Omicron variant as nature's solution to the COVID-19 pandemic.

WHAT IS KNOWN AND OBJECTIVE: Omicron is a variant of the COVID-19 virus that is causing considerable concern worldwide, with an increasing number of countries re-imposing national lockdowns. Our objective is to comment on its impact and to suggest that, threatening as it is, Omicron may well contribute to a resolution of the current pandemic. COMMENT: On 31 December 2019, the World Health Organization (WHO) reported on a cluster of cases of pneumonia in Wuhan, China. Soon after, Chinese investigators who made the discovery identified the causative virus as a new coronavirus, now known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). An effective vaccine was licenced for emergency use within a year of its first sequencing. SARS-CoV-2, in common with many respiratory viruses, mutates rapidly, and the challenge for vaccine developers is to obtain vaccines that are effective against the new variants. The licenced first-generation vaccines were fortunately all highly effective against the variant known as Delta. The variant of greatest current concern is the Omicron variant, a highly infectious agent, which seems to show a significant vaccine escape with existing vaccines. Infection protects against further infection. If Omicron turns out to cause less severe disease, it may well be a contributor to ending the pandemic. WHAT IS NEW AND CONCLUSION: It is unlikely that the available vaccines will bring rapid control of the current pandemic, given their patchy availability worldwide and the residual pool of unvaccinated people. New vaccines take time to develop and to deploy even in the age of mRNA vaccines. If Omicron turns out to be relatively mild, it may well be that when we look back at the history of the current pandemic, the variant would be seen as a contributor to its solution. The hand of nature may well show more largesse than the developed nations in immunizing the world.

Drug compliance and the Morisky Adherence Scale: An expression of concern and a warning.

WHAT IS KNOWN AND OBJECTIVE: Every prescriber knows that patients often do not take their medicines as prescribed. Hippocrates, the wise man of Kos, knew over two millennia ago. Our objective is to comment on the types of studies aimed at understanding and optimizing drug usage and to draw attention to the need to seek approval before using or citing the Morisky adherence scale. COMMENT: The study of prescribing and how patients use their medicines is important. As part of this effort, the results of investigations of how patients adhere to drug prescriptions can be informative. However, the results are meaningful only if the methods used for doing the measurements are valid and made explicit. We were surprised when a team of our authors were threatened with legal action for citing the Morisky Adherence Scale and explaining how some authors had obtained their adherence scores. Adherence studies are but one facet of the study of prescribing aimed at improving clinical outcomes. Other aspects include investigating the quality of prescribing, and how unnecessary medicines can be deprescribed to improve the quality of care and reduce the risk of adverse effects. WHAT IS NEW AND CONCLUSION: The study of optimal prescribing is an important endeavour and adherence studies are but one aspect. We report that using and citing the Morisky Adherence scale in any detail is a risky business. Prior approval is required unless one is prepared to pay up, retrospectively. We require all authors to certify they have no conflicts of interest with respect to the scale.

Genomic research delivering on promises: From rejuvenation to vaccines and pharmacogenetics.

WHAT IS KNOWN AND OBJECTIVE: There has been astounding progress made in the treatment of disease over recent years. This progress is particularly marked in cell therapy and in the personalization of therapy based on genetic insight, an approach known as genomic medicine. Our objective is to comment on the progress made in cell and genomic medicine against an historical backcloth of the search for rejuvenation. COMMENT: In 1741, close to seven decades after Antoine van Leeuwenhoek first saw his microscopic animalcules, Abraham Trembley, a tutor in Leiden, reported on an organism that could regenerate itself. The strange organism was thought to hold the secret of life. If it does, we have yet to prise the secret out. However, the ensuing study of cell programming and induced stem cells has shed considerable light on cellular development and provided new insights on the rejuvenative capacity of organisms. Inventive scientists have provided a deeper understanding of cell replication and, from this, developed new medicines for an increasing range of diseases. Targeted therapies, oligonucleotide therapy, therapeutic monoclonal antibodies and pharmacogenetics are all new therapeutic areas originating from the improved insights. More will surely follow. WHAT IS NEW AND CONCLUSION: Immortality is for the gods, but man's search for its elusive secrets, perhaps as old as man himself, will continue. Huge leaps have been made, and effective medicines have been developed from our improved insights into the mechanism of life. However, only the foolish will predict how far this new knowledge will lead us, and more particularly, at what speed new therapies will follow.

Clinical pharmacy in the genomic era / Farmacia clínica en la era del genoma

Over a century ago Gregor Mendel investigated quantitatively how physical traits of plants were passed on from one generation to the next. Soon after, William Bateson and Archibald Garrod showed the relevance of Mendel’s findings to human disease. Pharmacists have throughout history marketed themselves as experts who could treat disease with specific medicines. Their claims were however poorly validated until Louis Pasteur and Robert Koch established the microbial aetiology of many diseases. Effective antimicrobial agents and immunotherapies soon became available for an expanding range of infections, and personalisation of treatment became possible through sensitivity testing. Later, a greater understanding of the molecular pathogenesis of nonmicrobial diseases led to the development of effective drugs, such as antihypertensives and anticoagulants. As a result, current pharmacopoeias bear no resemblance to their predecessors cluttered with predominantly useless drugs. With the unravelling of the double helical structure of DNA and greater understanding of its implications for health and disease, pharmacopoeias are being rewritten again. The new drugs enable an unprecedented level of individualisation of therapy. To optimise the promise of these drugs, input from a new generation of well-informed clinical pharmacists is needed. In this presentation, we identify some of these developments, and where input from pharmacists is most likely to be required. Will clinical pharmacists deliver? (AU)

Hace más de un siglo Gregor Mendel investigó cuantitativamente cómo se transmitían los rasgos físicos de las plantas de una generación a la siguiente. Poco después, William Bateson y Archibald Garrod mostraron la relevancia de los hallazgos de Mendel en las enfermedades humanas. A lo largo de la historia, los farmacéuticos se han considerado como expertos que podían tratar la enfermedad con medicamentos específicos. Sin embargo, sus afirmaciones fueron mal validadas hasta que Louis Pasteur y Robert Koch establecieron la etiología microbiana de muchas enfermedades. Los agentes antimicrobianos eficaces y las inmunoterapias pronto estuvieron disponibles para un número de infecciones en expansión y la personalización del tratamiento se hizo posible a través de pruebas de sensibilidad. Posteriormente, una mayor comprensión de la patogénesis molecular de las enfermedades no microbianas condujo al desarrollo de fármacos eficaces, tales como antihipertensivos y anticoagulantes. Como resultado, las farmacopeas actuales no guardan ningún parecido con sus predecesoras llenas de drogas básicamente inútiles. Con la desintegración de la doble estructura helicoidal del ADN y una mayor comprensión de sus implicaciones para la salud y la enfermedad, las farmacopeas se están volviendo a escribir. Los nuevos fármacos permiten un nivel sin precedentes de individualización de la terapia. Para optimizar la promesa de estos fármacos, se necesita el aporte de una nueva generación de farmacéuticos clínicos bien informados. En esta presentación, identificamos algunos de estos desarrollos y el lugar en el que el papel de los farmacéuticos es más probable que sea necesario. ¿Cumplirán los farmacéuticos clínicos? (AU)

The human genome: its modifications and interactions with those of the microbiome, and the practice of genomic medicine.

In genomic medicine, the nuclear genome is usually the focus of discussion. However, recent developments in genomics show that our interaction with the biological world at large alters our susceptibility to disease and our response to drugs. For example, in addition to causing infection, the trillions of microbial cells that inhabit our bodies (our microbiome), are now known to shape our immune system and our metabolic health. Moreover, mitochondria, the long-assimilated symbionts, are the focus of considerable current genomic research that is making possible, interventions that were at one time in the realms of science fiction. Furthermore, genomics research of the cancer cell is sufficiently refined to enable us to define its genome as a distinct entity suitable for selective drug-targeting. In this contribution we discuss, within their historical contexts, some of these seemingly disparate scientific strands to highlight the importance of embracing a broader multiple-genomic vista when dealing with disease causation, prevention, and management.

The Pharmacogenetic Rescue of Side-Lined Anticancer Drugs to the Front-Line: Gefitinib as a Case Example.

OBJECTIVE: To illustrate the increasing importance of pharmacogenetics in drug development and clinical practice through a critical analysis of the validation and licensing of gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, as a treatment for non-small cell lung cancer (NSCLC). DATA SOURCES: Journal articles and the "grey" literature were identified through a systematic search of MEDLINE (to June 2010) and the Web sites of the major drug regulators. References identified through the reference lists of major published reviews of gefitinib and Erb receptors, including EGFR, were also reviewed. STUDY SELECTION AND DATA EXTRACTION: A broad appraisal of the titles and abstracts of articles on gefitinib and tyrosine kinase inhibitors in lung cancer was undertaken to identify pertinent concepts and relevant publications for further analysis. Articles deemed particularly relevant were retrieved for detailed appraisal. Dossiers on the licensing of gefitinib from the Food and Drug Administration Web site and major published reviews were retrieved. Relevant pharmacogenetic issues were identified and the clinical studies addressing these were evaluated. DATA SYNTHESIS: Initial promising trial data for gefitinib in NSCLC led to its conditional marketing approval. When the drug's efficacy was not confirmed in a pivotal Phase 3 trial, its prescribing was restricted. Subsequent discovery of activating mutations in the tyrosine kinase domain of EGFR led to further retrospective and prospective evaluation of the drug in patients with those mutations. The new evidence was sufficiently robust to persuade the drug regulators to license the drug as first-line treatment for patients with locally advanced or metastatic NSCLC who test positive for those mutations. CONCLUSIONS: Pharmacogenetic evidence has played a key role in rescuing gefitinib for front-line treatment of NSCLC. This case-example portends what will be increasingly likely scenarios in the regulation and clinical validation of targeted drug therapies.

Preventing the aortic complications of Marfan syndrome: a case-example of translational genomic medicine.

The translational path from pharmacological insight to effective therapy can be a long one. We aim to describe the management of Marfan syndrome as a case-example of how pharmacological and genomic insights can contribute to improved therapy. We undertook a literature search for studies of Marfan syndrome, to identify milestones in description, understanding and therapy of the syndrome. From the studies retrieved we then weaved an evidence-based description of progress. Marfan syndrome shows considerable heterogeneity in clinical presentation. It relies on defined clinical criteria with confirmation based on FBN1 mutation testing. Surgical advances have prolonged life in Marfan syndrome. First-line prophylaxis of complications with ß-adrenoceptor blockers became established on the basis that reduction of aortic pressure and heart rate would help. Over-activity of proteinases, first suggested in 1980, has since been confirmed by evidence of over-expression of matrix metalloproteinases (MMP), notably MMP-2 and MMP-9. The search for MMP inhibitors led to the evaluation of doxycycline, and both animal studies and small trials, provided early evidence that this widely used antimicrobial agent was useful. Identification of the importance of TGF-ß led to evaluation of angiotensin II type I receptor (AT(1) R) blockers with highly promising results. Combination prophylactic therapy would appear rational. Pharmacological and genomic research has provided good evidence that therapy with losartan and doxycycline would prevent the aortic complications of Marfan syndrome. If on-going well designed trials confirm their efficacy, the outlook for Marfan syndrome patients would be improved considerably.

Pharmacogenetics of CYP2C19: functional and clinical implications of a new variant CYP2C19*17.

AIMS: Cytochrome P450 2C19 metabolizes many important drugs. In 2006, a variant allele (CYP2C19*17) associated with increased activity was discovered, but its likely clinical significance is controversial. Investigators disagree about the phenotype to be assigned to the two CYP2C19*17 genotypes. The aim of this study was to provide a critical summary, helpful to prescribers. METHODS: We searched MEDLINE for papers on the allele from 2006 and then undertook historical searches through the reference lists of papers retrieved. The relevant information was critically assessed and summarized. RESULTS: CYP2C19*17 was associated with increased enzymic activity. Substrates studied were omeprazole, pantoprazole, escitalopram, sertraline, voriconazole, tamoxifen and clopidogrel. Most studies used pharmacokinetic variables as outcome measure. For clopidogrel, activated by CYP2C19, pharmacodynamic consequences focused on platelet aggregation. While for most pharmacokinetic parameters of the substrates studied the average value was altered, the range of values showed mostly complete overlap for CYP2C19*1/*17 heterozygotes and wild-type homozygotes. Even for CYP2C19*17 homozygotes, the absolute effect was modest compared with the effect of previously identified loss-of-function alleles. In Helicobacter pylori eradication CYP2C19*2 carriage was associated with an altered eradication rate (odds ratio 4.20, 95% confidence interval 1.23, 16.44) relative to the wild-type, but CYP2C19*17 homozygosity was not. Prevalence of the variant allele was typically <5% in Asians and about four times higher in White and African populations. CONCLUSIONS: Assignment of CYP2C19*17 homozygotes as extensive metabolizers rather than ultrarapid metabolizers is adequate. CYP2C19*17 genotyping is unlikely to have clinical utility except for drugs with very narrow therapeutic indices.

Integrating pharmacogenetics and therapeutic drug monitoring: optimal dosing of imatinib as a case-example.

PURPOSE: To illustrate the interface of pharmacogenetics and therapeutic drug monitoring and to estimate target blood level for imatinib in the treatment of chronic myelogenous leukemia METHODS: A literature review to provide the evidence and necessary data to support the case for the interface, and quantitative analysis of the data to estimate the target blood level for imatinib using receiver operating curve (ROC; signal detection theory) analysis. RESULTS AND DISCUSSION: One study estimated the optimum target level of imatinib in chronic myelogenous leukaemia as 1002 ng/mL (1.70 microM) through ROC analysis. Using individual-patient level data reported in another study and the same methodology, we estimated the target level as 0.95 microM. This is consistent with the results of other observational studies where dose-response was not the primary research objective. The available evidence suggests considerable inter-individual variability in dose-blood level response. In addition to the pharmacogenetics of metabolic enzymes and transporters, genetic mutations in genes participating in the signalling pathways may also account for the wide inter-individual variability in dose-blood level and dose-clinical response relationships. CONCLUSION: A single-dose regimen for all pharmacogenetically eligible patients is not the optimum strategy for prescribing imatinib to patients with chronic myelogenous leukaemia. We suggest that therapeutic drug monitoring aimed at ensuring a trough target level of 1 microM would reduce the incidence of pseudo-resistance and hence personalize treatment and optimise response to imatinib. Persistent resistance can then be probed further for other causes.

A mathematical model to improve on phenotyping for molecular genetic research in malignant hyperthermia.

BACKGROUND: The in-vitro contracture test is the standard test to diagnose malignant hyperthermia (MH) susceptibility. Maximum sensitivity is important for patient safety. For scientific purposes, the reduced specificity of contracture testing is a major drawback, and precise phenotyping is of utmost importance. Our study aimed to improve phenotyping for MH susceptibility to more accurately select patients for molecular genetic research in MH, thus, improving the probability to detect novel MH associated variants. METHODS: Patients who underwent contracture and molecular genetic testing were selected from the database of two MH investigation centres (Basel and Leipzig). The area under the curve of halothane and caffeine contracture tests was calculated and a logistic regression model was applied to determine the odds of carrying a MH associated genetic variant. This model was subsequently applied to patients without familial MH related genetic variant. RESULTS: Validation of the logistic regression model showed 98% concordance with molecular genetic results. Among patients with unclear in-vitro contracture test diagnosis (MH equivocal), half of the mutation carriers were classified as positive by the model, whereas 86% of those without familial mutation were classified as negative. Excluding the MH equivocal group, the model showed sensitivity of 0.99 (95% confidence interval: 0.95-0.99) and specificity 0.98 (95% confidence interval: 0.94-0.99), respectively, to identify genetically positive MH individuals. CONCLUSION: Our model is a valuable tool to select patients from MH families for further molecular genetic research. This preselection increases the probability of successful molecular genetic research and is important when available resources are limited.