in homozygous or compound heterozygous constellations. These alleles are of clinical significance, as they often cause altered drug clearance and drug response. Among the most important variants are CYP2D6*2, *3, *4, *5, *10, *17, and *41. On the other hand, the CYP2D6 gene is subject to copy number variations that are often associated with the UM phenotype. Marked decreases in drug concentrations have been observed in UMs with tramadol, venlafaxine, morphine, mirtazapine, and metoprolol. The functional impact of CYP2D6 alleles may be substrate dependent. For example, CYP2D6*17 is generally considered as an allele with reduced function, but it displays remarkable variability in its activity toward substrates such as dextromethorphan, risperidone, codeine, and haloperidol.

The clinical consequence of the CYP2D6 polymorphism can be either occurrence of adverse drug reactions or altered drug response. Drugs that are most affected by CYP2D6 polymorphisms are commonly those in which CYP2D6 represents a substantial metabolic pathway either in the activation to form active metabolites or clearance of the agent. For example, encainide metabolites are more potent than the parent drug, and thus QRS prolongation is more apparent in EMs than in PMs. In contrast, propafenone is a more potent β-blocker than its metabolites, and the β-blocking activity during propafenone therapy is more prominent in PMs than in EMs, as the parent drug accumulates in PMs. Since flecainide is mainly eliminated through renal excretion, and both R- and S-flecainide possess equivalent potency for sodium channel inhibition, the CYP2D6 phenotype has a minor impact on the response to flecainide. Since the contribution of CYP2D6 is greater for metoprolol than for carvedilol, propranolol, and timolol, a stronger gene-dose effect is seen with this β-blocker, while such an effect is lesser or marginal with other β-blockers.

Concordant genotype-phenotype correlation provides a basis for predicting the phenotype based on genetic testing, which has the potential to achieve optimal pharmacotherapy. However, genotype testing for CYP2D6 is not routinely performed in clinical practice, and there is uncertainty regarding genotype-phenotype, gene-concentration, and gene-dose relationships. Further prospective studies on the clinical impact of CYP2D6-dependent metabolism of drugs are warranted in large cohorts of subjects.

Polymorphism of Human Cytochrome P450 2D6 and Its Clinical Significance: Part II

Part I of this article discussed the potential functional importance of genetic mutations and alleles of the human cytochrome P450 2D6 (CYP2D6) gene. The impact of CYP2D6 polymorphisms on the clearance of and response to a series of cardiovascular drugs was addressed. Since CYP2D6 plays a major role in the metabolism of a large number of other drugs, Part II of the article highlights the impact of CYP2D6 polymorphisms on the response to other groups of clinically used drugs.

Although clinical studies have observed a gene-dose effect for some tricyclic antidepressants, it is difficult to establish clear relationships of their pharmacokinetic and pharmacodynamic parameters to genetic variations of CYP2D6; therefore, dosage adjustment based on the CYP2D6 phenotype cannot be recommended at present. There is initial evidence for a gene-dose effect on commonly used selective serotonin reuptake inhibitors (SSRIs), but data on the effect of the CYP2D6 genotype/phenotype on the response to SSRIs and their adverse effects are scanty. Therefore, recommendations for dose adjustment of prescribed SSRIs based on the CYP2D6 genotype/phenotype may be premature.

A number of clinical studies have indicated that there are significant relationships between the CYP2D6 genotype and steady-state concentrations of perphenazine, zuclopenthixol, risperidone, and haloperidol. However, findings on the relationships between the CYP2D6 genotype and parkinsonism or tardive dyskinesia treatment with traditional antipsychotics are conflicting, probably because of small sample size, inclusion of antipsychotics with variable CYP2D6 metabolism, and co-medication. CYP2D6 phenotyping and genotyping appear to be useful in predicting steady-state concentrations of some classical antipsychotic drugs, but their usefulness in predicting clinical effects must be explored. Therapeutic drug monitoring has been strongly recommended for many antipsychotics, including haloperidol, chlorpromazine, fluphenazine, perphenazine, risperidone, and thioridazine, which are all metabolized by CYP2D6. It is possible to merge therapeutic drug monitoring and pharmacogenetic testing for CYP2D6 into clinical practice.

There is a clear gene-dose effect on the formation of O-de-methylated metabolites from multiple opioids, but the clinical significance of this may be minimal, as the analgesic effect is not altered in poor metabolizers (PMs). Genetically caused inactivity of CYP2D6 renders codeine ineffective owing to lack of morphine formation, decreases the efficacy of tramadol owing to reduced formation of the active O-desmethyl-tramadol, and reduces the clearance of methadone. Genetically precipitated drug interactions might render a standard opioid dose toxic.

Because of the important role of CYP2D6 in tamoxifen metabolism and activation, PMs are likely to exhibit therapeutic failure, and ultrarapid metabolizers (UMs) are likely to experience adverse effects and toxicities. There is a clear gene-concentration effect for the formation of endoxifen and 4-OH-tamoxifen. Tamoxifen-treated cancer patients carrying CYP2D6*4, *5, *10, or *41 associated with significantly decreased formation of antiestrogenic metabolites had significantly more recurrences of breast cancer and shorter relapse-free periods. Many studies have identified the genetic CYP2D6 status as an independent predictor of the outcome of tamoxifen treatment in women with breast cancer, but others have not observed this relationship. Thus, more favorable tamoxifen treatment seems to be feasible through a priori genetic assessment of CYP2D6, and proper dose adjustment may be needed when the CYP2D6 genotype is determined in a patient.

Dolasetron, ondansetron, and tropisetron, all in part metabolized by CYP2D6, are less effective in UMs than in other patients. Overall, there is a strong gene-concentration relationship only for tropisetron. CYP2D6 genotype screening prior to antiemetic treatment may allow for modification of antiemetic dosing. An alternative is to use a serotonin agent that is metabolized independently of CYP2D6, such as granisetron, which would obviate the need for genotyping and may lead to an improved drug response.

To date, the functional impact of most CYP2D6 alleles has not been systematically assessed for most clinically important drugs that are mainly metabolized by CYP2D6, though some initial evidence has been identified for a very limited number of drugs. The majority of reported in vivo pharmacogenetic data on CYP2D6 are from single-dose and steady-state pharmacokinetic studies of a small number of drugs. Pharmacodynamic data on CYP2D6 polymorphisms are scanty for most drug studies. Given that genotype testing for CYP2D6 is not routinely performed in clinical practice and there is uncertainty regarding genotype-phenotype, gene-concentration, and gene-dose relationships, further prospective studies on the clinical impact of CYP2D6-dependent metabolism of drugs are warranted in large cohorts.

2. Cancer

Gefitinib: A Review of Its Use in the Treatment of Locally Advanced/Metastatic Non-Small-Cell Lung Cancer

Gefitinib (Iressa™) is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that offers treatment for patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC) — in particular, in those who are harboring EGFR mutations. In a large phase III trial (IPASS) in chemotherapy-naive Asian patients with adenocarcinoma who were never smokers or were former light smokers, oral gefitinib was more effective than carboplatin plus paclitaxel in prolonging progression-free survival (PFS). In a prespecified subgroup analysis, EGFR-mutation-positive status was associated with a positive response to gefitinib treatment. Furthermore, a trial in chemotherapy-naive patients with NSCLC that was restricted to those with EGFR mutations found that gefitinib recipients had significantly longer PFS than carboplatin plus paclitaxel recipients. In large phase III trials (INTEREST, V-15-32) in unselected, previously treated patients, the overall survival (OS) in gefitinib recipients was non-inferior to, or not significantly different from, that of docetaxel recipients. In a placebo-controlled trial in previously treated patients (ISEL), pre-planned subgroup analyses in Asian patients and non-smokers showed that in these subgroups, gefitinib prolonged OS, and that EGFR biomarkers predicted a positive response to gefitinib. Gefitinib was also associated with greater improvements in quality of life (QOL) in both chemotherapy-naive and previously treated patients. A head-to-head trial of gefitinib versus erlotinib in EGFR-mutation-positive patients would help position gefitinib relative to erlotinib in this population. Further research is also required to identify factors associated with non-response to EGFR-tyrosine-kinase inhibitors in EGFR-mutation-positive patients. Gefitinib was a generally well tolerated treatment, with rash and diarrhea being the most common treatment-emergent adverse events. Interstitial lung disease (ILD) is a serious co-morbidity of NSCLC associated with gefitinib and other cancer treatments; ILD-type events occurred with an overall incidence of ≈ 1% in gefitinib recipients participating in clinical trials, and were more common in Asian patients. Notably, gefitinib was associated with significantly fewer hematologic and neurologic adverse effects than comparator chemotherapy regimens. Gefitinib as monotherapy is an effective treatment for patients with locally advanced or metastatic NSCLC with EGFR mutations.

Lapatinib: A Review of Its Use in the Treatment of HER2-Overexpressing, Trastuzumab-Refractory, Advanced or Metastatic Breast Cancer

Lapatinib (Tyverb®, Tykerb®) is an orally active, small molecule, reversible, dual tyrosine kinase inhibitor of human epidermal growth factor receptor type 1 (HER1) and type 2 (HER2). In the EU, lapatinib in combination with capecitabine is indicated for the treatment of women with HER2-over-expressing, advanced or metastatic breast cancer that has progressed after treatment with regimens that include anthra-cyclines, taxanes and, in the metastatic setting, trastuzumab.

The orally administered combination of lapatinib and capecitabine was a more effective treatment than capecitabine alone, and was a generally well tolerated, conveniently administered combination for women with trastuzumab-refractory, HER2-positive advanced or metastatic breast cancer in a clinical trial. Lapatinib combined with capecitabine provides an effective therapeutic option for a group of patients who currently have few treatment choices.

Sunitinib: A Multitargeted Receptor Tyrosine Kinase Inhibitor in the Era of Molecular Cancer Therapies

Sunitinib is an oral oxindole multitargeted kinase inhibitor that inhibits certain receptor tyrosine kinases (RTKs). These include vascular endothelial growth factor receptors (VEGFR type 1 and 2), platelet-derived growth factor receptors (PDGFR-α and PDGFR-β), stem cell factor receptor (KIT), FMS-like tyrosine kinase-3 (FLT3), glial cell-line derived neurotrophic factor receptor (RET), and the receptor of macrophage-colony stimulating factor (CSF1R). Examination of the antitumor effect of sunitinib in a variety of cell lines in vitro suggested an antiproliferative activity that is dependent on the presence of constitutively active RTK targets. The use of sunitinib as first-line therapy in advanced renal cell carcinoma (RCC) has improved the overall survival compared with that observed after cytokine therapy, while its administration in patients with gastrointestinal stromal tumors (GISTs) after progression or intolerance to imatinib achieved an objective response of 7%. Sunitinib is currently approved for the treatment of GISTs in this setting and as first-line therapy for the treatment of advanced RCC. The relatively long half-life of sunitinib and its major metabolite allow for a once-daily dosing schedule. An interesting antitumor activity of sunitinib was reported in phase II studies of patients with a variety of malignancies, such as hepatocellular cancer, pancreatic neuroendocrine tumors, and non-small-cell lung cancer; results of phase III studies are urgently anticipated. Fatigue is one of the most common adverse effects of sunitinib, as 50–70% of patients with advanced RCC and GIST complained of this adverse effect. Other adverse effects are diarrhea, anorexia, nausea and vomiting, oral changes, and bleeding events. Most toxicities are reversible and should not result in discontinuation of sunitinib. If necessary, dose adjustments or interruptions should be made. Hypothyroidism has been described in the first 2 weeks of sunitinib therapy, and its incidence increases progressively with the duration of therapy. Sunitinib may exert its hypertensive activity through a direct effect on the vasculature, while its most important cardiac adverse effect is left ventricular dysfunction. A variety of skin adverse effects have been described with the use of sunitinib, such as hand-foot syndrome, yellow discoloration of the skin, dry skin, subungual splinter hemorrhages, acral erythema, and generalized skin rashes. Administration of sunitinib in the adjuvant and neoadjuvant setting of patients with RCC and of its combination with chemotherapy and other targeted therapies are currently under intensive investigation.

Therapeutic Breast Cancer Vaccines: A New Strategy for Early-Stage Disease

Treatment of breast cancer in the adjuvant setting has changed rapidly over the last few years. In addition to improvements in chemotherapy, radiation, hormone manipulation, and surgery, immunotherapy has emerged as an effective adjunct for the treatment of breast cancer. Passive immunotherapeutic agents such as trastuzumab have been widely adopted as the standard of care for HER-2/neu over-expressing breast cancer. Vaccine therapy in the metastatic setting has yet to demonstrate clinical significance in a phase III testing. This may be due to the enhanced immunosuppressive effects demonstrated in the tumor microenvironment. Lack of co-stimulatory molecules, activation of the cytotoxic T-lymphocyte antigen-4 (CTLA-4), increased T regulatory cells, and soluble immunosuppressive factors produced by the tumor contribute to the ineffectiveness of vaccine therapy. Based on these observations, there has been a shift toward treating patients with minimal residual disease and a high risk of relapse. In this adjuvant setting, immune mechanisms of tumor evasion are less formidable, and the use of vaccine therapy in these patients may offer a higher chance of clinical benefit. There are several different vaccine approaches, including the use of cell-based vaccines (autologous, allogeneic, or dendritic cell-based), tumor-associated peptide or protein vaccines, DNA vaccines, heat shock proteins, and recombinant technology using viral or bacterial vectors to enhance im-munogenicity of vaccine preparations. This review summarizes principles involving vaccine formulation and antigen selection, followed by a brief synopsis of therapeutic vaccines given in the metastatic setting and possible reasons for their lack of efficacy. The current literature regarding vaccine development for the treatment of breast cancer in the adjuvant setting is also reviewed.

3. Cardiovascular Disorders

A Policy Model to Evaluate the Benefits, Risks and Costs of Warfarin Pharmacogenomic Testing

Background: In 2007, the US FDA added information about pharmacogenomics to the warfarin label, based on the influence of the CYP2C9 and VKORC1 genes on anticoagulationrelated outcomes. Payers will be facing increasing demand for coverage decisions regarding this technology, but the potential clinical and economic impacts of testing are not clear.

Objective: To develop a policy model to evaluate the potential outcomes of warfarin pharmacogenomic testing, based on the most recently available data.

Methods: A decision-analytic Markov model was developed to assess the addition of genetic testing to anticoagulation clinic standard care for a hypothetical cohort of warfarin patients. The model was based on anticoagulation status (international normalized ratio), a common outcome measure in clinical trials that captures both the benefits and risks of warfarin therapy. Initial estimates of testing effects were derived from a recently completed randomized controlled trial (n = 200). Healthcare cost ($US, year 2007 values) and health-state utility data were obtained from the literature. The perspective was that of a US third-party payer. Probabilistic and one-way sensitivity analyses were performed to explore the range of plausible results.

Results: The policy model included thromboembolic events (TEs) and bleeding events and was populated by data from the COUMAGEN trial. The rate of bleeding calculated for standard care approximated bleeding rates found in an independent cohort of warfarin patients. According to our model, pharmacogenomic testing provided an absolute reduction in the incidence of bleeds of 0.17% but an absolute increase in the incidence of TEs of 0.03%. The improvement in QALYs was small, 0.003, with an increase in total cost of $US162 (year 2007 values). The incremental cost-effectiveness ratio (ICER) ranged from testing dominating to standard care dominating, and the ICER was <$US50 000 per QALY in 46% of simulations. Results were most sensitive to the cost of genotyping and the effect of genotyping.

Conclusion: Our model, based on initial clinical studies to date, suggests that warfarin pharmacogenomic testing may provide a small clinical benefit with significant uncertainty in economic value. Given the uncertainty in the analysis, further updates will be important as additional clinical data become available.

Changes in Endothelial Dysfunction and Associated Cardiovascular Disease Morbidity Markers in GH-IGF Axis Pathology

Arterial endothelial dysfunction is an early event in the pathogenesis of atherosclerosis and predisposes individuals to the deposition of unstable atherosclerotic plaques. It can also lead to increased arterial stiffness, which is an accepted cause of increased arterial pulse wave velocity (APWV). Endothelial dysfunction is reversed by recombinant human growth hormone (rhGH) therapy in patients with growth hormone (GH) deficiency (GHD), favorably influencing the risk of atherogenesis. Endogenous human growth hormone (hGH), secreted by the anterior pituitary, and levels of insulin-like growth factor-I (IGF-I), produced in response to hGH stimulation of the liver, peak during early adulthood but decline throughout adulthood. It is suspected that low-grade inflammatory cardiovascular pathophysiologic markers such as homocysteine, nitric oxide, C-reactive protein (CRP), and fibrinogen and plasminogen activator inhibitor, along with changes in lipid and glucose metabolism, may all contribute to GHD-associated metabolic and cardiovascular complications. These effects are associated with increased APWV but are attenuated by rhGH therapy in GHD. GH replacement increases IGF-I levels and reduces CRP and large-artery stiffness. Reviews of rhGH in the somatopause have not been overtly favorable. Whereas reviews of rhGH/rhIGF-I combinations in GH resistance are more positive than those for rhGH alone, their combined use in the somatopause is limited. Senescent individuals may benefit from such a combination.

4. CNS Disorders

Role of Infection in the Pathogenesis of Alzheimer’s Disease: Implications for Treatment

While our understanding of the neuropathology of Alzheimer’s disease continues to grow, its pathogenesis remains a subject of intensive debate. Genetic mutations contribute to a minority of early-onset autosomal dominant cases, but most cases are of either late-onset familial or sporadic form. CNS infections, most notably herpes simplex virus type 1, Chlamydophila pneumoniae, and several types of spirochetes, have been previously suggested as possible etiologic agents in the development of sporadic Alzheimer’s disease, but with little consistent evidence. However, peripheral infections may have a role to play in accelerating neurodegeneration in Alzheimer’s disease by activating already primed microglial cells within the CNS. Potential pharmacologic interventions could aim to modify this peripheral inflammatory response through targeting of various agents involved in this inflammatory pathway. However, benefit could also be gained clinically through meticulous detection, treatment, and prevention of infections in individuals, either alone or in combination with anti-inflammatory therapy.

Tumor Necrosis Factor Modulation for Treatment of Alzheimer’s Disease: Rationale and Current Evidence

Tumor necrosis factor (TNF), a key regulator of varied physiologic mechanisms in multiple organ systems, is an immune signalling molecule produced by glia, neurons, macrophages, and other immune cells. In the brain, among other functions, TNF serves as a gliotransmitter, secreted by glial cells that envelope and surround synapses, which regulates synaptic communication between neurons. The role of TNF as a gliotransmitter may help explain the profound synaptic effects of TNF that have been demonstrated in the hippocampus, in the spinal cord, and in a variety of experimental models. Excess TNF is present in the CSF of individuals with Alzheimer’s disease (AD) and has been implicated as a mediator of the synaptic dysfunction that is hypothesized to play a central role in the pathogenesis of AD. TNF may also play a role in endothelial and microvascular dysfunction in AD, and in amyloidogenesis and amyloid-induced memory dysfunction in AD. Genetic and epidemiologic evidence has implicated increased TNF production as a risk factor for AD.

Perispinal administration of etanercept, a potent anti-TNF fusion protein, produced sustained clinical improvement in a 6-month, open-label pilot study in patients with AD ranging from mild to severe. Subsequent case studies have documented rapid clinical improvement following perispinal etanercept in both AD and primary progressive aphasia, providing evidence of rapidly reversible, TNF-dependent, pathophysiologic mechanisms in AD and related disorders. Perispinal etanercept for AD merits further study in randomized clinical trials.

Iloperidone: In Schizophrenia

Iloperidone is an atypical antipsychotic that is approved for the treatment of adult patients with schizophrenia.

In several large (n > 570 per trial), 4- or 6-week, double-blind, multinational, multicentre trials in adult patients with schizophrenia, recommended target dosages of oral iloperidone (6–12 mg twice daily) generally showed better efficacy than placebo, in terms of improvements in Positive and Negative Syndrome Scale (PANSS) total scores or Brief Psychiatric Rating Scale (BPRS) scores (primary endpoints) and also for most secondary endpoints, including PANSS subscale scores.

In addition, pharmacogenomic studies identified single nucleotide polymorphisms (SNPs) that were associated with an enhanced response to iloperidone during acute treatment of schizophrenia. More limited data also support the role of these SNPs in enhancing responses to iloperidone during longer-term treatment.

In a pooled analysis of three 52-week, double-blind, multinational, multicentre trials (n = 473), iloperidone treatment was shown to be equivalent to that with haloperidol, based on Kaplan-Meier estimates of the time to relapse (primary end-point).

Iloperidone was generally well tolerated and was associated with few extrapyramidal symptoms or changes in metabolic parameters in short- and longer-term clinical trials in adult patients with schizophrenia.

Neuropeptide and Sigma Receptors as Novel Therapeutic Targets for the Pharmacotherapy of Depression

Among the most prevalent of mental illnesses, depression is increasing in incidence in the Western world. It presents with a wide variety of symptoms that involve both the CNS and the periphery. Multiple pharmacologic observations have led to the development of the monoamine theory as a biologic basis for depression, according to which diminished neurotransmission within the CNS, including that of the dopamine, noradrenaline (norepinephrine), and serotonin systems, is the leading cause of the disorder. Current conventional pharmacologic anti-depressant therapies, using selective monoamine reuptake inhibitors, tricyclic antidepressants, and monoamine oxidase inhibitors, aim to enhance monoaminergic neurotransmission. However, the use of these agents presents severe disadvantages, including a delay in the alleviation of depressive symptoms, significant adverse effects, and high frequencies of non-responding patients.

Neuroendocrinologic data of recent decades reveal that depression and anxiety disorders may occur simultaneously due to hypothalamus-pituitary-adrenal (HPA) axis hyperactivity. As a result, the stress-diathesis model was developed, which attempts to associate genetic and environmental influences in the etiology of depression. The amygdala and the hippocampus control the activity of the HPA axis in a counter-balancing way, and a plethora of regulatory neuropeptide signalling pathways are involved. Intervention at these molecular targets may lead to alternative antidepressant therapeutic solutions that are expected to overcome the limitations of existing antidepressants. This prospect is based on preclinical evidence from pharmacologic and genetic modifications of the action of neuropeptides such as corticotropin-releasing factor, substance P, galanin, vasopressin, and neuropeptide Y. The recent synthesis of orally potent non-peptide micromolecules that can selectively bind to various neuropeptide receptors permits the onset of clinical trials to evaluate their efficacy against depression.

Epidemiology and Management of Essential Tremor in Children

Essential tremor (ET) is a common, often familial, movement disorder characterized by tremor of the limbs, head, and voice. Epidemiologic surveys indicate that up to 5% of the adult population has ET, and 5–30% of adults with ET report symptom onset during childhood. There is, however, little published regarding ET in the pediatric population, and no prospective studies targeted specifically to children. Retrospective studies from subspecialty movement disorder clinics indicate that childhood-onset ET is usually hereditary, begins at a mean age of 6 years, and affects boys three times as often as girls. While ET occasionally results in disability during childhood, only one-quarter of children seeing a neurologist for ET require pharmacotherapy. Small case series suggest that propranolol is effective in approximately 50% of children with ET, but controlled treatment trials are lacking.

5. Dermatologic and Autoimmune Disorders

Cutaneous Lupus Erythematosus: Issues in Diagnosis and Treatment

Cutaneous lupus erythematosus (LE) may present in a variety of clinical forms. Three recognized subtypes of cutaneous LE are acute cutaneous LE (ACLE), subacute cutaneous LE (SCLE), and chronic cutaneous LE (CCLE). ACLE may be localized (most often as a malar or ‘butterfly’ rash) or generalized. Multisystem involvement as a component of systemic LE (SLE) is common, with prominent musculoskeletal symptoms. SCLE is highly photosensitive, with predominant distribution on the upper back, shoulders, neck, and anterior chest. SCLE is frequently associated with positive anti-Ro antibodies and may be induced by a variety of medications. Classic discoid LE is the most common form of CCLE, with indurated scaly plaques on the scalp, face, and ears, with characteristic scarring and pigmentary change. Less common forms of CCLE include hyperkeratotic LE, lupus tumidus, lupus profundus, and chilblain lupus. Common cutaneous disease associated with, but not specific for, LE includes vasculitis, livedo reticularis, alopecia, digital manifestations such as periungual telangiectasia and Raynaud phenomenon, photo-sensitivity, and bullous lesions. The clinical presentation of each of these forms, their diagnosis, and the inter-relationships between cutaneous LE and SLE are discussed. Common systemic findings in SLE are reviewed, as are diagnostic strategies, including histopathology, immunopathology, serology, and other laboratory findings.

Treatments for cutaneous LE initially include preventive (e.g. photoprotective) strategies and topical therapies (corticosteroids and topical calcineurin inhibitors). For skin disease not controlled with these interventions, oral antimalarial agents (most commonly hydroxychloroquine) are often beneficial. Additional systemic therapies may be subdivided into conventional treatments (including corticosteroids, methotrexate, thalidomide, retinoids, dapsone, and azathioprine) and newer immunomodulatory therapies (including efalizumab, anti-tumor necrosis factor agents, intravenous immunoglobulin, and rituximab). We review evidence for the use of these medications in the treatment of cutaneous LE.

Useful Tools for the Management of Atopic Dermatitis

Eczema, frequently named atopic dermatitis, is the most frequent chronic skin disease of early childhood, with a high prevalence in industrialized countries and a relapsing-remitting course that is responsible for a serious burden on affected children and their families. Even though most facets of this disease are nowadays well known and numerous guidelines are available, some confusion still exists regarding certain aspects. First, several names have been proposed for the disorder. We suggest that the name and definition adopted by the World Allergy Organization should be used: ‘eczema,’ divided into ‘atopic,’ when an allergic sensitization can be demonstrated; and ‘non-atopic’ in the absence of sensitization.

Several diagnostic criteria have been proposed but, at present, the two most reliable are the 2003 revision by the American Academy of Dermatology of the Hanifin-Rajka criteria, and those by Williams revised in 2005. To date, 20 different clinical scores have been published to assess the severity; however, only the EASI (Eczema Area and Severity Index), the SCORAD (SCORing Atopic Dermatitis), and the POEM (Patient-Oriented Eczema Measure) seem to have been adequately validated and are recommended for use in clinical practice and trials. The diagnostic tests to identify associated allergy or sensitization include skin-prick tests, determination of the specific IgE in serum using different assays, and atopy patch tests; in the case of suspected food allergy, a food challenge may be necessary to define the diagnosis.

To evaluate quality of life, tools exist that allow both the child’s and the family’s impairment to be considered. In addition, several algorithms exist to help decide therapy on a step-wise basis. However, such guidelines and algorithms represent only an aid to the physician and not an obligatory directive, since the ultimate judgment regarding any therapy must be performed by the physician and tailored to individual needs. A clear and validated definition of eczema control would permit better monitoring of the disease, similar to the situation with asthma in recent years. Finally, this review examines the role of special textiles in diminishing Staphylococcus aureus skin superinfection, of house dust-mite avoidance measures, and of educational programs for patients and their families, which may all help improve eczema.

Ichthyosis: Clinical Manifestations and Practical Treatment Options

Ichthyoses constitute a large group of cornification disorders that affect the entire integument. The skin is characterized by visible scaling and, in many cases, by inflammation — for example, in bullous/keratinopathic ichthyosis or Netherton syndrome. From the viewpoint of classification, it is useful to distinguish non-syndromic from syndromic types of ichthyosis. Ichthyosis vulgaris and recessive X-linked ichthyosis are common disorders and are often of delayed onset — in contrast to congenital ichthyoses, which belong to the group of rare diseases and present at birth with the features of either collodion membrane or congenital ichthyosiform erythroderma.

The diagnostic steps are based on clinical data, analyses such as the steroid sulfatase activity test, skin biopsies, and genetic results. However, the dramatic increase in knowledge about the pathophysiology of these conditions has not led to a curative therapy so far. The therapeutic management is multi-disciplinary and involves ichthyosis patient organizations in many countries. The mainstay of treatment remains moisturizing creams containing, for example, urea, lactic acid, and other humectants and keratolytics, regular bathing, and mechanical scale removal. Patients with lamellar ichthyosis or ichthyosiform erythroderma, in particular, profit from oral therapy with retinoids or retinoic acid metabolism-blocking agents.

Patient Characteristics in Behcet Disease: A Retrospective Analysis of 213 Turkish Patients during 2001–4

Background: Behcet disease (BD) is a chronic, inflammatory, multisystemic vasculitic disorder with a wide spectrum of clinical presentations. The highest prevalence is seen in Turkey. Specific diagnostic tools are yet to be discovered, thus the diagnosis relies on physicians being acquainted with the symptoms and signs of the disease.

Objective: To investigate the epidemiologic characteristics of BD and to emphasize the typical clinical and laboratory characteristics.

Methods: This was a retrospective analysis of all BD patients attending the Ankara Numune Education and Research Hospital throughout the years 2001–4. Diagnosis of BD was made according to the International Study Group criteria. A total of 213 patients were evaluated with respect to family history, clinical features, pathergy test, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), antistreptolysin O, and ferritin levels. When assessing disease activity, the active clinical manifestations on the day of the examination were taken into account. Correlations were analyzed between sex and age distribution, age of onset, disease duration, and family history; and between family history and age of onset, pathergy, clinical manifestations, and laboratory parameters. Correlations were also evaluated between pathergy positivity and clinical manifestations, and laboratory parameters. Correlations between activity scores and age of onset, duration, sex, family history, and laboratory data were also analyzed.

Results: The female : male ratio was 1.04, and the mean age of onset was 27 years. Family history did not affect age of onset or disease severity. Men presented with more active disease, and there was a weak but positive correlation between disease activity and CRP. No correlation was observed between duration and age of disease onset. The most common clinical presentations were oral aphthous lesions, genital ulcers, and skin lesions. Men more commonly presented with papulopustular lesions, pathergy positivity, and vascular, eye, and renal involvement, and women presented with arthritis/arthralgia more commonly than men. Vascular lesions, ESR, and CRP showed significant relationships with pathergy reaction. Eye involvement was not affected by age of onset.

Conclusions: We believe our results indicate that the pathogenesis of BD is multifactorial. Hormonal factors seem to be of some influence, while genetic background and environmental factors seem to be the major contributors. Infections seem to be among the triggering environmental factors. Predisposing genes may affect the influence of environmental factors. Prevalence studies should be carried out periodically in those countries with a high prevalence of BD to keep up with the changing dynamics of the disease, which may also shed light on the as-yet unknown pathogenesis of BD..

6. Infectious Diseases

Oseltamivir Resistance and the H274Y Neuraminidase Mutation in Seasonal, Pandemic and Highly Pathogenic Influenza Viruses

Along with influenza vaccines, the world is currently almost completely dependent on two licensed drugs for the treatment or prevention of seasonal (influenza A and B viruses) and pandemic influenza (influenza A viruses). These drugs — oseltamivir (Tamiflu®) and zanamivir (Relenza®) — are classified as neuraminidase inhibitors (NAIs) because they act by inhibiting one of the key surface proteins of the influenza virus, neuraminidase, which in turn reduces the ability of the virus to infect other respiratory cells. Our dependence on these drugs has arisen because of high levels of resistance with seasonal influenza viruses to the older class of anti-influenza drugs, the adamantanes (amantadine and rimantadine), combined with the lack of activity of these drugs against influenza B viruses. Recently, however, significant levels of oseltamivir-resistant influenza A (H1) seasonal influenza viruses have also been encountered, which has been associated with a single amino acid change in the viral neuraminidase (H274Y). Oseltamivir is the most widely used and stockpiled NAI and, while these A (H1) viruses are still sensitive to zanamivir, it highlights the ease with which the influenza virus can mutate and reassort to circumvent available drugs. Fortunately, the current pandemic A (H1N1) 2009 virus, which is circulating globally, remains largely sensitive to both NAIs, although a small number of oseltamivir-resistant viruses have been isolated from patients to date, again with the H274Y mutation. Clearly there is a need to use the NAI drugs prudently to ensure they remain an effective defence against future seasonal and pandemic influenza viruses, along with careful monitoring of levels of resistance in the circulating viruses, combined with further development of new anti-influenza drugs.

Predictors of Treatment Response in Chronic Hepatitis B

The ultimate goal of treatment for chronic hepatitis B is to reduce liver-related complications and mortality. Sustained hepatitis B e antigen (HBeAg) seroconversion and hepatitis B surface antigen (HBsAg) clearance 6–12 months after stopping treatment are the short-term surrogate outcomes for interferon or peginterferon therapy. As most patients require long-term nucleos(t)ide analog treatment, which also has the risk of drug resistance in the case of incomplete viral suppression, maintenance of hepatitis B virus (HBV) DNA suppression at an undetectable level is the appropriate surrogate outcome. Because no antiviral treatment is perfect, it is desirable for treatment response to be predicted and for the treatment regimen to be modified accordingly. At baseline, high ALT and low HBV DNA levels can predict response to both (peg)interferon and nucleos(t)ide analogs. Genotype A HBV responds best to peginterferon, but HBV genotype has no predictive value for nucleos(t)ide analog treatment. HBV DNA is a good on-treatment predictor of response for nucleos(t)ide analogs but not for (peg)interferon. The data supporting the use of quantitative HBsAg and HBeAg to predict response to peginterferon is stronger than that for nucleos(t)ide analogs. In conclusion, predictors of response are useful to provide the most appropriate antiviral therapy for the most suitable patients, in order to achieve the best response and improve the clinical outcome of chronic hepatitis B patients.

Clinical Pharmacokinetics and Pharmacodynamics of Etravirine

Etravirine is a next-generation, non-nucleoside reverse transcriptase inhibitor (NNRTI) developed for the treatment of HIV-1 infection. It has a high genetic barrier to the emergence of viral resistance and maintains its antiviral activity in the presence of common NNRTI mutations. The pharmacokinetics of etravirine in HIV-infected patients at the recommended dosage of 200 mg twice daily demonstrates moderate intersubject variability and no time dependency. Due to substantially lower exposures when taken on an empty stomach, etravirine should be administered following a meal. The drug is highly protein bound (99.9%) to albumin and α1-acid glycoprotein, and shows a relatively long elimination half-life of 30–40 hours. Etravirine is metabolized by cytochrome P450 (CYP) 3A, 2C9 and 2C19; the metabolites are subsequently glucuronidated by uridine diphosphate glucuronosyltransferase. Renal elimination of etravirine is negligible. Etravirine has the potential for interactions by inducing CYP3A and inhibiting CYP2C9 and 2C19; it is a mild inhibitor of P-glycoprotein but not a substrate. The drug interaction profile of etravirine has been well characterized and is manageable. No dosage adjustments are needed in patients with renal impairment or mild to moderate hepatic impairment. Race, sex, bodyweight, and age do not affect the pharmacokinetics of etravirine. In the two phase III trials DUET-1 and DUET-2, no relationship was demonstrated between the pharmacokinetics of etravirine and the primary efficacy endpoint of viral load below 50 copies/mL or the safety profile of etravirine.

7. Transplantation

Tacrolimus Population Pharmacokinetic-Pharmacogenetic Analysis and Bayesian Estimation in Renal Transplant Recipients

Objectives: The aims of this study were (i) to investigate the population pharmacokinetics of tacrolimus in renal transplant recipients, including the influence of biologic and pharmacogenetic covariates; and (ii) to develop a Bayesian estimator able to reliably estimate the individual pharmacokinetic parameters and inter-dose area under the blood concentration-time curve (AUC) from 0 to 12 hours (AUC12) in renal transplant patients.

Methods: Full pharmacokinetic profiles were obtained from 32 renal transplant patients at weeks 1 and 2, and at months 1, 3, and 6 post-transplantation. The population pharmacokinetic analysis was performed using the nonlinear mixed-effect modelling software NONMEM® version VI. Patients’ genotypes were characterized by allelic discrimination for PXR −25385C>T genes.

Results: Tacrolimus pharmacokinetics were well described by a two-compartment model combined with an Erlang distribution to describe the absorption phase, with low additive and proportional residual errors of 1.6 ng/mL and 9%, respectively. Both the hematocrit and PXR −25385C>T single nucleotide polymorphism (SNP) were identified as significant covariates for apparent oral clearance (CL/F) of tacrolimus, which allowed improvement of prediction accuracy. Specifically, CL/F decreased gradually with the number of mutated alleles for the PXR −25385C>T SNP and was inversely proportional to the hematocrit value. However, clinical criteria of relevance, mainly the decrease in interindividual variability and residual error, led us to retain only the hematocrit in the final model. Maximum a posteriori Bayesian forecasting allowed accurate prediction of the tacrolimus AUC12 using only three sampling times (at 0 hour [predose] and at 1 and 3 hours postdose) in addition to the hematocrit value, with a nonsignificant mean AUC bias of 2% and good precision (relative mean square error = 11 %).

Conclusion: Population pharmacokinetic analysis of tacrolimus in renal transplant recipients showed a significant influence of the hematocrit on its CL/F and led to the development of a Bayesian estimator compatible with clinical practice and able to accurately predict tacrolimus individual pharmacokinetic parameters and the AUC12.

African American Kidney Transplantation Survival: The Ability of Immunosuppression to Balance the Inherent Pre- and Post-Transplant Risk Factors

Among organ transplant recipients, the African American population historically has received special attention. This is because secondary to their disposition to certain disease states (for example, hypertension) an African American patient has a propensity to reach end-stage renal disease and to require renal replacement earlier than a Caucasian patient. Regardless of the initiative to replace dialysis therapy with organ transplantation, the African American patient has many barriers to kidney transplantation, thus extending their time on dialysis and their waiting time on the organ transplant list. These factors are among the many negative causes of decreased kidney graft survival, realized before kidney transplantation.

Unfortunately, once the African American recipient receives a kidney graft, the literature documents that many post-transplant barriers exist, which limit successful outcomes. The primary post-transplant barrier relates to designing proper immunosuppression protocols. The difficulty in designing protocols revolves around (i) altered genetic metabolism/lower absorption; (ii) increased immuno-active cytokines; and (iii) detrimental effects of noncompliance. Based on the literature, dosing of immunosuppression must be aggressive and requires a diligent practitioner. Research has indicated that, despite some success with proven levels of immunosuppression, the African American recipient usually requires a higher ‘dose per weight’ regimen. However, even with aggressive immunosuppressant dosing, African Americans still have worse outcomes than Caucasian recipients. Additionally, many of the targeted sites of action that immunosuppression exerts its effects on have been found to be amplified in the African American population. Finally, noncompliance is the most discouraging inhibitor of long-term success in organ transplantation. The consequences of noncompliance are biased by ethnicity and affect the African American population more severely.

All of these factors are discussed further in this review in the hope of identifying an ideal healthcare model for caring for the African American transplant recipient, from diagnosing chronic kidney disease through to successful kidney graft outcomes. An in-depth review of the literature is described and organized in a fashion that highlights all of the issues affecting success in African Americans. The compilation of the literature in this review will enable the reader to get closer to understanding the caveats of kidney transplantation in the African American patient, but falls short of delivering an actual ‘equation’ for post-transplant care in an African American kidney recipient.

8. News from Other Sources

BRCA Mutation Screening Cost Effective for Cancer Prevention

Genetic screening for BRCA mutations may be a cost-effective strategy to prevent breast and ovarian cancers if screening is applied only to women with a personal/family history of cancers or Ashkenazi Jewish ancestry, according to a study published in the Journal of Clinical Oncology.

Researchers utilized a Markov Monte Carlo simulation model to simulate screening strategies for BRCA mutations in patients with ovarian cancer, estimating the lifetime societal costs and outcomes for their first-degree relatives. First-degree relatives of women testing positive for a BRCA mutation were assumed to have the opportunity to undergo BRCA mutation testing and cancer-risk-reducing interventions. Four screening strategies were investigated: (i) no screening; (ii) screening of women with Ashkenazi Jewish ancestry, a family history of breast and/or ovarian cancer, or a personal history of breast cancer; (iii) screening only if invasive serous cancer; and (iv) screening of all women with invasive nonmucinous epithelial ovarian cancer.

Strategies 2, 3, and 4 provided 11.6, 3.6, and 2.7 quality-adjusted life days compared with their next most-effective (i.e. preceding) strategy. The respective incremental cost-effectiveness ratios for these strategies were $US32 670, $US131 113, and $US151 429 per QALY gained (year 2008 values). Strategy 2, the screening of women with a personal/family history of relevant cancers or relevant ancestry, was predicted to reduce US breast and ovarian cancer cases in first-degree relatives by 14% and 39%, respectively, compared with no screening.

Genetic Predictors of Toxicities to Chemotherapy

A number of studies presented at this year’s ECCO/ESMO Congress (the 15th European Cancer Conference and the 34th Congress of the European Society for Medical Oncology) investigated genetic predictors of toxicities to various types of chemotherapy.

Rhee et al.[1] from Korea investigated the association between toxicities to S-1 +cisplatin therapy and polymorphisms of genes relating to fluorouracil and cisplatin activity. They found that diarrhea and grade 3–4 anemia were more frequent in patients with a thymidylate synthase (TS) 3′-untranslated region (UTR) 6bp deletion homozygote. Grade 3–4 neutropenia was more frequent in patients with a C/C genotype of xeroderma pigmentosum group D (XPD)-Arg156Agr. Grade 3–4 thrombocytopenia was more frequent in patients with C/T or T/T genotypes of X-ray repair cross-complementing group-1 (XRCC-1)-Arg194Trp, a G/G genotype of XRCC1-Arg399-GIn or a C/C genotype of excision repair cross-complementation 1 (ERCC1)-C8092A.

Goekkurt et al.[2] from Germany found that polymorphisms in TS and methylenetetrahydrofolate reductase (MTHFR) were associated with grade 3 peripheral neuropathy in elderly patients with advanced gastric cancer treated with oxaliplatin-based chemotherapy. Patients with promoter genotypes associated with low TS expression were at greater risk of developing grade 3 peripheral neuropathy, as were patients carrying MTHFR1298AC or CC genotypes. The majority (89%) of patients experiencing grade 3 peripheral neuropathy expressed at least one of these risk genotypes.

Tsunoda et al.[3] from Japan investigated polymorphisms of genes relating to fluorouracil activity and their value with regard to predicting toxicities to uracil/tegafur + folinic acid [leucovorin] in patients with colorectal cancer. Orotate phosphoribosyltransferase (OPRT) polymorphism was shown to be a useful predictor of severe overall toxicity and diarrhea. The odds ratios for grade 3 overall toxicity and grade 3 diarrhea in patients with G638C homozygous type compared with heterozygous/wild type were 25.8 (p<0.01) and 23.25 (p<0.05), respectively. Polymorphisms in dihydropyrimidine dehydrogenase (DPD) A1627G and MTHFR C677T were also associated with moderate to severe toxicity, and polymorphisms in uridine diphosphate glucuronosyltransferase (UGT) 1A1 G211A and T3279G were predictors of hyperbilirubinemia.

Xu et al.[4] from GlaxoSmithKline in the UK also showed that UGT1A1 TA polymorphism was a strong predictor of hyperbilirubinemia in Caucasian patients with metastatic renal cancer treated with pazopanib. Of the patients who experienced pazopanib-induced hyperbilirubinamia, 84% were carriers of at least one TA7 allele.

Much Fluoropyrimidine Toxicity May Be Avoidable through Pretreatment Testing for Dihydropyrimidine Dehydrogenase (DPD) Polymorphisms

Much fluoropyrimidine toxicity may be avoidable through pretreatment testing for dihydropyrimidine dehydrogenase (DPD) polymorphisms, according to prospective research presented at the GASTRO 2009 joint meeting. Researchers screened for DPD mutations in 423 UK patients with GI malignancy undergoing fluorouracil or capecitabine combination therapy. Occurrences of diarrhea, mucositis, and neutropenia during the first four cycles of therapy were recorded. Over all patients, 25.3% experienced grade 3–4 toxicity. All of the 5.2% of patients who had a DPD mutation experienced such toxicity, accounting for 21% of the grade 3–4 toxicities recorded. It was concluded that significant toxicity could be avoided by prior testing of patients for these mutations and adjusting the treatment or dose appropriately.

SLCO1B1*5 Behind Statin-Induced Adverse Effects

Carriers of the reduced function allele (*5) of the organic acid transporter SLCO1B1 and women appear to be at a greater risk of developing statin-induced adverse effects, according to US-based researchers.

To identify single nucleotide polymorphisms associated with statin-induced adverse effects, the researchers used data from the STRENGTH (Statin Response Examined by Genetic Haplotype Markers) study, which was a 16-week, open-label study of atorvastatin, simvastatin, and pravastatin in 452 eligible patients with hypercholesterolemia. In the study, patients were randomly assigned to 8 weeks of treatment with atorvastatin 10 mg/day, simvastatin 20 mg/day, or pravastatin 10 mg/day, followed by 8 weeks of treatment with atorvastatin 80 mg/day, simvastatin 80 mg/day, and pravastatin 40 mg/day, respectively. The primary outcome was defined as a composite adverse event (CAE) of premature discontinuation of the study drug due to adverse effects, myalgia/muscle pain irrespective of creatine kinase (CK) levels, or elevations in CK levels of >3× the upper limit of normal, irrespective of the symptoms.

The CAE occurred in 99 patients, of whom 54 patients discontinued the study drug, 61 patients developed myalgia/muscle pain, and 9 patients developed CK elevations. The percentage of women in the CAE group was significantly higher than in the non-CAE group (67% vs 50%). After adjusting for race, SLCO1B1*5 and female sex were independently associated with the CAE, with respective odds ratios of 1.7 (95% CI 1.04, 2.8) and 2.2 (1.4, 3.6). Drug discontinuation due to an adverse effect was the primary determinant of the associations of female sex and SLCO1B1*5 with the CAE. There was evidence of a gene-dose effect with the SLCO1B1*5 allele in relationship to statin drug concentrations. Patients who had at least one allele of SLCO1B1*5 and who received simvastatin or atorvastatin had a greater incidence of CAE than those with no alleles; no such association was seen for pravastatin recipients.

Worth of Genotyping for Warfarin Therapy Unclear

The cost effectiveness of genotype-guided warfarin dosing appears nearly as uncertain as the accuracy of warfarin dosing itself, according to a study presented at the 25th International Conference on Pharmacoepidemiology and Therapeutic Risk Management.

The study investigated the cost effectiveness of CYP2C9 and VKORC1 genotyping for improving the accuracy of warfarin dosing. A state transition model was used to simulate the out-comes of patients aged 70 years with newly-diagnosed atrial fibrillation. Bleeding, mortality, costs, and other variables were based on published literature.

The cost effectiveness of genetically-guided dosing was found to be highly dependent on assumptions made of its effectiveness. Specifically, if genetic tests guided dosing such that the time spent in the target INR range was increased by <5%, the incremental cost-effectiveness ratio (ICER) of this strategy was calculated at over $US100 000/QALY. If time spent in the target INR range was increased by 9%, however, the ICER reportedly fell below $US50 000/QALY. Due to the current uncertainty over the efficacy of such genotyping, the researchers urged caution in advocating widespread implementation of this strategy.