Showing papers in "Expert Review of Clinical Pharmacology in 2008"

Challenges and solutions in topical ocular drug-delivery systems

Abstract: Vision significantly affects quality of life and the treatment of ocular disease poses a number of unique challenges. This review presents the major challenges faced during topical ocular drug administration and highlights strategies used to overcome the natural transport barriers of the eye. The circulation of tear fluid and aqueous humor decrease the residence time of topically delivered drugs, while ocular barriers in the corneal and conjuctival epithelia and the retinal pigment epithelium limit transport. Successful treatment strategies increase the residence time of drugs in the eye and/or enhance the ability of the drug to penetrate the ocular barriers and reach the target tissue. In this review, we discuss several drug-delivery strategies that have achieved clinical success or demonstrate high potential. We also draw attention to a number of excellent reviews that explore various ocular drug-delivery techniques in depth. Finally, we highlight cutting-edge drug-delivery technologies that improve the efficacy of current drug-delivery methods or use proven techniques to deliver novel therapeutics.

Modeling cumulative incidence function for competing risks data.

Abstract: A frequent occurrence in medical research is that a patient is subject to different causes of failure, where each cause is known as a competing risk. The cumulative incidence curve is a proper summary curve, showing the cumulative failure rates over time due to a particular cause. A common question in medical research is to assess the covariate effects on a cumulative incidence function. The standard approach is to construct regression models for all cause-specific hazard rate functions and then model a covariate-adjusted cumulative incidence curve as a function of all cause-specific hazards for a given set of covariates. New methods have been proposed in recent years, emphasizing direct assessment of covariate effects on cumulative incidence function. Fine and Gray proposed modeling the effects of covariates on a subdistribution hazard function. A different approach is to directly model a covariate-adjusted cumulative incidence function, including a pseudovalue approach by Andersen and Klein and a direct...

Argatroban therapy in heparin-induced thrombocytopenia.

Abstract: Argatroban is a direct thrombin inhibitor approved for anticoagulation in heparin-induced thrombocytopenia (HIT; in several countries) and in patients with or at risk of HIT undergoing percutaneous coronary intervention (PCI; in the USA). HIT is a relatively common extreme prothrombotic condition. When HIT is reasonably suspected, an alternative anticoagulant should be promptly initiated. In historical controlled studies, argatroban reduced new thrombosis, mortality from thrombosis and the composite of death, amputation or thrombosis, without increasing bleeding. With intravenous infusion, advantages include short half-life, easy monitoring and elimination primarily by hepatobiliary (rather than renal) means. In patients undergoing PCI, argatroban with or without glycoprotein IIb/IIIa inhibition leads to high rates of procedural success with low bleeding risk. Herein we review argatroban therapy for HIT and for PCI.

Pharmacokinetic approaches to treatment of drug addiction.

Abstract: The pharmacokinetic approach to treatment targets the drug molecules themselves, aiming to reduce their concentration at the site of action, thereby reducing or preventing any pharmacodynamic effect. This approach might be useful in the treatment of acute drug toxicity/overdose and in the long-term treatment of addiction. Early clinical trials with anticocaine and antinicotine vaccines have shown reduced drug use and good tolerability. Also showing promise in animal studies are monoclonal antibodies against cocaine, methamphetamine and phencyclidine, as well as the enhancment of cocaine metabolism with genetic variants of human butyrylcholinesterase, using a bacterial esterase or catalytic monoclonal antibodies. Pharmacokinetic treatments offer potential advantages in terms of patient compliance, absence of medication interactions and benefit for patients who cannot take standard medications.

Trends in generic prescribing and dispensing in Europe.

Abstract: Pressure to control pharmaceutical expenditure and price competition among pharmaceutical companies are fuelling the development of generic medicines markets in ambulatory care in Europe. The aim of this special report is to identify, interpret and discuss the main supply and demand trends affecting the European generic medicines market in ambulatory care. On the supply side, generic price-regulated systems and reference pricing systems are spreading across Europe. On the demand side, European countries have attempted to stimulate demand for generic medicines by focusing on physician prescribing, generic substitution by pharmacists and patient copayments. Finally, the development of biosimilars will probably become an important area of growth for the pharmaceutical industry over the next 5 years.

Clinical perspectives in drug safety and adverse drug reactions.

Abstract: Adverse drug reactions (ADRs) remain a common clinical problem since they can mimic many diseases and cause significant morbidity and mortality. Judicious prescribing is important to minimize their occurrence. Apart from the recent identification of a few pharmacogenomic biomarkers for serious reactions, many remain unpredictable. Spontaneous reporting continues to play an important role in pharmacovigilance and the value of astute clinical observation and well-documented reports of suspicions of a causal link cannot be underestimated. Many national reporting schemes have developed considerable experience and expertise over many years and have large ADR databases, which are national assets. Despite advances in pharmacovigilance, numerous deficiencies have been identified; postmarketing surveillance remains the weakest link in the regulatory process. Regulatory authorities have tended to act later rather than sooner in response to safety signals, and this, when combined with under-reporting, may have led to exposure of a large number of patients to drug-related harm before restriction or withdrawal. In an attempt to improve vigilance, international surveillance may benefit by moving from its current passive/reactive mode toward active surveillance systems with a prospective, comprehensive and systematic approach to monitoring, collecting, analyzing and reporting data on ADRs. This will include increased pressure on pharmaceutical companies to conduct postmarketing studies. Such an active/proactive approach, while maintaining focus on ADR detection, could also aim to extend knowledge of safety, such that emerging changes in risk-benefit during a drug's marketed life are effectively communicated to clinicians and patients. Drug safety monitoring and its regulation are now undergoing an overhaul and it is hoped that vigilance, public safety and trust will improve as a result.

Toxicophores, reactive metabolites and drug safety: when is it a cause for concern?

Abstract: It is generally accepted that bioactivation of relatively inert functional groups (toxicophores) to reactive metabolites is an obligatory step in the pathogenesis of certain idiosyncratic adverse drug reactions (IADRs). IADRs cannot be detected in regulatory animal toxicity studies and, given their low frequency of occurrence in humans (1 in 10,000 to 1 in 100,000), they are often not detected until the drug has gained broad exposure in a large patient population. The detection of IADRs during late clinical trials or after a drug has been released can lead to an unanticipated restriction in its use, and even in its withdrawal. To date, there is neither a consistent nor a well-defined link between bioactivation and IADRs; however, the potential does exist for these processes to be causally related. Thus, the formation of reactive metabolites with a drug candidate is generally considered a liability in most pharmaceutical companies. Procedures have been implemented to evaluate bioactivation potential of new drug candidates with the goal of eliminating or minimizing reactive metabolite formation by rational structural modification of the lead chemical class. While such studies have proven extremely useful in the retrospective analysis of bioactivation pathways of toxic drugs and defining toxicophores, their ability to accurately predict the IADR potential of new drug candidates has been challenged, given that several commercially successful drugs form reactive metabolites, yet, they are not associated with a significant incidence of IADRs. In this article, we review the basic methodology that is currently utilized to evaluate the bioactivation potential of new compounds, with particular emphasis on the advantages and limitation of these assays. Plausible reasons for the excellent safety record of certain drugs susceptible to bioactivation are also explored. Overall, these observations provide valuable guidance in the proper use of bioactivation assessments when selecting drug candidates for development.

Idiosyncratic drug hepatotoxicity: a 2008 update.

Abstract: Pharmaceutical preparations, and also herbal products and dietary supplements, are emerging contributors to severe forms of liver disease. Although acetaminophen intoxication is still the reason for many cases of drug-induced liver injury (DILI) in Western countries, the bulk of hepatic reactions to drugs are idiosyncratic. Only a small fraction of individuals exposed to a drug associated with liver injury will develop hepatotoxicity. Indeed, the rarity of this serious adverse event prevents its detection in clinical trials. The pathogenesis of idiosyncratic DILI is not well known because of a lack of reliable animal models, although it probably involves the metabolism of the drug and/or activation of the immune system. Different databases have described antibiotics, NSAIDs and anticonvulsants as the main group of drugs incriminated in DILI. Clinical presentation of DILI includes predominantly a hepatocellular type of damage, yet cholestatic and mixed types are also common; the determinants of the type of damage induced by a given drug are poorly understood. Analysis of pooled data has recently underlined the influence of older age in the cholestatic/mixed expression of liver injury, as well as the independent association of female gender, older age, aspartate aminotransferase levels with hepatocellular type of damage and high bilirubin levels with the risk of fulminant liver failure/death. In the long term (providing the patient survives the initial episode), persistent damage may occur in at least 6% of patients, with the cholestatic mixed type of damage more prone to becoming chronic, while in the hepatocellular pattern the severity is greater, with further likelihood of evolution to cirrhosis. Cardiovascular and CNS drugs are the main groups leading to chronic liver damage. The diagnosis of hepatotoxicity remains a difficult task owing to the lack of reliable markers for use in general clinical practice. Diagnostic algorithms may add consistency to clinical judgment by translating a suspicion into a quantitative score. Currently, the Council for International Organizations of Medical Sciences/Roussel Uclaf Causality Assessment Method instrument is considered the gold standard in causality assessment of hepatotoxicity, although there is probably room for improvement. Current efforts in collecting bona fide cases will make refinements of existing scales feasible. Efforts should also be directed towards the development of an abridged instrument for use in evaluating suspected drug-induced hepatotoxicity at the very beginning of the diagnosis and treatment process when clinical decisions need to be taken. The treatment of idiosyncratic DILI is largely supportive. Early suspicion and withdrawal of the offending agent is the most important therapeutic measure.

Regulating impurities in pharmaceutical products: a tolerability of risk approach?

Abstract: This paper explores the implications of the EMEA guideline EMEA/CHMP/QWP/251344/2006 for pharmaceutical risk decisions. The guidelines propose to consider the intake of 1.5 µg/day of a genotoxic impurity as a 'threshold of toxicological concern', and to treat this level as an acceptable risk (excess cancer risk of <10(-5) over a lifetime). The guidance document also introduces a specific decision-tree to assess the acceptability of genotoxic impurities. According to this decision-tree, when the presence of genotoxic impurities is unavoidable, their levels should be reduced 'as low as reasonably practicable' (ALARP). In the UK, the Health and Safety Executive has developed a 'tolerability of risk' (ToR) model to support ALARP requirements. The paper compares the EMEA risk-reduction requirements and the ToR model. EMEA/CHMP/QWP/251344/2006 introduces a risk-avoidance principle based on a controversial interpretation of 'pollution control'. The paper supports the view that this model is not optimal from a risk-management point of view. Using a ToR model could bring improvements to pharmaceutical risk decisions and would support a more practical and consensual approach to meeting the ALARP requirements.

Drug–drug interaction with statins

Abstract: 3-hydroxy-3-methyl-glutaryl (HMG)-CoA reductase inhibitors (the so-called statins: atorvastatin, fluvastatin, pravastatin, lovastatin, rosuvastatin and simvastatin) are a well-established class of drugs in the treatment of hypercholesterolemia. Statin monotherapy is generally well tolerated, with a low frequency of adverse events. The most important adverse effects associated with statins are myopathy and an asymptomatic increase in hepatic transaminases, both of which occur infrequently. Since statins are prescribed on a long-term basis, possible interactions with other drugs deserve particular attention, as many patients will typically receive pharmacological therapy for concomitant conditions during the course of statin treatment. Moreover, a combination of therapy between statins and other classes of lipid-lowering agents (e.g., ezetimibe, fibrates, resins and nicotinic acid) is recommended for some patients by current guidelines. Therefore, the potential for drug-drug interactions emerges as a relevant factor in determining the safety profile of statins. This review summarizes the pharmacokinetic properties of statins and emphasizes their clinically relevant drug interactions.

Pharmacokinetic drug interactions between drugs of abuse and antiretroviral medications: implications and management for clinical practice.

Abstract: Substance abuse and HIV/AIDS are two of the most serious, yet treatable diseases worldwide. Global access to HIV treatment continues to expand. In settings where both active illicit drug use and HIV treatment are concurrent, potentional problematic pharmacokinetic drug interactions may arise and complicate therapy. Clinical case series and carefully controlled pharmacokinetic interaction studies have been conducted between only a few drugs of abuse and approved antiretroviral therapies. Important pharmacokinetic drug interactions have been described for benzodiazepines, 3,4-methylenedioxymethamphetamine, methadone and buprenorphine; however, most have not been studied and few well-controlled studies have been conducted to adequately address the clinical implications of these interactions. The metabolism of drugs of abuse, description of the known interactions, and clinical implications and management of these interactions are reviewed. Certain interactions between drugs of abuse and antiretroviral therapi...

Measuring the mind: assessing cognitive change in clinical drug trials

Abstract: Forgive the pun, but it seems as though everyone is thinking about cognition. Until recently, the main concern in CNS drug development was the extent to which new compounds might have deleterious e...

Once-daily oral deferasirox for the treatment of transfusional iron overload.

Abstract: The increasing use of blood transfusions, combined with extended patient survival, has led to an increase in the number of patients at risk of developing transfusional iron overload. Clinical data have shown that the once-daily oral iron chelator deferasirox is effective in adults and children with various transfusion-dependent anemias, including β-thalassemia and the myelodysplastic syndromes. Deferasirox has a defined, clinically manageable safety profile. The most common treatment-related adverse events are mild gastrointestinal disorders, skin rash and mild, nonprogressive serum creatinine increases. The deferasirox clinical trial program is continuing in Phase II/III extension phases and Phase IV trials. Long-term data continue to support the efficacy and safety of deferasirox. Convenient, effective and tolerable chelation therapy with deferasirox is a significant development in the treatment of transfusional iron overload.

Possible dose–side effect relationship of antipsychotic drugs: relevance to cognitive function in schizophrenia

Abstract: Management of adverse events is a major concern of clinicians who use antipsychotic drugs. The incidence of motor side effects is dose dependent. Atypical antipsychotic drugs are less likely to induce neurologic side effects compared with typical (conventional) antipsychotics, such as haloperidol. Some recent, large-scale studies have shown that the incidence of metabolic side effects often associated with atypical agents does not differ among typical and atypical antipsychotics. Cognitive function, such as verbal learning memory, working memory, executive function, verbal fluency and attention/information processing, is the most influential determinant of outcome in patients with schizophrenia. Atypical antipsychotic drugs have been shown to be more efficacious in treating cognitive disturbances of schizophrenia compared with typical antipsychotic drugs. Serotonin (5-hydroxytryptamine [5-HT]) receptor subtypes, such as the 5-HT1A receptor, are considered to mediate the ability of antipsychotic drugs to enhance cognition. On the other hand, treatment with some atypical agents, such as risperidone, may deteriorate working memory in some people with early-stage schizophrenia. The paradoxical side effects of these antipsychotic drugs in terms of cognition may be attributable to dose, duration of treatment and type of cognitive domain. Further research will add to the worldwide endeavor to develop more effective psychotropic drugs accompanied with minimal side effects, for the improvement of cognition, adherence and long-term outcome in patients with schizophrenia or other major psychiatric illnesses.

New-generation efflux pump inhibitors.

Abstract: The development of novel efflux pump inhibitors is an emerging and challenging research field. Besides the use of such excipients in cancer therapy, efflux pump inhibitors are gaining increasing interest with regards to drug delivery. In particular, inhibition of efflux pumps located in the intestine and the blood–brain barrier offers promising prospects. Nowadays, third-generation inhibitors, such as elacridar, zosuquidar, laniquidar, OC144-093 and tariquidar, have been evaluated in clinical trials. Apart from these small, molecular inhibitors, which will be discussed within the current review, a focus has been set on polymeric or polymer-based inhibitors, including poly(ethylene glycol) and derivatives, poloxamers and thiomers.

Major malformations after first trimester exposure to aspirin and NSAIDs.

Abstract: The use of aspirin and other NSAIDs during the first trimester of pregnancy is widespread, despite inconclusive evidence regarding the possible risks for the baby. We present an overview of the current evidence relating to the associations between aspirin or NSAID use during the first trimester of pregnancy and the risk of congenital malformations. We systematically searched Medline, Embase, the Cochrane Library and the reference lists of all relevant articles from 1966 to March 2008 that examined the association between aspirin and NSAID use during the first trimester of pregnancy and the risk of congenital malformations in humans. We analyzed 30 studies that met the predefined inclusion criteria: 22 case–control studies, seven cohort studies and one randomized, controlled trial. There are not enough human data available to assess the effect of high-dose aspirin and NSAIDs in pregnant women, such as those used in the treatment of rheumatoid arthritis, osteoarthritis and pain relief. This review suggests ...

New approaches to the pharmacotherapy of neuropathic pain.

Abstract: Pain is one of the most debilitating symptoms that presents with neuropathy. Neuropathic pain syndrome is a challenge to treat and, even with appropriate evidence-based treatment, only a 40% reduction of symptoms can be achieved in approximately half of patients. Furthermore, efficient doses are often difficult to obtain because of adverse effects. These observations underline that the treatment of neuropathic pain is still an unmet medical need. New approaches to the pharmacotherapy of neuropathy embrace different lines of work, including a fundamental mechanism-based approach, a clinical mechanism-based approach and an evidence-based approach. Moreover, interindividual variability in drug response, and genetic polymorphism in particular, is an emerging aspect to consider. Together with reviewing recent evidence-based guidelines as well as briefly discussing genetic polymorphisms that may influence the individual responses to treatments, this article will focus on what a mechanism-based approach is bringing to the clinical setting, on the perspective in fundamental research and on the difficulty of bridging the gap between fundamental notions and positive clinical outcomes.

Role of the serotonin transporter in pulmonary arterial hypertension.

Abstract: Pulmonary arterial hypertension is a disease in which pulmonary arterial pressure is raised, leading to right heart failure. Survival is poor despite current therapeutic strategies. The 'serotonin hypothesis of pulmonary arterial hypertension' arose in the 1960s following an 'epidemic' of pulmonary arterial hypertension in women taking the indirect serotinergic agonist aminorex as an anorexigen. In the 1980s, the hypothesis was revisited following the occurrence of pulmonary arterial hypertension associated with the use of fenfluramines as anorexigens; these are also indirect serotinergic agents. Research has identified changes in serotonin synthesis, serotonin receptor activation and serotonin uptake via the serotonin transporter in experimental and clinical pulmonary arterial hypertension. This review will discuss our current understanding of this serotonin hypothesis with particular reference to the role of the serotonin transporter.

Inflammatory reactions and drug response: importance of cytochrome P450 and membrane transporters

Abstract: Inflammatory reactions (IRs), both infectious and aseptic, downregulate numerous enzymes of cytochrome P450 (CYP) and ATP-binding cassette transporters. The mechanism involves proinflammatory cytokines and activation of transcription factors, nuclear factor-κB, CCAAT-enhancer-binding protein-β and c-myc, which bind to negative regulatory elements and/or impede the binding of nuclear receptors to promoter elements. Downregulation of CYP enzymes and transporters modulates the kinetics of a drug, resulting in increased plasma and tissue concentrations of the drug and enhanced effect and/or toxicity. Clinical trials have shown that IRs increase the risk of myocardial infarction and stroke. In this article, we speculate that IRs downregulate cardiac and vascular CYP enzymes (CYP2C8/9 and CYP2J2) responsible for the formation of vasorelaxant products. Patients with IRs should be advised that the risk of drug adverse effects and of cardiovascular diseases is increased; therefore, the benefit-risk ratio and use of drugs with narrow therapeutic index should be revaluated, as well as the conditions precipitating cardiovascular events.

Pharmacological enhancement of protease inhibitors with ritonavir: an update

Abstract: Advances in HIV treatment since the approval of the first antiretroviral (ARV) medication have occurred at a rapid pace. However, resistance to these medications can occur quickly owing to inadequate plasma concentrations resulting from poor adherence related to intolerable drug toxicities and complex dosing schedules. Drug–drug and drug–food interactions can also result in inadequate ARV drug exposure. Ritonavir is a potent cytochrome P450 3A4 inhibitor and low doses can be used in combination with almost all protease inhibitors to overcome most drug–drug and drug–food interactions. Little toxicity can be attributed to the addition of low-dose ritonavir to an ARV regimen, and most patients find that the added pills do not adversely affect adherence. This article reviews the pharmacological use of ritonavir for pharmacokinetic enhancement (or boosting) and updates the clinical use of boosted protease inhibitors.

Ebastine fast-dissolving tablets versus regular tablets: acceptability and preference in patients with allergic rhinitis.

Abstract: A new fast-dissolving tablet (FDT) formulation of ebastine has been developed that dissolves rapidly in the mouth without the need for water. This new formulation of ebastine FDT offers an opportunity to tailor prescribing in a way that meets patient’s preferences. The aim of the reported study was to evaluate the preferences of allergic rhinitis patients who were given either a placebo version of ebastine FDT or a placebo version of ebastine regular tablet (RT). Allergic rhinitis patients from Germany, Italy and Mexico, who were regular consumers of oral antihistamines, were recruited to a randomized, crossover study comparing placebo forms of ebastine FDT and ebastine RT. Patients were interviewed at home and were given both a FDT and RT (10 and 20 mg doses were used with a 1:1 ratio). Data on patient preferences were recorded by an interviewer and analyzed using descriptive statistics. A total of 420 individuals participated (140 in each country), 70% with intermittent and 24% with persistent allergic ...

Drug discovery based on genetic and metabolic findings in schizophrenia

Abstract: Recent progress in the genetics of schizophrenia provides the rationale for re-evaluating causative factors and therapeutic strategies for this disease. Here, we review the major candidate susceptibility genes and relate the aberrant function of these genes to defective regulation of energy metabolism in the schizophrenic brain. Disturbances in energy metabolism potentially lead to neurodevelopmental deficits, impaired function of the mature nervous system and failure to maintain neurites/dendrites and synaptic connections. Current antipsychotic drugs do not specifically address these underlying deficits; therefore, a new generation of more effective medications is urgently needed. Novel targets for future drug discovery are identified in this review. The coordinated application of structure-based drug design, systems biology and research on model organisms may greatly facilitate the search for next-generation antipsychotic drugs.

Ethnic differences in drug therapy: a pharmacogenomics perspective.

Abstract: “Pharmacogenetics deals with pharmacological responses and their modification by hereditary influences.” This definition, offered by Werner Kalow in the first book dedicated to pharmacogenetics, highlights the three pillars of this discipline: pharmacology, genetics and human diversity [1]. Pharmacogenetics has evolved greatly over the 50 years since Kalow ́s book was published, and was rechristened pharmacogenomics (PGx) in the fashion of the ‘omics’ revolution, but its conceptual development and praxis remain contingent upon a better understanding of human genomic diversity and its impact on drug pharmacokinetics and pharmacodynamics. Ethnic specificity has become an integral part of pharmacogenetics/PGx research to the extent that, at the writing of this editorial, the PubMed database lists over 400 entries, including 141 reviews, for a query combining the terms ‘pharmacogen* and ethnicity’. The accumulated data reveal that allele, genotype and haplotype frequency of polymorphisms in ‘pharmacogenes’ (genes of pharmacological relevance) may differ significantly among populations categorized by ‘race’, ethnicity or continental origin. Such differences may be large (>50%) as is the case, for example, of the CYP3A5*3 and GSTM3*B allele frequency between Europeans and sub-Saharan Africans. However, equally large or even larger intraethnic PGx variability is also evident, such as the fivefold range of CYP3A5*3 frequency among sub-Saharan Africans or the 17-fold range of CYP2C19*2 frequency within Europeans [2,101]. Two other facts conflict with the notion of race-based drug therapy in the context of PGx-informed clinical pharmacology: first, only rarely, if ever, is a PGx polymorphism absent or common (>5%) exclusively in one specific population. Although large-scale resequencing studies of PGx candidate genes are more likely to identify low-frequency polymorphisms that are ‘private’ to a given population group, the implications of these findings on the praxis of PGx are still debatable. Second, data from a worldwide analysis of CYP2D6 polymorphisms disclosed that the patterns of variation within and among populations are best described as a broad geographic cline, with no continental structure, similar to those shown by neutral markers [3].

Development of individualized medicine for epilepsy based on genetic information

Abstract: Despite the continuous development and release of new anti-epileptic drugs (AEDs), almost one in four patients are resistant to AED therapy. Current therapy requires trial and error to determine the most effective AED and dosage for a patient. The development of individualized medicine for epilepsy is critical for improving AED treatment, particularly that based on genetic information. However, several crucial issues remain to be resolved before the development of AED therapy can proceed further. The epilepsy genes responsible for common phenotypes have not yet been identified and ongoing pharmacogenetic studies continue to search for an explanation as to why 20-25% of patients do not respond to AEDs. There is no convincing clinical evidence that P-glycoprotein at the blood-brain barrier limits the uptake of AEDs into the brain of epileptic patients and contributes to the development of the drug-resistant phenotype. This article provides a critical review of the status and perspectives for the development of individualized medicine for epilepsy, based on genetic polymorphisms/mutations in relation to three major components: the pharmacodynamic pathway, the pharmacokinetic pathway and the mechanisms of action of AEDs. The development of multiplex assay technologies, together with the generation of epilepsy animal models bearing human epilepsy genes, are also discussed.

Biomarkers of drug-induced adverse events.

Abstract: Many drugs on the market have the potential to cause undesirable side effects. Biomarkers used today, at best, diagnose an existing injury, such as cell death or abnormal functioning of an organ. More valuable would be biomarkers that could be used to prevent a patient from receiving an inappropriate drug or to identify very early signs of injury so the offending drug may be discontinued prior to overt tissue injury. Biomarkers currently used to identify drug-induced injury to the liver, heart and kidney will be discussed, as will some newer biomarkers. Progress on finding new biomarkers through the use of pharmacogenetics and pharmacogenomic approaches, consortia that may assist in their discovery and qualification for use, regulatory issues and the pharmacoeconomic considerations that may drive or hinder such new tests are also described.

Opioid-induced hyperalgesia and tolerance: understanding opioid side effects

Abstract: Opioid-induced pain or opioid tolerance should be considered when opioid therapy fails to provide expected analgesic effects or when there is unexplainable pain exacerbation following opioid treatment. As a result, an increase in the opioid dosage may not be the solution to ineffective opioid therapy for chronic pain management. A decrease in the opioid mass may actually provide pain relief in many instances. At one time, it was anticipated that opioid-induced pain was related to upregulation of NMDA receptors with a downregulation of mu receptors. However, there is growing evidence to suggest the opioid receptor-based hyperalgesic mechanism may be directly modulated by the NMDA receptor. Furthermore, the mechanism that causes opioid tolerance may be the same mechanism that causes opioid-induced pain. Current evidence suggests that opioid-induced pain sensitivity could be prevented by interrupting the cellular and molecular changes associated with the development of opioid tolerance. Continued research ma...

TGF-β1 as a therapeutic target for pulmonary fibrosis and COPD

Abstract: TGF-β1 is a multifunctional molecule that is expressed in an exaggerated fashion during injury, inflammation and repair. Its expression is dysregulated in lung tissues from patients with pulmonary fibrosis and chronic obstructive pulmonary disease. In animal models, introduction of TGF-β1 expression in the lung causes prominent tissue fibrosis and alveolar destruction. On the other hand, the exaggerated production of TGF-β1, an inability to activate TGF-β1 or a block in TGF-β1 signaling have all been associated with the development of emphysematous pulmonary lesions. A number of studies have demonstrated that TGF-β1 is a major player in the pathogenesis of pulmonary fibrosis and emphysema. In this review, we discuss how TGF-β1 expression is regulated and mechanistically related to the development of tissue fibrosis and emphysema in experimental animal models and humans. We further highlight potential therapeutic options that control TGF-β1-associated genes or signals to restore extracellular matrix homeostasis in which TGF-β1 plays a central role.

Current Japanese regulatory situations of pharmacogenomics in drug administration

Abstract: Pharmacogenomics (PGx) has the potential impact to improve drug-development efficiencies and proper usages of drugs in clinical practice. However, in order to translate PGx into practical applications, multidisciplinary challenges, such as cost and time in development, processes of genomic biomarker qualification, PGx test availabilities and reimbursements, and education on PGx, still remain in clinical, pharmaceutical and regulatory settings. Japanese regulatory bodies for drug approval (i.e., Ministry of Health, Labour and Welfare and Pharmaceutical and Medical Devices Agency) have been taking proactive actions, both internally and internationally, toward translating PGx from bench to bedside. In this article, we summarize the current situations and projects in regulatory implementations of PGx in drug administrations in Japan, including activities to promote PGx-based drug/device developments and therapies. Moreover, we also discuss the future tasks for utilization of PGx in drug evaluations and clinical practices.

Clinical pharmacology of linezolid: an oxazolidinone antimicrobial agent

Abstract: The oxazolidinones are a new class of antibiotics whose mechanism of action is the inhibition of bacterial protein synthesis by binding to the 50S ribosomal subunit. Linezolid is the first member of this class of antibiotics to be approved by the US FDA and other regulatory bodies for the treatment of infections caused by antibiotic-resistant Gram-positive pathogens, such as methicillin-resistant Staphylococcus aureus, glycopeptide-intermediate S. aureus and vancomycin-resistant Enterococcus, in adults and children.

Pharmacogenetics of drug-induced arrhythmias

Abstract: Abnormal functioning of cardiac ion channels can disrupt cardiac myocyte action potentials and thus cause potentially lethal cardiac arrhythmias. Ion channel dysfunction has been observed at all stages in channel ontogeny, from biogenesis to regulation, and arises from genetic or environmental factors, or both. Acquired arrhythmias - including those that are drug induced - are more common than solely inherited arrhythmias but, in some cases, also contain an identifiable genetic component. This interplay between the pharmacology and genetics - known as 'pharmacogenetics' - of cardiac ion channels and the systems that impact them presents both challenges and opportunities to academics, pharmaceutical companies and clinicians seeking to develop and utilize therapies for cardiac rhythm disorders. In this review, we discuss ion channel pharmacogenetics in the context of both causation and treatment of cardiac arrhythmias, focusing on the long QT syndromes.