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Medical Specialties / Pharmacology

A Prospective, Randomized, Double-Blind Study Assessing the Clinical Impact of Integrated Pharmacogenomic Testing for Major Depressive Disorder

Abstract: Objective: A prospective double-blind randomized control trial (RCT) to evaluate the benefit of a combinatorial, five gene pharmacogenomic test and interpretive report (GeneSight) for the management of psychotropic medications used in the treatment of major depression in an outpatient psychiatric practice. Methods: Depressed adult outpatients were randomized to a treatment as usual (TAU, n=25) arm or a pharmacogenomic-informed GeneSight (n=26) arm. Subjects were blinded to their treatment group and depression severity was assessed by blinded study raters. Within two days of enrollment, clinicians of subjects in the guided group received the GeneSight report that categorized each of 26 psychotropic medications within a green, yellow, or red "bin" based on the relationship of each medication to a subject's pharmacokinetic and pharmacodynamic combinatorial gene variant profile. Antidepressant medication changes began within 2 weeks after baseline assessments. Depression severity was assessed by blinded study raters using the HAMD-17, PHQ-9, QIDS-SR, and QIDS-CR administered 4, 6, and 10 weeks after baseline assessment. Results: Between-group trends were observed with greater than double the likelihood of response and remission in the GeneSight group measured by HAMD-17 at week 10. Mean percent improvement in depressive symptoms on HAMD-17 was higher for the GeneSight group over TAU (30.8% vs 20.7%; p=0.28). TAU subjects who had been prescribed medications at baseline that were contraindicated based on the individual subject's genotype (i.e., red bin) had almost no improvement (0.8%) in depressive symptoms measured by HAMD-17 at week 10, which was far less than the 33.1% improvement (p=0.06) in the pharmacogenomic guided subjects who started on a red bin medication and the 26.4% improvement in GeneSight subjects overall (p=0.08). Conclusions: Pharmacogenomic-guided treatment with GeneSight doubles the likelihood of response in all patients with treatment resistant depression and identifies 30% of patients with severe gene-drug interactions who have the greatest improvement in depressive symptoms when switched to genetically suitable medication regimens. ... Read more

Pharmacogenetics of Antidepressants, Mood Stabilizers, and Antipsychotics in Diverse Human Populations

Abstract: An increasing focus on personalized medicine is driving a renewed effort to understand the impact of ethnic and genetic background on treatment outcomes. Since responses to psychopharmacological treatments continue to be sub-optimal, there is a pressing need to identify markers of tolerability and efficacy. Pharmacogenomic studies aim to find such markers within the human genome, and have made some progress in recent years. Progress has been slower in populations with diverse racial and ethnic backgrounds. Here we review 10 genome-wide association studies (GWAS) that assessed outcomes after antidepressant, antipsychotic, or mood stabilizer treatment. These studies used samples collected by the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), Sequenced Treatment Alternatives to Relieve Depression (STAR*D), and Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) studies. We highlight findings from African American and European American participants since they are the largest groups studied, but we also address issues related to Asian and Hispanic groups. None of the GWAS we reviewed identified individual genetic markers at genome-wide significance, probably due to limited sample sizes. However, all the studies found poorer outcomes among African American participants. Some of this disparity seems to be explained by psychosocial and economic disadvantages, but at least 2 studies found that widespread genetic differences between participants of European and African ancestry also play an important role. Non-European groups are underrepresented in these studies, but the differences that are evident so far suggest that poorer outcomes among African Americans are not inevitable and may be particularly suited to pharmacogenomic strategies. The vision of more personalized psychopharmacology may critically depend on larger studies in more diverse human populations. ... Read more

Statin Pharmacogenomics: Pursuing Biomarkers for Predicting Clinical Outcomes

Abstract: Indicated for treating hyperlipidemias and for the prevention of cardiovascular disease (CVD), statins rank among the most commonly prescribed drug classes. While statins are considered to be highly effective in preventing atherosclerotic events, a substantial portion of treated patients still progress to overt CVD. Genetic factors are thought to contribute substantially to treatment outcome. Several candidate genes have been associated with statin dose requirements and treatment outcomes, but a clinically relevant pharmacogenomics test to guide statin therapy has not yet emerged. Here we define basic pharmacogenomics terminology, present strong candidate genes (CETP, HMGCR, SLCO1B1, ABCB1, and CYP3A4/5), and discuss the challenges in developing much-needed statin pharmacogenomics biomarkers for predicting treatment outcomes. ... Read more

Advances in Management of Acute Hypertension: A Concise Review

Abstract: Chronic hypertension affects >1 billion people worldwide and >70 million people in the United States. Acute hypertensive episodes (AHE) are defined as severe spikes in blood pressure that may result in end-organ damage. Although AHE may arise independently as de novo events, they are more likely to occur in patients with pre-existing hypertension. One of the controversies regarding the clinical approach to AHE is the selection of anti-hypertensive medication. Depending on the clinical presentation of the patient and the threat of end-organ damage resulting from blood pressure elevation, appropriate and prompt treatment is warranted. There are multiple agents available for the management of hypertension. However, the greatest challenge lies in the acute care setting where the need exists for better initial and sustained control of blood pressure spikes. Many anti-hypertensive agents effectively lower blood pressure, yet only few have the capacity to achieve strict control of hypertension in the acute setting. Clevidipine butyrate is an ultra short-acting intravenous dihydropyridine calcium-channel blocker. Clevidipine has unique pharmacodynamic and pharmacokinetic properties that enable the fast, safe, and adequate reduction of blood pressure in hypertensive emergencies, with the ability to provide highly precise titration necessary to maintain a narrowly-defined target blood pressure range. Several recently published phase I, II, and III clinical studies have shown Clevidipine to be an effective blood pressure modulator in such capacity. ... Read more

Transporter Pharmacogenetics: Transporter Polymorphisms Affect Normal Physiology, Diseases, and Pharmacotherapy

Abstract: Drug transporters mediate the movement of endobiotics and xenobiotics across biological membranes in multiple organs and in most tissues. As such, they are involved in physiology, development of disease, drug pharmacokinetics, and ultimately the clinical response to a myriad of medications. Genetic variants in transporters cause population-specific differences in drug transport and are responsible for considerable inter-individual variation in physiology and pharmacotherapy. The purpose of this review is to provide a broad overview of how inherited variants in transporters are associated with disease etiology, disease state, and the pharmacological treatment of diseases. Given that there are thousands of published papers related to the interplay between transporter genetics and medicine, this review will provide examples that exemplify the broader focus of the literature. ... Read more

Recovery from Post-stroke Aphasia: Lessons from Brain Imaging and Implications for Rehabilitation and Biological Treatments

Abstract: Aphasia, a condition defined as the partial or complete loss of language function after brain damage, is one of the most devastating cognitive deficits produced by stroke lesions. Over the past decades, there have been great advances in the diagnosis and treatment of post-stroke language and communication deficits. In particular, the advent of functional brain imaging and other brain mapping methods has advanced our understanding of how the intact and lesioned brain takes over the activity of irretrievably damaged networks in aphasic patients. This review examines the contribution of these ancillary methods to elucidate the neural changes that take place to promote improvement of language function in early, late, and very late stages of recovery. Also, functional neuroimaging is helpful to identify brain areas involved in language recovery as well as to characterize the plastic reorganization of neural networks produced by scientifically-based language therapies and biological treatments (drugs, transcranial magnetic stimulation). ... Read more

Pharmacogenomics in Ophthalmology

Abstract: Inter-individual variation in drug response and adverse drug reactions (ADRs) are well known in medicine. This individual variation in drug response could be at least, in part, due to genetic diversity among individuals. Although substantial studies that connect genetic variants to inter-individual variation in drug response have been documented in several diseases such as cancer and heart diseases, such studies are slowly progressing in ophthalmology. In recent years, advancement in technologies has led to the identification of genes associated with several eye disorders. At the same time, some small-scale studies have demonstrated the association of various genotypes or haplotypes with response to drug therapies. However, its integration into clinical practice in ophthalmology is not possible at present. This is because there are many challenging questions that remain to be addressed. For instance, in the case of complex disorders a single gene study is not enough. Multiple genes, environmental factors, multiple single nucleotide polymorphisms (SNPs), and rare or low frequency variants may contribute to the disease and they must be considered. The functional aspects of many genetic variants are not known. This raises questions of their biological importance and their clinical usefulness. In addition, there are legal, ethical, and social issues that need to be regulated. Moreover, physicians and patients must be educated about the limitation and sensitivity of genetic testing. At present pharmacogenetic studies in ophthalmology are still in their infancy and do not suggest that a pharmacogenetic basis of drug development in ophthalmology is a concept that can yield immediate results, but can become a reality in the future. In this article an attempt has been made to summarize some of the recent small-scale pharmacogenetic studies on two major eye disorders, age-related macular degeneration (AMD) and glaucoma. ... Read more

New Insight into Clinical Development of Nucleic Acid Aptamers

Abstract: Nucleic acid-based aptamers have been shown as high-affinity ligands and potential antagonists of disease-associated proteins. Aptamers, isolated from combinatorial libraries by an iterative in vitro selection process, discriminate between closely related targets and are characterized by high specificity and low toxicity thus representing a valid alternative to antibodies to target specific proteins of biomedical interest. Moreover, they are non-immunogenic and can be easily stabilized by chemical modifications thus expanding their therapeutic potential. Here, we will focus on the structural and functional features of aptamers that have entered the clinical development pipeline together with those aptamers holding great potential as therapeutics in preclinical studies. The future perspectives of aptamers as therapeutics will be discussed as well. ... Read more

Pharmacogenetic Mechanisms Underlying Unanticipated Drug Responses

Abstract: Because most medicines have not been encountered by individuals of our species prior to treatment, it follows that treatment could uncover a previously silent genetic predisposition or could interact with a known genetic variation(s) to produce an unintended outcome. Pharmacogenetics encompasses the discovery, testing, and application of genetic variation as applied to therapeutic treatment and outcome. Two broad divisions of pharmacogenetics are recognized: pharmacokinetics, which describes genetic variations that affect drug metabolism, and pharmacodynamics which describes similar processes that have effects on drug targets, including downstream signaling pathways. The genetic mechanisms that underlie an altered drug response recapitulates most known sources of genomic variation. The most commonly encountered is sequence variation. This includes changes in the primary nucleotide sequence of coding, regulatory, and splice regions of a gene, the product of which affects, or is affected by, a drug. Less common forms of variability in the structure and function of the genome have also been found to underlie an individualized response to medicines. Among these are sequence variation in microRNA (miRNA) binding sites, which affects the ability of miRNA to regulate translation; pharmacoepigenetics, which examines heritable chromatin modifications; and copy number variation. Among the 158 currently registered pharmacogenetic clinical trials, the most frequent conditions or disease processes being studied are cancer, psychiatric disorders, and coagulation/thrombosis. From this observation, it is postulated that pharmacogenetics has its greatest potential for optimizing the use of drugs with a high rate of failure or adverse outcomes. ... Read more

Genome-wide Approach to Identify Novel Candidate Genes for Beta Blocker Response in Heart Failure Using an Experimental Model

Abstract: Background: We explored use of a canine model of heart failure (HF) for pharmacogenomic discovery, specifically analyzing response to beta blockers (BB). Methods: Dogs with HF that received BB (n=39) underwent genome-wide genotyping to test the association with changes in left ventricular (LV) volume and ejection fraction after treatment. Resulting candidate genes underwent RNA quantification in cardiac tissue from normal (n=5), placebo-HF (n=5), and BB-HF (n=7) dogs. Results: Three markers met whole-genome significance for association with improved LV end-systolic volume after BB therapy (each p<5x10-7). RNA quantification of three candidate genes near these markers -- GUCA1B, RRAGD, and MRPS10 -- revealed that gene expression levels in BB-HF dogs were between that of placebo-HF dogs and normal dogs. Conclusion: Genome-wide pharmacogenomic screening in a canine model of HF suggests 3 novel BB response candidate loci. This approach is adaptable to discovering mechanisms of action for other drug therapies, and may be a useful strategy for identifying candidate genes for drug response in the pre-clinical setting. ... Read more

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