Showing papers in "International Journal of Pharmaceutical Medicine in 2002"
TL;DR: It is suggested that the guideline’s introduction could lead to more placebo-control and that the extent of such shift would depend on the increase in cost for active-control trials and possible changes in the requirements for approval, as well as the possible impact of a new international guideline (ICH-E10) that focuses on the intrinsic defects of active control trial.
Abstract: Clinical trials that aim to establish efficacy in the target population need to have an adequate control group. Although scientific principles for efficacy evaluation apply universally, actual choices of control in each region seem to be unique, reflecting differences in regional guidelines for clinical evaluation, preferences of the population, and constraints in study environments. Our survey targeted 76 drugs approved in Japan between April 1999 and July 2000 and showed that active-control was adopted in a significant proportion of controlled phase III trials (74%), while trials with placebo-control accounted for only 18% of the total. The placebo-control was also not so common in phase II (23%). Preference for active-control was observed in many therapeutic fields, but in a few categories such as anti-diabetics placebo-control trials seemed to be the norm. We analysed the possible impact of a new international guideline (ICH-E10) that focuses on the intrinsic defects of active control trial. An economic model suggested that the guideline’s introduction could lead to more placebo-control and that the extent of such shift would depend on the increase in cost for active-control trials and possible changes in the requirements for approval. Future patients seem to be major beneficiaries from the new guideline’s introduction, considering the history of Japanese efficacy evaluation.
18 citations
TL;DR: The primary objective of this study was to survey vaginal preparations available in the Indian market to determine the types of products that are most frequently used by Indian women and to provide information about the active ingredients and dosage forms of these products.
Abstract: The vagina is a potential site for the local and systemic delivery of drugs. Presently, significant attention is given to the development of vaginal formulations (‘microbicides’) that prevent sexual acquisition of acquired immunodeficiency syndrome (AIDS) and other sexually transmitted diseases. Acceptability of vaginal dosage forms may vary among women from different geographical and socioeconomic backgrounds. Therefore, in the drug development process, selection of an appropriate dosage form is crucial for consumer acceptance and use. The primary objective of this study was to survey vaginal preparations available in the Indian market to determine the types of products that are most frequently used by Indian women. In addition, this survey provides information about the active ingredients and dosage forms of these products. The physicochemical properties of selected products were compared in order to help formulation scientists to design vaginal formulations with desired properties. Indian vaginal products are available in several different dosage forms. Tablets are marketed most frequently (38%), followed by gels (15%) and creams (15%). The evaluated products varied greatly in their physicochemical properties such as colour, pH, disintegration, viscosity, osmotic pressure and bioadhesive properties. The information can serve as reference on vaginal products in the Indian market and to aid in the development of new vaginal formulations, especially for India and other tropical countries.
11 citations
TL;DR: In this paper, the authors compared the psychometric properties of the McGill Pain Questionnaire (MPQ) with the 17-item Short Pain Inventory (SPI) in 60 outpatients with osteoarthritic knee pain.
Abstract: We compared the psychometric properties of the McGill Pain Questionnaire (MPQ) with the 17-item Short Pain Inventory© (SPI) in 60 outpatients with osteoarthritic knee pain. Split-half reliability, Guttman split-half reliability, Cronbach alpha and the correlation between the first and second half of the test were higher in the SPI total pain disturbance than any of the summary or subscales of the MPQ: 0.94, 0.94. 0.88 and 0.90, versus 0.71, 0.70, 0.69 and 0.55 for the MPQ sensory present pain intensity, 0.59, 0.57, 0.65 and 0.43 for the affective and 0.62, 0.55, 0.49 and 0.45 for the evaluative MPQ scale, respectively. The parameters for the SPI total mood disturbance were superior to all MPQ-derived scales. Dividing into high and low ‘pain experienced right now’ identified screening samples. The SPI ‘pain right now’ was more discriminating than the comparative MPQ item on both the SPI and MPQ. Additionally, none of the summary scales of the MPQ could show significant internal discrimination whereas the SPI did achieve this. There were 23 significant correlations with the SPI severity compared with 15 with the MPQ. SPI sadness, anxiety, anger, total mood disturbance and total pain disturbance were significantly correlated with the MPQ severity rating. The MPQ variables fared less well than the SPI in the degree of association between various pain parameters and physical severity. Factor analyses revealed that the SPI accounts for the majority of the variance (50%) compared with 17% for Factor 2. This second factor is best indexed by the McGill ‘pain now’ and also with the SPI ‘pain severity now’ item. Since the SPI indexes the severity as accurately (0.79) as the McGill, the only difference between the two is the sensory MPQ variance. However, since the SPI (Factor 1) also indexes some of the common variance of the MPQ sensory variable, the SPI also gains in this respect. If it were the case that the outcome of an analgesic clinical trial was the sensory aspects of the pain (cutting, throbbing, rasping) then the McGill should be the obvious outcome measure. For the patient, the most important feature of pain surely must be the physical severity and the unpleasantness of the experience. The MPQ is a rather long procedure and the evaluative scale is of dubious value. The majority of the pain variance is captured by the SPI and, secondly, by the sensory aspect of the MPQ. The SPI measures the emotional aspects of pain well and the McGill assesses the physical or sensory aspects of pain better than any other available. Both have their place according to one’s research interests and the clinical relevance. For example, if an investigation involves opiates like morphine, the SPI may be the better placed instrument, since the induced euphoria may present as a patient who can still feel the pain but is no longer bothered by it. Algesimetry requires measuring both the physical and emotional sensations of the patient.
8 citations
TL;DR: The review process was facilitative, rigorous and often protracted, and more care and effort in preparing applications, particularly the patient information leaflet, would improve the success rate.
Abstract: To analyse applications to the London multicentre research ethics committee (MREC) for duration, efficiency and outcome of the ethical review process. Retrospective review of applications for the period October 1997–November 2000, from discussion at first announced meeting to outcome. Completed application forms, minutes of meetings, and correspondence between the MREC and researchers. Of 353 applications, 14 (4%) were approved, 217 (62%) were conditionally approved, 103 (29%) were deferred, and 19 (5%) were rejected at first meeting. All deferred and rejected applications were reconsidered at up to four other meetings and required more profound changes than conditionally approved applications. Most applications required changes to the patient information leaflet. A total of 330 (93%) applications were approved eventually. The estimated median time from first meeting to approval was 64 days (range 7–386). The review process was facilitative, rigorous and often protracted. More care and effort in preparing applications, particularly the patient information leaflet, would improve the success rate. When the European Clinical Trials Directive (CTD) is implemented, the MREC will have to either shorten the approval time of some applications or reject more applications.
6 citations
TL;DR: A comprehensive guide for the use of electrocardiographic (ECG) assessments in clinical trials, for non anti-arrhythmic products, drawing together scientific information and current and proposed regulatory requirements and guidelines is provided.
Abstract: This article provides a comprehensive guide for the use of electrocardiographic (ECG) assessments in clinical trials, for non anti-arrhythmic products, drawing together scientific information and current and proposed regulatory requirements and guidelines. Standard definitions of normal values of ECG intervals, ECG diagnostic criteria for myocardial infarction and left ventricular hypertrophy, and the frequency of expected ECG abnormalities are presented. A focus on the problem of drugs that affect the QTc interval including the regulatory concern and associated factors are reviewed. The high spontaneous variability in QTc duration requires careful attention to the planning and interpretation of ECG data if a true QTc effect of a new drug is to be detected adequately. Too much additional extrinsic variability may compromise the ability to detect a signal amongst the noise. The sources of extrinsic variability that must be considered in clinical research include: ECG acquisition methods; adequacy of ECG collection, especially at baseline and at steady state or peak drug concentration; sample size; presence of control groups; ECG measurement accuracy; and proper use of formulae for correcting QT to QTc. There are several compelling reasons to utilize centralized ECG analysis as the primary method of collation and analysis of 12-lead ECGs in clinical studies. While ECG effects are initially well defined in phase I studies, confirmation in phases II and III is still required since safety in the target population with co-morbidities and concomitant medications must be confirmed. All ECGs should be statistically analysed and reported according to pre-defined standards. These should be developed according to the specific project requirements, the known or suspected properties of the test compound and the intended treatment regimen. A standard analysis plan is proposed.
3 citations
TL;DR: This book fills a real need for a basic textbook for those new to this discipline, but should also be of interest to well-established pharmacovigilantes.
Abstract: On the whole, this is a very good book. The text is well-written and easy to understand. The authors have covered international regulatory aspects of drug safety surveillance, conventional pharmacovigilance methodologies and pharmacoepidemiology. However, what really makes this book a good read rather than just a good textbook is the inclusion of numerous interesting examples of drug safety problems from the past: for example, market withdrawal of troglitazone, the banning of tretinoin in cosmetics in Germany, and neonatal mortality from benzyl alcohol. What also makes it more useful than just a textbook are descriptions of information sources, such as the British National Formulary, Drug Information Journal, Reactions Weekly and of relevant organizations like Health Action International and the Uppsala Monitoring Centre. It may be particularly valuable to non-medics because of narratives on clinical conditions that are commonly adverse reactions to drugs, such as Stevens–Johnson syndrome, angioedema and torsade de pointes. Because of its layout, the book could be used as a quick reference for workers new to the subject of drug safety. Entries range in length from one line (on Notice of Compliance) to several pages (eight pages on Reporting Rate). However, it is no great chore to read it from cover to cover. Of course, the book is not perfect. There is plenty of scope for additional entries and there are some rather odd terms (at least to British English ears), such as pneumovigilance, phytovigilance. There are also some obvious errors (the CSM is not a ‘British governmental department . . . inside the Medicines Control Agency’); the Company core safety information is certainly not to be used ‘for determining whether a particular AE is labeled or unlabeled (expected or unexpected) for regulatory safety reporting’. Nevertheless, the book would be a useful inclusion in every drug safety department library. It fills a real need for a basic textbook for those new to this discipline, but should also be of interest to well-established pharmacovigilantes.
3 citations
3 citations
TL;DR: The Conference addressed the underlying problem of the large number of medicinal products used in children that have not been evaluated in young patients and not been authorized for their use, leading to unacceptable variations in efficacy and to a substantial incidence of adverse events in children.
Abstract: This 2-day international Conference hosted 165 European and other international experts from 24–25 January 2002 in the Résidence Palace in Brussels, adjacent to the European Parliament. It was the occasion of the Annual Conference of the European Forum for Good Clinical Practice (EFGCP), jointly organized with the Confederation of European Specialists in Paediatrics (CESP), a section of the Union of European Medical Specialists (UEMS). This collaboration was appropriate, as both organizations had already contributed greatly to European initiatives to improve clinical research in children. The Conference was also timely, as new proposals for European legislation and regulatory action on paediatric medicinal products were due shortly. All sectors with an interest in clinical research in children were represented. The Conference addressed the underlying problem of the large number of medicinal products used in children that have not been evaluated in young patients and not been authorized for their use. This ‘off-label’ and ‘off-licence’ exposure to medicines has led to unacceptable variations in efficacy and, in the case of some products, to a substantial incidence of adverse events in children. There is a need for a European framework for research on paediatric medicines that will focus on all the issues involved and will lead to better drug therapy for children. In doing so, basic and therapeutic research must be facilitated, so that both new and existing medicines are tailored for paediatric use, but the science and ethics of research in children must be strengthened equally. First day
2 citations
TL;DR: Investigation of the pharmacokinetics of the anxiolytic alprazolam after administration of a single 0.5 mg dose of the drug in tablets designed for sublingual administration suggests that measurable plasma concentrations of the sublingUAL test product are achieved more rapidly than with oral orSublingual Administration of a standard reference preparation of alpazolam, which might have therapeutic advantages.
Abstract: A rapid onset of drug action is desirable for patients experiencing panic attacks or episodes of acute anxiety. The aim of this single-dose, three-sequence, crossover study was to investigate the pharmacokinetics of the anxiolytic alprazolam after administration of a single 0.5 mg dose of the drug, in tablets designed for sublingual administration (Tranquinal sublingual; Laboratorios Bago, test product, Ts) compared with oral (Ro) and sublingual (Rs) administration of 0.5 mg of alprazolam of a reference product (Xanax; Pharmacia Upjohn) manufactured for standard oral administration. Blood samples were taken at 0 (before) and 4, 6, 8, 10, 12, 15, 20, 30, 45, 60, 120, 180 and 240 min and 30 h after drug administration, and plasma concentrations of alprazolam were determined by high performance liquid chromatography. The area under the time-concentration curve (AUC) over 0 to 15 min (ng ml−1 hr−1) was 0.12±0.03 for Ts, 0.07±0.03 for Ro and 0.05±0.02 for Rs (P<0.05). The AUC0–4 h values were 22.09±1.96; 22.50±0.99 and 19.65±0.95 for Ts, Ro and R s, respectively, and the AUC0–30 h values were 109.05±12.21, 121.30±4.82 and 111.28±4.87 for Ts, Ro and Rs, respectively. C
max values were 6.79±0.85, 7.11±0.64 and 6.14±0.30 ng/ml for Ts, Ro and Rs, respectively, whereas the Tmax was 2 h for all three. The results suggest that measurable plasma concentrations of the sublingual test product are achieved more rapidly than with oral or sublingual administration of a standard reference preparation of alprazolam, which might have therapeutic advantages.
2 citations
2 citations
TL;DR: The recent debâcle concerning allegations of intentionally withholding damaging longitudinal outcomes data by investigators supported with funds from the manufacturer of Celebrex as discussed by the authors once again raises the issue of a temptation to compromise ethics in research.
Abstract: The recent debâcle concerning allegations of intentionally withholding damaging longitudinal outcomes data by investigators supported with funds from the manufacturer of Celebrex [1–3] once again raises the issue of a temptation to compromise ethics in research. Researchers and authors supported by pharmaceutical manufacturers are in an unenviable position due to pressures from their ‘dual relationship’, wherein they are simultaneously functioning in two conflicting roles – to serve as doctoral level scientists, and to recognize and report findings satisfactory to the parent drug maker on whom the scientist may be dependent for current and future remuneration. Medical journals generating revenue from drug advertisements and the journal editors themselves also experience this dependent, symbiotic, dual relationship. ‘The journals are the major force for quality control in scientific work’ [4] and, coincidentally, the journals become the easiest point in the system to implement fail-safe mechanisms rapidly, in order to increase further the integrity of the manuscript’s findings. The following are equitably and respectfully proposed:
TL;DR: Evaluating the long-term tolerability of QVAR in a patient population treated in primary care found no statistically significant differences between groups in terms of safety outcomes for any outcome.
Abstract: Beclomethasone dipropionate (BDP) is an established inhaled therapy for the management of asthma. BDP is commonly delivered via a pressurized metered-dose inhaler (MDI) using a chlorofluorocarbon (CFC) propellant system. A new extrafine aerosol of BDP (QVAR, 3M Pharmaceuticals) has been developed which uses hydrofluoroalkane-134a (HFA) as its propellant. This study, conforming to the UK Safety Assessment of Marketed Medicines (SAMM) guidelines, evaluates the long-term tolerability of QVAR in a patient population treated in primary care. In an open-label, non-randomized study conducted in 124 UK general practices over a period of 12 weeks, 6161 patients were prescribed either QVAR or CFC-BDP. The primary outcome was the number of patients with at least one hospital admission due to the condition for which BDP was prescribed. Other outcome parameters included the number of unscheduled visits to Accident and Emergency (A&E) departments, and general practitioner (GP) home visits for the condition for which BDP was prescribed. This study reflected prescribing patterns in primary care. After analysis to adjust for demographic discrepancies in gender, age, baseline consultations and baseline BDP dose, there were no statistically significant differences between groups in terms of safety outcomes for any outcome. For the primary outcome variable the adjusted odds ratio was 0.67 (95% confidence interval = 0.36–1.32). In addition, it was shown that patients can be successfully switched to CFC-free MDIs.
TL;DR: It is concluded that ethical review was fast, and that successful completion of many studies was dependent on protocol amendments, which means almost all of the authors' studies will require simultaneous applications to the Medicines Control Agency (MCA) and the REC.
Abstract: We assessed the potential impact of the European Union (EU) Clinical Trials Directive (CTD) on studies of investigational medicinal products (IMPs) in healthy volunteers using data from our studies in 1993–2001. The main outcome measures were time to approval of applications, including protocol amendments, by the research ethics committee (REC); types of study; types of study drug; and country of origin of sponsors. Of 312 applications to the REC, 208 (67%) were approved and 104 (33%) were approved conditionally at first review. We completed 280 (90%) studies. Ninety-five (34%) were sponsored by UK companies and 185 (66%) were sponsored by companies in 15 other countries. Seventy (25%) studies were first-administration-to-man studies. One hundred and sixty-six (61%) of 274 study drugs were new molecules. Forty-two per cent of IMPs were manufactured or imported from countries outside the EU. The median time from application to written approval by the REC was 19 days. We completed 181 (65%) studies without amending the protocol. During the other 99 (35%) studies, we submitted 167 protocol amendments for REC review. One hundred and forty-three (86%) amendments were for expedited review. The median time from request to written approval was 4 days. We conclude that ethical review was fast, and that successful completion of many studies was dependent on protocol amendments. When the CTD is implemented, almost all of our studies will require simultaneous applications to theMedicines Control Agency (MCA) and the REC. MCA response times will have to match REC times if we are to continue to carry out studies efficiently and to attract overseas sponsors, as recommended by the Pharmaceutical Industry Competitiveness Task Force (PICTF). When guidelines that support the CTD are written, they should include sensible definitions of protocol changes that require submission to the MCA and the REC, and they should have reasonable requirements for manufacturing, reconstituting and packaging IMPs from outside the EU. The notification procedure should be as simple as possible. Also, RECs should ensure that when they implement the new Governance Arrangements for National Health Service Research Ethics Committees (GAREC), there is no conflict with the CTD about procedures for reviewing protocol changes.
TL;DR: The European Commission’s Consultation Document introduces incentives and obligations that will provide paediatric versions of both new and old medicines in Europe, and introduces provisions for already marketed products appear to mimic the US incentives.
Abstract: Over half the medicines prescribed in Europe for children have never been licensed for them. The European Commission has now published proposed incentives and obligations for the prospective and retrospective development and licensing of paediatric medicinal products. Interested parties have been invited to comment on the Consultation Document by the end of April, after which the Commission will draft legislation. The proposals mirror much in the federal legislation and other effective measures taken in the USA over the last 5 years. In this issue, the European Forum for Good Clinical Practice/Confederation of European Specialists in Paediatrics (EFGCP/CESP) Conference Report [1] and the European Agency for the Evaluation of Medicinal Products/International Federation of Associations of Pharmaceutical Physicians (EMEA/IFAPP) Conference Report [2] provide background facts and debate. The European Commission’s Consultation Document is reproduced in the former report [1] (see p. 24) and warrants close attention. The complete package of the Commission’s proposals is forward-looking and robust. All stakeholders attending the EFGCP/CESP Conference viewed the current situation as unacceptable and backed the need for a stronger regulatory framework and other supporting measures [1]. The failure to provide licensed medicines for European children leads to drug formulations and dosages that were designed for adults being modified for children, resulting in an excessive number of medication errors and related adverse events [2]. Experience from EMEA marketing authorization shows that the proportion of medicinal products developed for children remains low. There are several reasons. Clinicians are hesitant to perform controlled clinical trials with children because of ethical concerns and perceived risks. Pharmaceutical companies are reluctant to provide technical and financial assistance for such studies. Public research funds are not readily available. More significantly, the current European Union (EU) Directive and the Committee For Proprietary Medicinal Products/International Conference on Harmonisation (CPMP/ ICH) guidelines on how to develop medicinal products for children are not always being followed or imposed by the regulatory agencies. The number of paediatric studies performed for medicines approved under the mutual recognition procedure are significantly fewer than the number that supported medicines approved by the EMEA centralized procedure. The Consultation Document introduces incentives and obligations that will provide paediatric versions of both new and old medicines in Europe. In the case of new medicines or those submitted for new marketing authorizations, studies in paediatric populations will be routinely and legally required as part of the licensing dossier. A dedicated European paediatric expert group in the EMEA will screen the paediatric section of the dossier to determine if the studies are acceptable in principle before the normal assessment process begins. One can foresee that the intended paediatric development plan might also be submitted for a similar opinion before studies are commissioned. Such up-front discussion is part of a general move by the Commission to improve the European centralized procedure for marketing authorization. Waivers for paediatric studies will be considered for medicines where there is no foreseen paediatric need, but the sponsor must apply for and justify the waiver. For old medicines, the Commission adopts incentives, similar to those in the USA, to stimulate the necessary studies in the paediatric population, especially those already being used ‘offlabel’ for children. It is proposed to introduce an additional period of market exclusivity for submitting one or more validated clinical studies on children in one or more age groups. These commercial incentives would commence at the end of the existing period of patent protection or Supplementary Protection Certificate protection. Companies may be asked to submit a development plan beforehand that would be assessed by the European paediatric expert group. Where no intellectual property exists, it is proposed to introduce a period of data protection for a marketing authorization for a paediatric product, allowing companies that were not the originator to exploit an opportunity to develop appropriate formulations of established adult medicines. This ‘kid’ marketing authorization would protect the paediatric data and the commodity. These provisions for already marketed products appear to mimic the US incentives, but the duration of the additional periods of market exclusivity or data protection are not mentioned. Some have suggested 12 months, but the public may want to know the expected profits and the extent to which children will benefit. The Commission’s other main incentive is the creation of a fund to finance paediatric research. This would be necessary in order to reduce the enormous backlog of medicines not tested in children. However, compared with the US $200 million programme, the proposed EU euro 100 million seems rather modest, aiming to support up to 20 clinical trials each year. Moreover, whereas the US Congress in the Best Pharmaceuticals for Children Act is able to allocate this money directly to INTERNATIONAL JOURNAL OF PHARMACEUTICAL MEDICINE 2002, 16:5 – 6 & 5
TL;DR: The pharmaceutical physician is well placed to use this statistical tool more often, but still judiciously, to look at the benefit (or risk) of drugs in development or on the market, and then to act upon that information appropriately.
Abstract: A meta-analysis of nine large clinical studies that had looked at a clinical dilemma, which option to use at ‘Step 3 of the British Guidelines on Asthma Management’, was conducted to attempt to determine the better option for adult asthma. All studies had reported results demonstrating superiority of the addition of a long-acting bronchodilator to inhaled corticosteroid for lung function, but, taken singly, none of the studies had sufficient power to provide conclusive evidence on the relative effect of either treatment option on the incidence of asthma exacerbations. However, a carefully conducted meta-analysis of the nine studies was able to provide a conclusive answer to this question. The work was further developed after abstract presentation and subsequently published. This article argues that the pharmaceutical physician is well placed to use this statistical tool more often, but still judiciously, to look at the benefit (or risk) of drugs in development or on the market, and then to act upon that information appropriately.
TL;DR: Diltiazem is a calcium antagonist effective in the treatment of stable and unstable angina and mild to moderate systemic hypertension with a generally favourable side-effect profile and modified preparations enabling once a day dosing are available.
Abstract: Diltiazem is a calcium antagonist effective in the treatment of stable and unstable angina and mild to moderate systemic hypertension with a generally favourable side-effect profile. A number of published studies have attempted to formulate a therapeutic target range, but there appears to be little consensus of opinion. A minimum effective concentration of 40 ng/ml has been proposed by some authors whilst others have chosen 50 ng/ml and others upwards to 100 ng/ml. A review of the reports suggests that a trough concentration of above 50 ng/ml confers a better therapeutic outcome than does the lower concentrations. A number of modified release preparations enabling once a day dosing are available, all purporting to give adequate therapeutic concentrations. However, based on the above assumptions it would appear that those giving sustained concentrations above 50 ng/ml would be those of choice. Furthermore the benefits of once daily preparations lead to improved compliance and therefore improved therapeutic outcome and thus confirm that the modified preparations are the delivery of choice. Once chosen, it is advisable to maintain the same preparation in order to derive maximum clinical benefit.
TL;DR: A large number of the patients in this study had no prior history of asthma or COPD, and the care they received at either Sherrington Park Medical Centre or Birmingham Heartlands Hospital was suitable for routine use.
Abstract: Jon G. Ayres, Chris Frost, William F. Holmes, Katherine M. Venables and Susan M. Ward Department of Respiratory Medicine, Birmingham Heartlands Hospital, Birmingham, UK; Department of Epidemiology and Population, London School of Hygiene and Tropical Medicine, London; Sherrington Park Medical Centre, Nottingham; Division of Public Health and Primary Care Institute of Health Sciences, University of Oxford, Oxford; 3M Healthcare Ltd., Loughborough, UK
TL;DR: It is concluded that EchoGen with or without administration of sevoflurane significantly enhances echocardiographic image quality compared with saline placebo, however, image quality is significantly better with EchoGen in the absence of seVofLurane.
Abstract: The aims of this study were to investigate possible interactions between EchoGen, a transpulmonary contrast agent in development that vaporizes after injection, and sevoflurane, and to determine the safety of the co-administration of sevoflurane and EchoGen. A phase I, double-blind, randomized, placebo-controlled, three-way crossover study was done in 12 healthy male volunteers receiving: EchoGen alone, sevoflurane+ EchoGen or sevoflurane+saline placebo. Safety was assessed using physiological and haematological monitoring and by documenting adverse events. The mean degree of echocardiography image enhancement was significantly higher for EchoGen alone (78.2) than when combined with sevoflurane (61.2) P=0.036. Both were significantly better than saline placebo (P<0.0001). The mean minimum alveolar concentration of sevoflurane was 2.5% with EchoGen and 2.3% with saline (NS). There were no marked differences in the distribution of reported adverse events between the sevoflurane/EchoGen and sevoflurane/ saline treatments. Results of other safety analyses, including vital signs, laboratory evaluations and physical examinations, were unremarkable. It is concluded that EchoGen with or without administration of sevoflurane significantly enhances echocardiographic image quality compared with saline placebo. However, image quality is significantly better with EchoGen in the absence of sevoflurane. EchoGen does not interfere with the anaesthetic action of sevoflurane. No new safety concerns were identified for either EchoGen or sevoflurane, alone or in combination.
TL;DR: The British Thoracic Society recently adopted a policy document on this topic, which gives sensible advice on matters including therapeutic guidelines, commercial sponsorship of educational activities, industry-funded research, and the independence of industry-sponsored nursing staff and pharmaceutical physicians working sessions in National Health Service departments.
Abstract: The relationship between prescribing physicians and the pharmaceutical industry has long been a topic for debate. Particularly contentious has been the question of industrysponsored clinical trials, which has been debated recently in this journal [1, 2]. Further examples of potential conflict of interest emerge with monotonous regularity. Most recently, correspondence critical of the principal investigator of the Losartan Intervention for Endpoint (LIFE) Reduction in Hypertension Study has appeared in the Lancet [3] from physicians who had received personalized letters purporting to come from the principal investigator, Dr Dahlof, which extolled the virtues of losartan. The letters were actually prepared and mailed by the study’s sponsoring company, Merck. In 1986, the Royal College of Physicians of London published a pioneering report entitled The Relationship between Physicians and the Pharmaceutical Industry [4]. An updated review of the situation was published in the college’s journal earlier this year [5]. Recently, professional bodies representing medical specialties have also begun producing guidelines on the relationships between their professional membership and the industry. The British Thoracic Society recently adopted a policy document on this topic, which was subsequently posted on the society’s website. The draft document underwent extensive review, including comments from pharmaceutical industry employees, before adoption, and gives sensible advice on matters including therapeutic guidelines, commercial sponsorship of educational activities, industry-funded research, and the independence of industry-sponsored nursing staff and pharmaceutical physicians working sessions in National Health Service departments. It is a helpful document, which repays reading. With the kind permission of the British Thoracic Society, we are reproducing it below.
TL;DR: Adrian Salter, one of the founding members of the Society of Pharmaceutical Medicine and indeed its first Secretary, contributed greatly to the development of Zyloric and Septrin, both important drugs then and now.
Abstract: It is a great honour to give the Salter lecture in this historic building, to your Society. Adrian Salter [1] was born in 1934 and died aged 59 in 1993. He was trained at St Thomas’s Hospital, did national service with the Royal Army Medical Corps, returned to work with Professor John Yudkin at Queen Elizabeth College and was awarded an MD for his work on dietary sugar and disease. In 1967 he joined Sandoz in Basle, Switzerland, and then moved to the Wellcome Foundation in 1969, where he became head of clinical investigation and contributed greatly to the development of Zyloric and Septrin, both important drugs then and now. He moved up to be European Medical Director interested particularly in the treatment of Aids and Hepatitis. He was one of the founding members of the Society of Pharmaceutical Medicine and indeed its first Secretary and I was interested to learn of the chord that had been struck when 400 people were present at the first inaugural meeting of the society in 1985–despite the Faculty of Pharmaceutical Medicine of the Royal College of Physicians there was clearly a need for an additional forum which would bring together both medical and non-medical scientists involved in the development of new medicines. Adrian Salter was plainly a sound professional man to whose memory I would like to pay tribute today.
TL;DR: A detailed review of actual and potential bioweapons highlighted the potential role of the pharmaceutical industry, particularly the concern over the number of countries thought to be using pharmaceutical or biotechnology companies as ‘fronts’ for covert bioweapon research and production.
Abstract: In August 2000 the International Journal of Pharmaceutical Medicine published a paper entitled ‘Biological weapons and the pharmaceutical industry’ [1]. This detailed review of actual and potential bioweapons highlighted the potential role of the pharmaceutical industry, particularly the concern over the number of countries thought to be using pharmaceutical or biotechnology companies as ‘fronts’ for covert bioweapon research and production. Confirmed cases are the Biopreparet biotechnology company in the former Soviet Union and the Roodeplat Research Laboratories in South Africa that were involved in the development of bioweapons for use in political assassinations. Iraq is also known to have employed statecontrolled biotechnology companies to produce the anthrax bacillus and botulinum toxin, when it was notionally involved in the production of legal biopesticides. The history of biological warfare goes back at least to the Middles Ages, with anecdotal reports that dead horses (and subsequently plague-infected corpses) were catapulted into besieged castles and cities. In the eighteenth century smallpoxinfected blankets were deliberately distributed by British forces to the native American Delaware tribe, with the intent of spreading disease among them. Few deliberate acts of biological warfare have been documented since, although Germany did attempt to spread glanders to horses in the first World War, and the Japanese experimented with operational weapons charged with typhoid, cholera, anthrax and plague against the Soviet Union and China during World War II. Somewhat surprisingly biowarfare research in Germany was vetoed by Hitler [2]. All the major international powers had biological warfare programmes at some stage during the 20th century; it is only recently that Gruinard island, in Scotland, was decontaminated after being used as the testing ground for British anthrax bombs in World War II. The Collison nebulizer (prototype for several nebulizers used for the therapeutic administration of inhaled drugs) was used in wartime experiments with nebulized bacterial suspensions at Porton Down [3]. Bioterrorism (the use of bioweapons by terrorist groups) as opposed to biowarfare (use by nation-states) is a late 20th century development. The sensational terrorist attack on the World Trade Center in New York on 11 September last year was followed in October by reports of pulmonary anthrax in Florida, and subsequently among postal workers in New Jersey and Washington DC. Deliberately contaminated letters were identified as the source of explosive, and a programme of antibiotic prophylaxis for potentially exposed people (eventually 32 000 were treated) was initiated. The US government ordered a large quantity of ciprofloxacin from Bayer Pharmaceuticals, which was welcome since the company was still recovering from the global withdrawal of its cholesterol-lowering agent cerivastatin [4]. Since anthrax is normally sensitive to standard antibiotics such as penicillin and tetracycline, the implication of this order was that the strain of the bacillus used might have been deliberately rendered resistant. The US government caused some unease in the industry by threatening to buy generic ciprofloxacin unless Bayer cut the price of its patent-protected drug substantially. After stockpiling some 120 million ciprofloxacin tablets the Centers for Disease Control (CDC) changed its advice and began to recommend doxycycline for prophylaxis [4]. The perpetrator has yet to be apprehended: suspicion currently points to a disgruntled government research worker. Heightened awareness of the real threat from terrorist activity, and bioterrorism in particular, has led to a number of consequences, many of them relevant to the pharmaceutical industry. The CDC has updated its assessment of potential bioterrorism agents [5]; in addition to well-recognized (category A) threats, such as smallpox, anthrax, plague and viral haemorrhagic fevers, the list has a category B for less lethal agents, including organisms causing food poisoning, and a category C for emerging threats, such as Nipah virus and hantavirus. The US government is requesting an extra $1.5 billion to fight bioterrorism [6], some of which will be spent on stockpiling vaccines and antibiotics, the rest on research and development. Anthrax and smallpox are recognized as particular problems. The need for new antibiotics, antitoxins and vaccines against anthrax has become clear [7]. The US Food and Drugs Administration (FDA) has already (March 2002) issued a ‘Guidance for Industry’ on developing antimicrobial drugs for post-exposure prophylaxis of inhalational anthrax (http:// www.fda.gov/cder/guidance/index.htm). Smallpox was considered to have been eradicated and vaccination was discontinued in the 1970s; the level of herd immunity is now so low that deliberate infection could cause a major epidemic [8]. Although in theory only the USA and Russia possess stocks of the virus, it is strongly suspected that ‘rogue nations’ such as Iraq may have obtained specimens. It is also possible that related viruses such as camelpox and monkeypox could be engineered to become pathogenic in humans, or even that terrorists might obtain viable smallpox virus from 20th century victims buried in the Arctic permafrost [9]. Recently, an orally active derivative of the antiviral agent cidofovir has been shown to be highly active against smallpox in vitro, and in a mouse (cowpox) model [10]. INTERNATIONAL JOURNAL OF PHARMACEUTICAL MEDICINE 2002, 16:63 – 64 & 63
TL;DR: Faecal porphyrins, plasma prostanoid concentrations and PAH clearance offer sensitive markers for assessment of non-steroidal anti-inflammatory drug (NSAID) mechanistics in the clinical environment.
Abstract: The aim of this study was to assess the pharmacological effects of aspirin on prostanoid biosynthesis — as measured by plasma thromboxane B2 (TXB2) and prostaglandin E2 (PGE2) concentrations — and two physiological functions thought to be mediated via prostanoids, namely gastrointestinal mucosal integrity — as measured by faecal porphyrins — and renal blood flow — as measured by para-aminohippuric acid (PAH) and creatinine clearance. The trial was a randomized, double-blind, placebo-controlled crossover design, with each volunteer taking 750 mg aspirin (British Pharmacopoeia) or placebo, three times a day for 5 days, with an 18-day washout period between treatments. Faecal porphyrins were measured before the first dose and on days 2 to 5 inclusive of each dosing period; plasma TXB2 and PGE2 concentrations were measured before dosing and 0.5 hours after the final dose on day 5 of each of the dosing periods; PAH clearance was measured before dosing and at 90, 120 and 150 min after the start of the infusion of PAH on day 1 and day 5 of each dosing period; creatinine clearance was measured before dosing and prior to the final dose on day 5 of each dosing period. Faecal porphyrins, in volunteers dosed with aspirin for 5 days, were increased by 195% compared with placebo (P>0.01); plasma TXB2 and PGE2 concentrations were reduced by >99% in volunteers dosed with aspirin for 5 days compared with placebo (both P>0.001); PAH clearance was significantly (P>0.045) lower in volunteers dosed with aspirin, 150 minutes after the start of infusion on day 5 of the treatment period; creatinine clearance was unaffected by aspirin treatment. Faecal porphyrins, plasma prostanoid concentrations and PAH clearance offer sensitive markers for assessment of non-steroidal anti-inflammatory drug (NSAID) mechanistics in the clinical environment.