Pharmacological Society Research Articles

Investigation of the novel pharmacology of Neuropeptide Y (NPY) receptor dimers constrained by bimolecular fluorescence complementation (BiFC)

Dimerisation of GPCRs potentially influences their pharmacology via binding site cooperativity or modified signalling. We have used bimolecular fluorescence complementation (BiFC; Kilpatrick et al. (2012) Methods Mol Biol 897) to constrain Neuropeptide Y (NPY) Y1 receptor (Y1R) homo and heterodimers of known composition. Using quantitative platereader imaging we measured the internalisation of BiFC receptor dimers simultaneously with endocytosis of SNAP tagged Y1R protomer to compare the pharmacology of Y1/Y1, Y1/Y4 or Y1/Y5 BiFC dimers.Y1/Y1 and Y1/Y4 BiFC dimers internalised in response to NPY or PP (Y1/Y4), with potencies comparable to individually expressed YR subtypes. Endocytosis of Y1/Y1 or Y1/Y4 dimers to NPY was also inhibited by the Y1 antagonist BIBO3304, with expected pKb values ((8.2–8.5) from NPY concentration‐response curve shifts). However, the Y5 selective agonist PP(1–17)(Ala31, Aib32) NPY(18– 36) showed reduced potency for constrained Y1/Y5 BiFC dimers, compared to Y5‐GFP internalisation. BIBO3304 demonstrated a lower apparent affinity (pKb 7.4 ± 0.1) for Y1/Y5 BiFC dimers compared to the SNAP‐Y1 sub‐population (pKb 8.2 ± 0.4). This suggests an interaction between Y1 and Y5 orthosteric binding sites of Y1/Y5 BiFC dimers, with implications for selective targeting of this dimer as a mediator of central NPY appetite responses. LK is supported by the British Pharmacological Society.

English

The objective of this study was to establish a high performance liquid chromatography (HPLC) method for the determination of levo-tetrahydropalmatine (l-THP) in rat plasma, and to investigate the pharmacokinetics after oral administration of l-THP in rats. The plasma samples were extracted by ethyl acetate. The mobile phase consisted of a mixture of phosphoric acid (0.1%) and methanol (60: 40 v/v). The flow rate was 1.0 ml/min and the ultraviolet detection wavelength was at 280 nm. Plasma concentrations at different time were determined after oral administration at the dose of 20, 40 and 80 mg/kg. The data of concentration-time were fitted and the pharmacokinetics parameters were calculated with 3p97 program (Chinese Pharmacology Society). The limit of quantitation was 0.02 µg/ml, the linear range was 0.02-20.0 µg/ml (R2= 0.9989). The mean absolute recoveries of l-THP at three different concentrations (0.04, 5.00 and 20.00 μg/ml) were 97.5 ± 4.9, 98.2 ± 3.6 and 99.2 ± 3.2%, respectively. The relative standard deviations (RSD) of intra-day and inter-day were both less than 10%. The parameters of low, middle and high doses were as follows: t1/2α were (0.79 ± 0.04), (0.66 ± 0.02), (4.42 ± 0.07) h, t1/2β were (20.26 ± 1.21), (19.28 ± 1.04), (31.96 ± 0.85) h, while AUC were (6.95 ± 0.98), (9.91 ± 1.11), (19.19 ± 3.35) mg·h/L, respectively. The proposed method was found to be convenient, accurate and reliable, and it can be used for determination of l-THP in rat plasma. The pharmacokinetics studies also provided the theoretical foundation and reference for the safe and reasonable clinic exploitation of l-THP.   Key words: High performance liquid chromatography (HPLC), levo-tetrahydropalmatine, pharmacokinetics, rat.

CPC-139 Therapeutic Drug Monitoring For Glycopeptides and Aminoglycosides: Actual Situation and Perspectives in a French University Hospital

BackgroundOptimising glycopeptide and aminoglycoside treatment with Therapeutic Drug Monitoring is recommended. Under-dosing can lead to resistance and ineffective treatment while over-dosing is associated with toxicity.Purpose To evaluate current practise by...

Offline: Falling out with pharma

I am grateful to Tom Yates, from University College London, for alerting me to a campaign that deserves our support. His target is a document, whose creation was led by the Association of the British Pharmaceutical Industry (ABPI), entitled “Guidance on collaboration between healthcare professionals and the pharmaceutical industry”. It is signed by some great and good institutions: the Royal Colleges of Physicians, Psychiatrists, and General Practitioners, the British Pharmacological Society, Department of Health, the Scottish and Welsh Governments, and even the British Medical Association. And The Lancet. Let me quote Tom Yates in his own words, with additions for clarification. “The guidelines are problematic as they contain claims that are demonstrably false. For example, points 4 [Industry plays a valid and important role in the provision of medical education] and 6 [Medical representatives can be a useful resource for healthcare professionals] in ‘10 things you should know’ are at odds with Geoff Spurling's recent [PLoS Medicine, 2010] systematic review on the impact that information from pharmaceutical companies has upon prescribing [“With rare exceptions, studies of exposure to information provided directly by pharmaceutical companies have found associations with higher prescribing frequency, higher costs, or lower prescribing quality…”]. Point 3 [Information about industry-sponsored trials is publicly available] implies that hidden trials data is a historical problem, where, as you will know, it is now the focus of a major campaign and at least one [UK] parliamentary enquiry…Do you think there is any possibility that The Lancet might be able to publicly distance themselves from the Guidelines?” The statements made in the “guidance” certainly do not match the latest evidence about the behaviour of pharmaceutical companies today. Indeed, this evidence undermines the principles we originally signed up to, principles that attempted to forge a new and more constructive partnership between medicine and the pharmaceutical industry. It's time for us to withdraw our name from the “guidance” as it currently stands. Falling out with pharmaIn response to Richard Horton's Offline piece “Falling out with pharma” (Feb 2, p 358),1 I'd like to clarify that the Guidance on collaboration between healthcare professionals and the pharmaceutical industry2 is not a document produced by the Association of the British Pharmaceutical Industry (ABPI), nor is it led by the ABPI, but is something that was agreed across the group of organisations that signed up to it. The guidance is a live document and is reviewed regularly (the next scheduled review will take place this month) to ensure that it represents best practice across all the organisations involved. Full-Text PDF

Problem Based Pharmacotherapy Teaching for Pharmacy Students and Pharmacists

Pharmacy profession also involves identifying, solving and preventing drug-related problems, as well as encouraging proper use of medications, thus improving clinical outcome of the treatment. Pharmacotherapy is usually thaught as lectures in pharmacy schools and many students have a difficulty in implementing the theoretical knowledge into practice. Therefore courses on "rational drug use or rational pharmacotherapy" should be given by problem based teaching methods. Since 2009, "Rational Drug Use" courses are given in Marmara University School of Pharmacy by such a method (based on simulated patients and dispensing score) developed by the 'Turkish Pharmacological Society'. The method enables problem based learning and it is also used in some of the pharmacy schools in Turkey and in Near East University in Northern Cyprus. This kind of learning will provide ability for critical thinking, improve problemsolving skills and decision making during pharmacotherapy.

The Guide to PHARMACOLOGY portal: A one-stop pharmacology shop

Most medicines are chemical substances that work by interacting with specific target proteins in the body. The International Union of Basic and Clinical Pharmacology (IUPHAR) and the British Pharmacological Society (BPS) have joined forces to develop the Guide to PHARMACOLOGY (www.guidetopharmacology.org), a portal to information on the targets of licensed drugs and other targets of current research interest, such as those linked to human disease. Over the next 3 years, with support from the Wellcome Trust, IUPHAR and BPS, the Guide to PHARMACOLOGY portal will be expanded to cover all the targets of current licensed drugs and those with potential to be targets of future therapeutics. Our goal is to provide scientists, doctors, allied professions and the general public with a ‘one-stop shop’ source of information on how drugs work, and to help researchers to design experiments using the appropriate reagents.

1．学術委員会研究倫理小委員会設立の背景と活動

1．学術委員会研究倫理小委員会設立の背景と活動

Joint position statement by "Sociedad Española de Patología Digestiva" (Spanish Society of Gastroenterology) and "Sociedad Española de Farmacología" (Spanish Society of Pharmacology) on biosimilar therapy for inflammatory bowel disease

Biological drugs or biopharmaceutical products, manufactured with or from living organisms using biotechnology, have represented a therapeutic revolution for the control of inflammatory bowel disease (IBD). At present, in this indication and in our country, only two biological are approved, infliximab (IFX) and adalimumab (ADA), both of them monoclonal antibodies against tumor necrosis factor alpha. Effectiveness data are strong for both therapies, with maximum levels of scientific evidence.The upcoming expiry date for these biologicals´ patents has allowed the potential marketing of so-called biosimilar agents for the IBD indication. While biosimilars are conceptually for biological what generics are for chemical drugs, the structural complexity of biosimilars and their biological and manufacturing variability lead to consider validation processes for these two types in humans as highly differential. Thus, in our setting, under the coverage of "Agencia Española del Medicamento y Productos Sanitarios (AEMPS)" (Spanish Agency of Medicines and Medical Devices), guidelines issued by the European Medicines Agency (EMA) are to be applied, which states that a number of stages or steps must be overcome in order to obtain approval for a biosimilar agent.However, despite the presence of these recommendations by EMA, which must be met by a biosimilar in order to be licensed in our marketplace, relevant uncertainties persist that only future decisions by EMA and AEMPS may clarify. The present stance by our task force is that biosimilar development should be undertaken according to established regulations, thus certifying their efficacy and safety. Similarly, this task force considers that results obtained from studies in rheumatoid arthritis (RA) should not be extrapolated to IBD since the biological variability of these complex structures will not ensure a lack of noticeable changes in efficacy and safety.

Calling all pharmacologists with time to spare! We need you! Build the drug discovery knowledge base, GuidetoPharmacology.org

The contraction of the pharmaceutical industry has resulted in the underuse of a great deal of human capital and brainpower. This editorial appeals to pharmacologists who may be currently underemployed to volunteer their skills by contributing to the British Pharmacological Society's (BPS) Guide to Receptors and Channels (GRAC), and the NC-IUPHAR database (IUPHAR-DB). NC-IUPHAR has 60 subcommittees on specialized pharmacological areas where scientists freely give their time for articles on receptors or channels, and to populate IUPHAR-DB. These are freely available to all on the Web via a new resource: http://www.guidetopharmacology.org. The site features articles on all aspects of pharmacology, particularly new areas: microRNAs, epigenetics and transporters. One aspect that would be covered, alongside nomenclature and key pharmacology, is the drug discovery challenges in each area. Here the knowledge base from the pharmaceutical industry would be particularly valuable. In a separate editorial, Anne Hayes and Jackie Hunter discuss the scientific fallout from the recent contraction of the pharmaceutical industry, intended to stimulate further discussion concerning the best way to achieve the publication of negative data in drug discovery research: http://dx.doi.org/10.1111/j.1476-5381.2012.02215.x.

Pharmacometrics: a quantitative tool of pharmacological research

Pharmacometrics is an interdisciplinary science with tremendous potential to influence decision making through the construction of mathematical and statistical models combined with graphical methods that define, challenge, and resolve queries surrounding the biological processes of a drug. In 2004, FDA published the white paper the Challenge and Opportunity on the Critical Path to New Products, which advocates the model-based drug development (MBDD). Since then, pharmacometric analysis has become an increasingly important component of New Drug Application (NDA) and Biological License Application (BLA) submitted to FDA for drug approval, labeling and trial design decisions1,2. The academic clinical researchers are likewise confronted with the need to use data from various sources (experimental biology, preclinical models of disease, etc) in order to organize translational clinical studies in a therapeutic area. The administrators are faced with bringing together a variety of data (preclinical and clinical data, literatures, and other regulatory submissions of similar therapies) in order to make regulatory decisions. A great deal has been published in the literatures on quantitative research, especially in the field of clinical pharmacology. Therefore, wherever in industry, academia, or regulatory agencies, pharmacometrics is at the center of the translational medicine paradigm3,4. It is difficult to imagine a more efficient, powerful, and informative drug development and evaluation process without comprehensive pharmacometric studies. China is growing to be not only one of the biggest pharmaceutical markets in the world, but potentially one of most productive countries in R&D of new drugs as well. since 1979, the Professional Committee of Mathematical Pharmacology (PCMP) led by the Chinese Society of Pharmacology has been devoting to promote research, education and training of Chinese scientists in academia, industry and regulatory agencies with regard to the use of PK/PD modeling to help drug development and to optimize drug application in clinical therapies5,6. The papers organized by PCMP in this Special Issue of Acta Pharmacologica Sinica are focused on phase I trial design7, phase I PK study8,9, physiologically based PK modelling (PBPK)10, PK/PD linking11,12,13,14, population approach15,16,17, dose finding18, and stochastic simulation19. We hope that these papers serve as an introduction for the readers in academia, regulatory authorities and pharmaceutical industry to understand the role of pharmacometrics in drug development and approval processes, which will improve the success rate in drug development, and the beneficiaries will ultimately be the patients in need.

Pills, pills, pills

How good is your prescribing? Not very good at all, if statistics are to be believed. Junior doctors make nearly a fifth of prescribing errors; just 35% of medical students have filled in a drug chart more than three times before qualifying. The blame is being laid at the feet of inconsistent and inadequate clinical pharmacology teaching in medical schools. One pharmacology professor described teaching in French medical schools as “insufficient, uncoordinated, and likely to get worse.” (p 10) The British Pharmacological Society and the Medical Schools …

Prescribing and the core curriculum for tomorrow's doctors: BPS curriculum in clinical pharmacology and prescribing for medical students

Prescribing is one of the commonest tasks expected of new doctors and is a complex process involving a mixture of knowledge, judgement and skills. Preparing graduates to be prescribers is one of the greatest challenges of modern undergraduate medical education and there is some evidence to suggest that training could be improved. The aims of this article are (i) to review some of the challenges of delivering effective prescribing education, (ii) to provide a clear statement of the learning outcomes in clinical pharmacology and prescribing that should be expected of all medical graduates and (iii) to describe a curriculum that might enable students to achieve these outcomes. We build on the previous curriculum recommendations of the British Pharmacological Society and take into account those of other key bodies, notably the General Medical Council. We have also reviewed relevant evidence from the literature and set our work in the context of recent trends in medical education. We divide our recommended learning objectives into four sections: principles of clinical pharmacology, essential drugs, essential therapeutic problems and prescribing skills. Although these will not necessarily be accepted universally we believe that they will help those who design and map undergraduate curricula to explore potential gaps and identify improvements.

Celebrating the 80th anniversary of the Shanghai Institute of Materia Medica, Chinese Academy of Sciences (SIMM)

Acta Pharmacologica Sinica (APS) celebrates the 80-year anniversary of the establishment of SIMM by publishing this special issue to commemorate this event. APS, the official journal of the Chinese Pharmacological Society, has been published in association with SIMM since its launch in 1980. The founding editor-in-chief, Prof Guang-sheng DING, and many prominent SIMM scientists have served on the APS editorial board in the past. With consistent support from SIMM, APS has grown to be China's leading international journal in the fields of pharmacology and pharmacy, publishing high quality papers from all over the world. To commemorate the 80th anniversary of SIMM, APS has organized this special issue including perspective, review and original articles contributed by principle investigators from SIMM in various disciplines1,2,3,4,5,6,7,8,9,10,11,12. These articles highlight some of the research achievements accomplished at SIMM and provide an insight into the progress of drug research in China. SIMM, established in 1932, is a comprehensive institute engaged in fundamental and applied research in drug discovery and development. Throughout its 80-year history, SIMM has trained many outstanding pharmaceutical scientists and technologists who have developed a number of new drugs that have made their mark in the international arena, such as artemisinin (anti-malarial), sodium dimercaptosuccinate (antidote against heavy metal poisonings), sobuzoxan (anti-tumor) and huperzine A (to treat Alzheimer's disease), to name a few. Since the implementation of the “Knowledge Innovation Program” at the Chinese Academy of Sciences, a series of major achievements have transpired in drug discovery: Antofloxacin hydrochloride is the first patented quinolone-class antibiotic agent discovered at SIMM following a relentless pursuit that lasted more than 10 years; and depsides salt from Salvia miltiorrhiza has emerged in prominence with the modernization of traditional Chinese medicine. We remain confident that the achievements made by SIMM scientists during the past 80 years have laid a solid foundation to advance the drug discovery capabilities in China and that newly developed drugs will continue to be introduced to the international market in growing numbers. In tandem, APS will uphold its objective to publish excellent research being performed by both domestic groups and those abroad. Given the development of drug research in China and improved international cooperation, we believe that APS will remain as a platform for publishing high quality papers of key significance in the multidisciplinary field of pharmacology and related life sciences. I hope this issue will appeal to the broad readership with an interest in the drug discovery and development efforts being performed in China. Join us in celebrating the 80th anniversary of SIMM and enjoy the articles in this special issue.

Abstracts of the European Behavioural Pharmacology Society Workshop ‘Eating Behaviour and Obesity’, Lecce, 7–9 September 2012

Abstracts of the European Behavioural Pharmacology Society Workshop ‘Eating Behaviour and Obesity’, Lecce, 7–9 September 2012

Pharmacological approaches to feeding behaviour and eating disorders

Pharmacological approaches to feeding behaviour and eating disorders

Using Journal Review Articles to Increase the Dissemination of Keynote and Symposia Lectures at International Medical Congresses

Using Journal Review Articles to Increase the Dissemination of Keynote and Symposia Lectures at International Medical Congresses

Methodological innovations expand the safety pharmacology horizon

Almost uniquely in pharmacology, drug safety assessment is driven by the need for elaboration and validation of methods for detecting drug actions. This is the 9th consecutive year that the Journal of Pharmacological and Toxicological Methods (JPTM) has published themed issues arising from the annual meeting of the Safety Pharmacology Society (SPS). The SPS is now past its 10th year as a distinct (from pharmacology to toxicology) discipline that integrates safety pharmacologists from industry with those in academia and the various global regulatory authorities. The themes of the 2011 meeting were (i) the bridging of safety assessment of a new chemical entity (NCE) between all the parties involved, (ii) applied technologies and (iii) translation. This issue of JPTM reflects these themes. The content is informed by the regulatory guidance documents (S7A and S7B) that apply prior to first in human (FIH) studies, which emphasize the importance of seeking model validation.The manuscripts encompass a broad spectrum of safety pharmacology topics including application of state-of-the-art techniques for study conduct and data processing and evaluation. This includes some exciting novel integrated core battery study designs, refinements in hemodynamic assessment, arrhythmia analysis algorithms, and additionally an overview of safety immunopharmacology, and a brief survey discussing similarities and differences in business models that pharmaceutical companies employ in safety pharmacology, together with SPS recommendations on ‘best practice’ for the conduct of a non-clinical cardiovascular assessment of a NCE.

An agenda for UK clinical pharmacology: Developing and delivering clinical pharmacology in the UK National Health Service

Clinical pharmacologists are active in the delivery of general and specialist medical services across the UK. They also make major contributions, both locally and nationally, to medicines management and appraisal in the National Health Service. Most are also heavily involved in the organization and delivery of teaching and training of a range of healthcare professionals, both undergraduates and postgraduates. In the past, these contributions may not have been fully recognized, perhaps in part because the discipline is small. However, the British Pharmacological Society, particularly through its Clinical Section, is committed to initiatives to ensure that all clinical pharmacologists (whatever their background, training or subsequent working environment) can work together to improve patient care, nationally and internationally. Effective engagement with universities, the National Health Service and pharmaceutical companies will be vital if these initiatives are to have sustained benefits and improve health outcomes for patients.

David Grahame Grahame‐Smith

David Grahame Grahame‐Smith

Antinociceptive and anti‐inflammatory effects of Essential oil of Nepeta pogonosperma Jamzad et Assadi in rats

Pain management is a common but difficult medical challenge. Species richness, variation in chemical properties and diversified use in folk medicine attracted much research on the Nepeta genus of Iran. This study was designed to evaluate the antinociceptive effects of essential oil of Nepeta pogonosperma Jamzad et Assadi (NP) by tail flick and formalin tests and its anti‐inflammatory activity in rat paw edema model by water plethysmometer. Total 24 male Wister rats weighing 225±25gm were studied. Essential oil of NP was introduced intraperitoneally at the doses of 50mg/kg (in 6 rats), 100mg/kg (in 6 rats) and 200mg/kg (in 6 rats) for the experimental groups. Six (6) rats were treated with equal volume (200μl/100gm of body weight) of normal saline (control group). Antinociception was assessed by tail flick test (after 30 minutes) and by formalin test (for further 60 minutes) followed by paw edema test for anti‐inflammation by water plethysmometer (after sacrifice). All the doses of NP showed antinociception and anti‐inflammation, though higher two doses were significant in most cases in comparison to control. This study reveals that the essential oil of NP may minimize both the acute and chronic forms of nociception and may have potent role against inflammation, but the dose should be maintained precisely to obtain the intended effect. This study was supported by Iranian Society of Physiology and Pharmacology (ISPP).