bluuebunny/crossref_metadata_2025 huggingface dataset:
Outpatient parathyroid surgery and the differences seen in the morbidly obese
Authors: Norman James , Aronson Kelly
Published: February 2007

Objective

This prospective study examined rapid patient discharge after routine parathyroidectomy to identify differences between morbidly obese and non‐morbidly obese patients. The efficacy of supplemental calcium in preventing postoperative hypocalcemia was also assessed.

Methods

Between March 2003 and June 2004, 842 patients with primary hyperparathyroidism underwent outpatient parathyroid surgery. Morbid obesity was defined as 100 pounds above ideal body weight and/or body mass index greater than 39.

Results

Fifty‐one (6.1%) patients were morbidly obese (mean, 261 lbs; body mass index = 45) compared with 791 non‐morbidly obese patients (mean, 172 lbs; body mass index = 28, P <. 001). Morbidly obese patients were more likely to require conversion of laryngeal masked airway to endotracheal intubation (P <. 05). Incision length, total operative times, and the total time spent in the post‐anesthesia care unit were longer for morbidly obese patients (all, P <. 05). Of the 842 patients, only four, all non‐morbidly obese, spent the night after their operation. No postoperative untoward events occurred in either group.

Conclusions

Immediate discharge after routine parathyroid surgery is extremely safe for nearly all patients although morbid obesity is associated with a longer operation, a more difficult airway, and a longer stay in the recovery room.
Adult outpatient tracheostomy care: Practices and perspectives
Authors: Garner Justin M. , Shoemaker‐Moyle Michael , Franzese Christine B.
Published: February 2007

Objectives

To determine the attitudes, opinions, and current practice of adult outpatient tracheostomy care from the surgeon and primary care physician's perspective.

Study Design

Multidisciplinary physician survey.

Results

Found 53.4% (667 of 1250) and 28.9% (404 of 1400) of otolaryngologists and internists responded, respectively; 47% of otolaryngologists lack standardized tracheostomy discharge protocols. General ward nurses most commonly (33%) provide discharge education. A total of 64% of otolaryngologists felt primarily responsible for tracheostomy care and follow‐up; 48% expect the primary physician to provide some or all tracheostomy care. Ninety‐seven percent of internists received little or no residency training in tracheostomy care, which was significantly associated with decreased comfort (P< 0.0001) and willingness (P< 0.0001) to care for these patients.

Conclusions

Tracheostomy care is a concerted effort between the patient, surgeon, primary physician, and interdisciplinary team. Otolaryngologists should strive to standardize tracheostomy discharge, education, and follow‐up practices.

Significance

Disparities are highlighted between disciplines in their comfort, willingness, and knowledge of outpatient tracheostomy care.
Caregiver well‐being and child quality of life
Authors: Boruk Marina , Paul Lee , Yelena Faynzilbert , Rosenfeld Richard M.
Published: February 2007

Objective

To describe the impact of otitis media on the child's family and caregiver, and how this impact influences the caregiver's perception of child's quality of life (QOL) and functional health status (FHS).

Study Design and Setting

Prospective study of children aged 6 months to 12 years with recurrent or chronic otitis media recruited from a primary care pediatrics practice and a referral‐based pediatric otolaryngology practice. Survey measures were assessed for test‐retest reliability, internal consistency, and validity. Multiple regression analysis was used to explore relationships.

Results

We enrolled 159 families, with mean age of 3.3 years for the child and 34 years for the caregiver. Most caregivers attended college (80%) and 64% were employed. The Caregiver Impact Questionnaire (CIQ) had good test‐retest reliability (r = 0.83), internal consistency (α = 0.88), and construct validity (r = 0.37 to 0.62). Most caregivers (52%) were nervous or agitated at least “some of the time” because of their child's ear problems, 29% lost sleep “a good bit of time,” and 56% had to change daily activities. Multivariate analysis showed that caregiver QOL explained 62% of variability in child disease‐specific QOL, and that caregiver FHS explained up to 45% of the variability in child FHS.

Conclusion

The 6‐item CIQ survey permits a valid and reliable assessment of otitis media impact on caregivers and family functioning. Caregiver ratings of child QOL and FHS are largely influenced by caregiver perceptions of their own personal situation.

Significance

The caregiver QOL and FHS should be considered when using proxy‐completed surveys to assess the impact of otitis media on children.
Efficacy of dexamethasone for reducing postoperative nausea and vomiting and analgesic requirements after thyroidectomy
Authors: Fujii Yoshitaka , Nakayama Masahiro
Published: February 2007

Objective

To evaluate the efficacy of dexamethasone for reducing postoperative nausea and vomiting (PONV) and analgesic requirements after thyroidectomy.

Study Design and Setting

In a prospective, randomized, double‐blind, placebo‐controlled study, 75 patients, 20 men and 55 women, received intravenously placebo or dexamethasone at 2 different doses (4 and 8 mg) (n = 25 of each) at the end of surgery. A standard general anesthetic technique was used. PONV and analgesic requirements were evaluated.

Results

The rate of patients experiencing PONV during the first 24 hours after anesthesia was 64% with dexamethasone 4 mg (P = 0.269) and 28% with dexamethasone 8 mg (P = 0.001), compared with placebo (76%). The need of indomethacin for intolerable pain was less in patients who had received dexamethasone 8 mg than in those who had received placebo (P = 0.009).

Conclusion

Dexamethasone 8 mg effectively decreases PONV and analgesic requirements after thyroidectomy.
Adenotonsillectomy and obstructive sleep apnea in children: A prospective survey
Authors: Guilleminault Christian , Huang Yu‐shu , Glamann Christine , Li Kasey , Chan Allison
Published: February 2007

Objective

Prospective survey of children up to 14 years of age with OSA submitted to adenotonsillectomy.

Methods

Clinical evaluation, with questionnaires and clinical scales evaluating facial structures including tonsils and Mallampati scales and otolaryngologic evaluation; nocturnal polysomnography and repeat evaluation three to five months postsurgery.

Results

Of 207 successively seen children, 199 had follow‐up polysomnography, and 94 had still abnormal sleep recording. Multivariate analysis indicates that Mallampati scale score 3 and 4, retro‐position of mandible, enlargement of nasal inferior turbinates at +3 (subjective scale 1 to 3), and deviated septum were significantly associated with persistence of abnormal polysomnography (with high 95% CI for Mallampati scale and deviated septum).

Conclusion

Mallampati scale scores are resultant of several facial factors involving maxilla, mandible, and oral versus oral breathing but add information on risk of partial response to adenotonsillectomy.

Significance

Adenotonsillectomy may not resolve obstructive sleep apnea in children.
Hearing outcome of sudden sensorineural hearing loss: Long‐term follow‐up
Authors: Yeo Sang‐Won , Lee Dong‐Hee , Jun Beom‐Cho , Park So‐Young , Park Yong‐Soo
Published: February 2007

Objective

To evaluate the time‐dependent progress and delayed improvement in patients who were treated with combination therapy including oral corticosteroid for idiopathic sudden sensorineural hearing loss.

Study Design and Setting

This retrospective study at a secondary referral and university‐based center included 156 patients who were treated by 10‐day course of admission therapy and followed for at least three months.

Results

Of 121 patients who recovered over three months of follow‐up, 45.5% showed a delayed recovery after the end of 10‐day course of therapy. Of these 55 patients, 78.2% recovered within one month, 5.5% recovered within one to two months, 12.7% recovered in two to three months, and 3.6% recovered later than three months after discharge.

Conclusions

This study describes the long‐term results for a three‐month retrospective series of 156 patients diagnosed with idiopathic sudden sensorineural hearing loss, although this result should be further studied by additional research.
Guidelines for management of acute bacterial rhinosinusitis: Impact on Quebec physicians' prescriptions for antibiotics
Authors: Melanie Duval , Desrosiers Martin
Published: February 2007

Objective

To determine the impact of widely distributed guidelines on the diagnosis and treatment of acute bacterial rhinosinusitis (ABRS) on physician prescribing patterns.

Study Design and Setting

The overall numbers of prescriptions were compared between Quebec and the rest of Canada (excluding Quebec) using IMS Health Canada Canadian Disease and Therapeutic Index and CompuScript data on the antibiotics use for ABRS for the 3‐month period immediately following the distribution of the guidelines and the corresponding period the previous year.

Results

In comparison to the corresponding period during the previous year, antibiotic prescriptions for ABRS decreased 5.5% overall in Quebec compared with a 30.1% increase recorded in Canada excluding Quebec.

Conclusion

While the reduction in antibiotics use noted may be multifactorial, it nevertheless suggests that it may be able to affect physician prescribing habits.

Significance

Knowledge of the effectiveness of this method of distribution of guidelines could be used to plan more effective means of distribution of future guidelines.
CHAPTER 1 Biology of genital human papillomaviruses
Authors: Villa Luisa Lina
Published: February 2007

Human papillomaviruses (HPVs) are small DNA viruses that infect various epithelial tissues. The more than 100 types of HPV described share a circular DNA genome of about 8000 base pairs organized into an early, a late, and a long control region. The products of 2 genes from the early control region, E6 and E7, are essential in the HPV‐induced processes of cellular transformation and immortalization, and 2 genes from the late control region, L1 and L2, encode the viral capsid proteins. A few high‐risk types of HPV types, including HPV‐16 and HPV‐18, are asso‐ciated with more than 99% of cervical carcinomas. Continuous expression of the E6 and E7 oncoproteins by high‐risk types of HPV often leads to genomic aberrations, a step toward malignant conversion. Although in most cases innate and adaptive im‐mune responses control HPV infection, the high‐risk types of virus have the ability to subvert immune defenses, which explains persistent infection and progression to neoplasia.
CHAPTER 6 Secondary prevention of cervical cancer
Authors: Denny Lynette , Sankaranarayanan Rengaswamy
Published: February 2007

Cervical cancer continues to be the commonest cause of death among women in developing countries, largely due to the failure to initiate or sustain effective cytology‐based screening programs. Experience from countries with successful screening programs indicates that target age and the extent of coverage of the target group are key indicators of success in reducing cervical cancer. Alternative methods for the secondary prevention of cervical cancer have been evaluated in numerous studies over the past 10 years in different countries. These include visual inspection with acetic acid and linking screening to treatment. Although longitudinal data are scanty, these alternative approaches have been shown to be feasible, acceptable, and effective in reducing cervical cancer.
Vaccines for amoebiasis: barriers and opportunities
Authors: STANLEY S. L.
Published: February 2007

Amoebiasis, infection by the protozoan parasiteEntamoeba histolytica, remains a global health problem, despite the availability of effective treatment. While improved sanitation could lead to the eradication of this disease, it is unlikely that this will occur worldwide in the foreseeable future; thus alternative measures must be pursued. One approach is to develop a vaccine to prevent this deadly disease. Clinical studies indicate that mucosal immunity may provide some protection against recurrent intestinal infection withE. histolytica, but there is no clear evidence that protective immunity develops after amoebic liver abscess. Over the past decade, progress in vaccine development has been facilitated by new animal models that allow better testing of potential vaccine candidates and the application of recombinant technology to vaccine design. Oral vaccines and DNA-based vaccines have been successfully tested in animals models for immunogenicity and efficacy. There has been significant progress on a number of fronts, but there are unanswered questions regarding the effectiveness of immune responses in preventing disease in man and, as yet, no testing of any of these vaccines in humans has been performed. In addition, there are strong economic barriers to developing an amoebiasis vaccine and questions about how and where an effective vaccine would be utilized.
Leishmaniavaccines: progress and problems
Authors: KEDZIERSKI L. , ZHU Y. , HANDMAN E.
Published: February 2007

Leishmaniaare protozoan parasites spread by a sandfly insect vector and causing a spectrum of diseases collectively known as leishmaniasis. The disease is a significant health problem in many parts of the world resulting in an estimated 12 million new cases each year. Current treatment is based on chemotherapy, which is difficult to administer, expensive and becoming ineffective due to the emergence of drug resistance. Leishmaniasis is considered one of a few parasitic diseases likely to be controllable by vaccination. The relatively uncomplicated leishmanial life cycle and the fact that recovery from infection renders the host resistant to subsequent infection indicate that a successful vaccine is feasible. Extensive evidence from studies in animal models indicates that solid protection can be achieved by immunisation with protein or DNA vaccines. However, to date no such vaccine is available despite substantial efforts by many laboratories. Advances in our understanding ofLeishmaniapathogenesis and generation of host protective immunity, together with the completedLeishmaniagenome sequence open new avenues for vaccine research. The major remaining challenges are the translation of data from animal models to human disease and the transition from the laboratory to the field. This review focuses on advances in anti-leishmania vaccine development over the recent years and examines current problems hampering vaccine development and implementation.
Global Love wave overtone measurements
Authors: Visser K. , Lebedev S. , Trampert J. , Kennett B. L. N.
Published: February 2007

Love wave phase velocities for fundamental and higher modes are difficult to measure because the different modes cannot easily be separated. Following Yoshizawa and Kennett (2002), we generate suites of path specific one‐dimensional shear wave velocity profiles using the Neighbourhood Algorithm of Sambridge (1999a). From this family of O(104) models both fundamental and higher mode phase velocities with mutually consistent uncertainties are calculated. We have fully automated the method and analysed over forty thousand Love wave seismograms from the GDSN and GEOSCOPE global networks from 1994–2004. Our phase velocity measurements agree remarkably well with previous studies, but we have been able to enlarge the available dataset dramatically. We present global Love wave phase velocity maps (up to the fifth overtone) with unprecedented resolution due to the improved path coverage. Comparing these maps to existing tomographic models, we discern evidence of significant anisotropy in the lower mantle around a depth of 1000 km in the Pacific.
Development and response of a coupled catchment fan system under changing tectonic and climatic forcing
Authors: Densmore Alexander L. , Allen Philip A. , Simpson Guy
Published: February 2007

Sediment fans are a potentially useful and underexploited recorder of Earth's climatic and tectonic history, but historical observations have led to conflicting views on the importance of tectonic, climatic, and lithologic variables in controlling fan morphology and deposition. A one‐dimensional model of a sediment fan and its associated catchment is used to explore the sensitivity of such simple sediment routing systems to perturbations in fault slip and precipitation rates. A transport‐limited catchment is coupled to a fan whose surface slope is set by the balance between catchment sediment efflux and the available tectonically generated basin accommodation. Rock uplift rate is spatially variable across the model space. Increasing the fault slip rate, or decreasing the precipitation rate, leads to an increase in fan slope, temporary back‐stepping of the fan toe, and a pronounced angular unconformity. Conversely, a decrease in slip rate, or an increase in precipitation rate, results in a decrease in fan slope, and progradation and eventual stabilization of the fan toe. Once perturbed, the system evolves toward a new equilibrium state with time constants of ∼0.5 to 2 Myr; these response times are insensitive to slip rate but are strongly dependent on precipitation rate. Variations in fan slope are well described by a dimensionless parameter that expresses equilibrium slope as a function of slip rate, precipitation rate, system size, and catchment lithology. This parameter holds promise as a predictive tool in inverting the morphology of natural fans for environmental variables.
A common topology for bacterial and eukaryotic transcription initiation?
Authors: Travers Andrew , Muskhelishvili Georgi
Published: February 2007

DNA supercoiling is a major regulator of transcription in bacteria. Negative supercoiling acts both by promoting the formation of nucleoprotein structures containing wrapped DNA and by altering the twist of DNA. The latter affects the initiation of transcription by RNA polymerase as well as recombination processes. Here, we argue that although bacteria and eukaryotes differ in their mode of packaging DNA supercoils, increases in DNA twist are associated with chromatin folding and transcriptional silencing in both. Conversely, decreases in DNA twist are associated with chromatin unfolding and the acquisition of transcriptional competence. In other words, at the most fundamental level, the principles of genetic regulation are common to all organisms. The apparent differences in the details of regulation probably represent alternative methods of fine‐tuning similar underlying processes.
Steroid-resistant sarcoidosis: is antagonism of TNF-α the answer?
Authors: Denys Bart G. , Bogaerts Yves , Coenegrachts Kenneth L. , De Vriese An S.
Published: February 2007

Steroid-resistant sarcoidosis has conventionally been treated with various drugs, including methotrexate, azathioprine, cyclophosphamide, cyclosporine, antimalarial drugs and thalidomide, with variable success. There is a compelling need for more efficient and safer alternatives to these agents. Several lines of evidence suggest a critical role of TNF-α (tumour necrosis factor-α) in the initiation and organization of sarcoid granulomas. Inhibition of TNF-α with monoclonal antibodies has therefore received attention as a potential treatment option in therapy-resistant sarcoidosis. A number of case reports and small case series describe successful treatment of refractory disease with infliximab. Preliminary evidence from an RCT (randomized controlled trial) with infliximab in pulmonary sarcoidosis suggests a modest improvement in functional and radiological parameters. In contrast, the results with etanercept have been disappointing, perhaps related to differences in the mechanism of TNF-α blockade. The experience with adalimumab in sarcoidosis is too limited to draw conclusions. An open-label study and an RCT evaluating the efficacy of adalimumab in sarcoidosis with pulmonary and cutaneous involvement respectively, have been initiated. Although TNF-α antagonists appear relatively safe, especially when compared with conventional agents, caution is warranted in view of the increased incidence of tuberculosis, which may be a particular diagnostic challenge in patients with sarcoidosis. Pending publication of the RCTs, the use of TNF-α blockade in sarcoidosis should remain in the realm of experimental treatment.
Supplying Pharmaceuticals to Countries without Manufacturing Capacity: Examining the Solution Agreed upon by the WTO on 30th August, 2003
Authors: Correa Carlos M.
Published: February 2007

The Trade-Related Aspects of Intellectual Property Rights (TRIPS) Agreement and most national patent laws allow for the granting of compulsory licences for a variety of reasons. Compulsory licenses may be an important tool enabling a country to get access to drugs at affordable prices. While any country may use compulsory licences for this purpose, however, many — especially the least developed countries (LDCs) — lack or have insufficient pharmaceutical manufacturing capacities to make effective use of the system. Paragraph 6 of the Doha Declaration on the TRIPS Agreement and Public Health instructed the Council for TRIPS to find an expeditious solution to this problem. This paper1 reviews the solution reached, as contained in the World Trade Organization (WTO) Decision adopted on 30th August, 2003, and the steps that should be taken in order to make it operative. It argues that a permanent solution to this problem should be based on a more straightforward and simpler approach.
Patents, Access to Medicines and the Role of Non-Governmental Organisations
Authors: Ford Nathan
Published: February 2007

One-third of the world's population lacks access to the most basic essential drugs. For the destitute sick in the developing world, the price of medicines can determine whether they will be treated. Patents drive drug prices up, the resultant monopoly status allowing the producer to charge whatever price the market will bear. The World Trade Organization Trade-Related Aspects of Intellectual Property Rights (TRIPS) Agreement, which provides 20 years' patent protection for pharmaceuticals, also includes safeguards such as compulsory licensing, to ensure that countries can override patents whenever they are a barrier to access to medicines. Intense lobbying from the multinational pharmaceutical industry and some Western governments, however, has frustrated the use of these safeguards. Experience from South Africa, Thailand, Kenya and Guatemala shows the enormous pressures countries face in implementing the TRIPS Agreement in a manner that protects public health and underscores the vital role played by civil society in defending the right to access affordable medicines.
Granting Emergency Interim Injunction Pending Trial in the GSK Generic Patent Litigation
Authors: Burdon Michael , Sloper Kristie
Published: February 2007

This paper looks at the criteria that the UK courts will apply when considering whether or not to grant an interim injunction in a patent action in the light of two recent decisions of the UK courts concerning GlaxoSmithKline's Seroxat product. These two recent decisions are highly significant for patent holders and for generics companies, since they mark the first interim injunctions to be granted in patent actions in the UK for a number of years. The authors consider the implications of these decisions for patent holders and for generics companies in formulating their commercial strategies. The message is clear: interim injunctions are back on the menu. Patent holders should be aware of these decisions and the possibility of obtaining immediate and effective relief in appropriate circumstances, provided that rapid action is taken. Generics companies should also take note of these decisions. The overriding message from the courts is that generics companies ignore the existence of other companies' patents at their peril when considering the launch of a new and potentially infringing product.

The law is correct as at 18th September, 2003.
TRIPS-Plus Provisions in Trade Agreements and Their Potential Adverse Effects on Public Health
Authors: Jorge María Fabiana
Published: February 2007

Governments face a difficult challenge to achieve a balance between the need to provide an incentive for investment in research and development of new drugs and access to affordable medicines. As the US Federal Trade Commission recently stated, a proper balance between competition and patent policies is necessary to promote innovation. Since the adoption of the Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS), trade agreements have changed intellectual property laws in many nations, emphasising the rights of patent holders. This paper calls into question the advantages to developing countries of stringent intellectual property protection, and recommends II measures to ensure a better balance between the interests of inventors, consumers and brand-name and generics companies.
Pharmaceutical Pricing and Hatch–Waxman Reform: The Right Prescription
Authors: Young Allison K. , Andrus Meredyth Smith
Published: February 2007

Pharmaceutical pricing in the USA has been habitually plagued by sizeable discrepancies between brand-name drugs and generic alternatives. Traditional notions of competition and free market enterprise fail to narrow the gap, since drugs cannot be sold in the USA unless they obtain regulatory approval from the US Food and Drug Administration (FDA). As a consequence of the legislation and administrative procedures governing market access for pharmaceuticals, generic drug manufacturers encounter a great deal of difficulty in challenging traditionally patent-protected brand-name drugs during the regulatory approval process. During the past two decades, via a series of legislative manoeuvres and statutory amendments (most notably the Hatch–Waxman Act), Congress has created a number of quid pro quos granting generics greater access to quick market entry while simultaneously protecting important intellectual property rights.

In 2003, Congress amended Hatch–Waxman, in an attempt to close many of the statutory loopholes that had been exploited in ways unintended by the legislators to block generic pharmaceutical approval. The purpose of this paper is not specifically to critique the new legislation, but rather to suggest a different strategy. Instead of further complicating an already intricate and perplexing statutory scheme with myriad ways for ingenious patent experts to circumvent the intended purposes, the authors propose the following: (1) a repeal of unnecessary incentives; (2) a reassignment of esoteric issues of patentability and enforcement inherent in the determination of listability to the exclusive authority of the US Patent and Trademark Office; and (3) return of legitimate patent infringement disputes to courts of competent jurisdiction.
Review of the European Pharmaceutical Legislation
Authors: De Stasio Susan , McClay Nadene
Published: February 2007

EU pharmaceutical legislation has been revised (Directive 2001/83/EC and Regulation 2309/93). Will this mean that the registration of generic medicines becomes easier? What will be the effect on a new enlarged EU and its member states?

Following a protracted European co-decision procedure, which required a lot of to-ing and fro-ing between the European Commission, European Parliament and Council, an agreed position was voted by the European Parliament in December 2003 and formally agreed by the Council in March 2004. It was imperative that the revision of the law be finalised (and at least certain parts put in place) before the 1st May, 2004 accession to the EU of ten new member states. During this process, numerous amendments were introduced and the positions of a number of concerned parties heavily lobbied.

The final outcome has been roundly criticised in terms of reaching a fair compromise between the various interests — in that no one group seems specifically pleased. The revised law does, however, contain a number of important new aspects for generic medicines. These are outlined here in tabular format for convenience of reference.
If You Thought That Dawn Raids Were to do with Antitrust … a Critique of the Directive on the Enforcement of Intellectual Property Rights
Authors: Lowe Veronica
Published: February 2007

This paper presents a thorough appraisal of the new Directive on the Enforcement of Intellectual Property Rights, which will become law in all 25 EU member states within two years, and reviews its effect on legitimate generic product development. The paper commences with an examination of the mixed motives behind the Directive. It contrasts the European Commission's desire to eradicate counterfeiting and piracy, with its sponsor's purpose of creating tough sanctions against any intellectual property rights infringement. Claimed as a tool to wrest research and development (R&D) initiative from the USA, the Directive has potential for being a tool of protectionism within the EU. This paper then goes on to discuss the stifling effect on generics competition. It describes the extensive range of civil measures culled from any member state and presented as a single menu available in all. This is applicable both to counterfeiting and piracy, and to complex patent disputes. The Directive's encouragement of criminal sanctions completes the picture.
Global Generics Profitability: Increasing Need for Business Development and Licensing
Authors: Hoffman Jean
Published: February 2007

This paper examines key success factors for global and regional generics companies, including the ability to license in or acquire products. It explores the importance of business development deals to secure early, exclusive access to active pharmaceutical ingredients for patent challenges, as well as more profitable dose-form products that fuel growth. Further explanation of consolidation among global generics companies, and the limited number of independent, high-calibre active pharmaceutical ingredient manufacturers to support these companies, is provided.
M&A Strategy within the Generic Pharmaceuticals Sector: Vertical Integration into Active Pharmaceutical Ingredients
Authors: Erdei Tommy
Published: February 2007

The generics sector has been very active within mergers and acquisitions (M&A). One key strategic M&A opportunity for firms within the sector is to focus on vertical integration between active pharmaceutical ingredients (APIs) and finished form. The combination not only provides further critical mass but also, most importantly, creates strong synergies to help to position the firm in the market. Moreover, with continued increased competition from former API suppliers, such as some of the Indian producers, Western firms will need to seek new sources of APIs and meet the increased competition which these firms present through their vertical integration.
International Guiding Principles for Ethical Conduct of Clinical Trials: Implications for Generics
Authors: Idänpään-Heikkilä Juhana E.
Published: February 2007

As a result of intensive international debate, consultations and collaboration, a number of ethical documents and guidelines have been developed by the World Medical Association (Declaration of Helsinki), Council for International Organizations of Medical Sciences (CIOMS), World Health Organization (WHO Guidelines for Good Clinical Practice) and the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH Good Clinical Practice Guideline). From May 2004, all 25 EU member states will be required to implement the legally binding EU Directive on clinical trials. In general, the ethical principles regarding clinical research are consistent in these documents; however, some have been developed more for regulatory purposes whereas others are recommendations and guiding principles. Some documents focus particularly on ethical guidance for clinical trials conducted in developing countries. Taken literally, the Declaration of Helsinki and the CIOMS Guidelines do not indisputably support the ethics of pharmacokinetic studies in which the aim is solely to demonstrate bioequivalence for commercial purposes in non-therapeutic trials. This paper reviews the evolution of ethical guidance in clinical research and discusses how the current international ethical documents advise on drug development research in the generic pharmaceuticals industry.
Outlook on China's Pharma Development — 2004
Authors: Capie Susan
Published: February 2007

China's pharmaceutical industry is undergoing tremendous positive transformations, spurred both by the government's economic and political policies and the increasing investment/involvement by foreign pharma firms in China. This paper will describe the three major forces driving the changes: economic, regulatory and China's entrance into the World Trade Organization. These changes will contribute to China's emergence in the next decade as a major force in the international pharmaceutical arena, but the speed with which this will happen is contingent on overcoming the still-existing problems of intellectual property enforcement, regulatory capabilities, innovative skills and meeting EU/US good manufacturing practice quality and compliance requirements.
Medicine Utilisation and Pricing in Malaysia: The Findings of a Household Survey
Authors: Ud din Babar Zaheer , Ibrahim Mohamed Izham Mohamed , Bukhari Nadeem Irfan
Published: February 2007

The objectives of this study were to identify the most commonly used medicines for mainly prevalent ailments and to compare retail sector prices (RSPs), public sector prices (PSPs) and international reference prices (IRPs). A convenient sampling method was employed to survey 33 households in a metropolitan city. Each family was followed once a week for eight weeks to observe their diseases and medication usage. The RSPs and PSPs for per unit doses and defined daily doses (DDDs) were compared with the IRPs. The most common ailments identified were cardiovascular and endocrine disorders followed by central nervous system and musculoskeletal disorders. Accordingly, the most common drugs used were for the treatment of the above ailments. Among 81 commonly used medicines, 63 were branded and 18 were generic. Of the 81 drugs, 26 were essential drugs. Angiotensin-converting enzyme (ACE) inhibitors, beta-blockers and calcium channel blockers were among the most commonly used medicines. The differential between the prices of branded medicines and IRPs were found to be remarkable. This study further revealed that the majority of patients also used traditional medicines and nutritional supplements alongside their modern medicines. Wide variations were observed in RSPs and IRPs, warranting critical evaluation, regulation and emphasis on the economic aspects of drug policy. Widespread use of branded medicines in the absence of a national health insurance programme can lead to high out-of-pocket expenditures. Concomitant use of traditional medicines and nutritional supplements may have drug interaction potential, invoking detailed investigation for relevance.
Balancing Customer Expectations with cGMP Compliance
Authors: Batshon Lynne Jones ,   The Bulk Pharmaceuticals Task Force
Published: February 2007

This paper presents a guiding tool, designed by the Bulk Pharmaceuticals Task Force, to be used alongside the Food and Drug Administration's guidance for industry ‘Q7A Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients’. The ‘Responses to Customer cGMP Expectations’ section of this paper addresses key current good manufacturing practice (cGMP) compliance issues frequently encountered during cGMP audits and inspections of active pharmaceutical ingredient (API) manufacturing facilities. The purpose of this tool is to provide API manufacturers and their customers with a strategy for allocating resources in a manner that maximises effectiveness, minimises costs and ensures sustainable growth while balancing customer requirements. This tool provides answers to cGMP and regulatory questions involving several key areas: audits, cleaning, computer systems, method validation, packaging, process and equipment validation, stability, storage, temperature controls and water quality.
Marketing and Globalising Biosimilars in a Competitive Landscape
Authors: Harris James
Published: February 2007

The aim of this paper is to shed light on the controversial topic of biosimilars, biogenerics and bioequivalence with regard to recombinant DNA (rDNA) products. This phenomenon has garnered extensive press and yet is very much in its infancy. Although the terms ‘biosimilar’ and ‘biogeneric’ are basically interchangeable for purposes of argument, here, the term ‘biosimilar’ will be used. What is a biosimilar? In its broadest definition a biosimilar is an rDNA molecule/biopharmaceutical that is comparable to the originator's molecule. Biopharmaceuticals are drugs derived from living organisms. These substances are quite complex and are therefore more difficult to manufacture consistently, characterise, quantify, purify and copy. What happens if the molecule cannot be classified as biosimilar? In most cases it will then be classified as a new entity in and of itself. Herein lies the paradox that many originators/innovators use to increase barriers to entry that competitive manufacturers must overcome.

In terms of barriers to entry, it must be stated that patents often pose a worthy obstacle for many firms to overcome. Patents or intellectual property (IP) are very specific deterrents for competitors to manoeuvre around and are a worthwhile defence mechanism for originators to have in their arsenal. Additionally, regulatory guidance, or the lack thereof, is a key variable for firms to consider; they must weigh the pros and cons prior, during and after such considerations are made to decide whether to invest major resources within this new venture, and how those sacrifices will or will not pay off.
Strategic Issues in the Development of a Generics Market: Lessons from Spain and the Netherlands
Authors: de Vázquez Emma Gutiérrez Mesa , Lara Pedro Reinares
Published: February 2007

The authors have carried out a comparative study between two countries with a huge difference in terms of development of the generics market: Spain and the Netherlands. The main conclusion of this paper is that, currently, the most important factor for the development of a generics market is the existence of a suitable regulatory structure (explicit and implicit, formal and informal rules) adapted to the characteristics of each country and limited by the arguments that the pharmaceutical industry (branded and generics companies) can support in order to control the pharmaceutical invoice and, as a consequence, healthcare expenditure. The current development models are expensive and complex and, moreover, do not contribute to the consolidation of their development, given that they are influenced by agents and variables that are certainly difficult to control. If the objective is to develop a generics market because it will contribute in a positive way to reducing the public pharmaceutical expenses there is an urgent need to act on end consumers, eg patients, to enrich their perception of generic medicines.
The Case of the Disappearing Polymorph: ‘Inherent Anticipation’ and the Impact of SmithKline Beecham Corp. v Apotex Corp. (Paxil®) on Patent Validity and Infringement by Inevitable Conversion
Authors: Rakoczy William A. , Mazzochi Deanne M.
Published: February 2007

In two separate decisions, the United States Court of Appeals for the Federal Circuit invalidated the key patent protecting GlaxoSmithKline's (GSK) widely prescribed antidepressant drug Paxil®, generically known as paroxetine hydrochloride. The broadest claim of GSK's patent simply covered the chemical compound ‘crystalline paroxetine hydrochloride hemihydrate’, an allegedly new ‘polymorphic’ form of the drug. Generic challenger Apotex designed around the patent by making the old, off-patent ‘anhydrate’ polymorph of paroxetine that is the subject of the now-expired US Patent No. 4,007,196 (the ′196 patent). To prove infringement, GSK relied on the so-called ‘disappearing polymorph’ theory, under which the old polymorphic form of the drug effectively ‘disappears’ by ‘naturally’ converting into the new form. GSK thus argued that Apotex's non-infringing, prior art anhydrate form would ‘inevitably’ convert into GSK's new patented hemihydrate form. The Federal Circuit eventually invalidated the patent relying, in part, on the same conversion theory that GSK used to prove infringement. In the first decision, the Federal Circuit based its invalidity decision on GSK's early work and public use of the patented compound in US clinical trials. But after GSK petitioned for rehearing, the Panel modified its invalidity finding, basing it on the prior art disclosure of paroxetine in the expired ′196 patent that ‘inherently anticipated’ GSK's patent. The Court held that producing paroxetine anhydrate according to the expired ′196 patent inherently results — by a process of natural or inevitable conversion — in at least trace amounts of GSK's patented hemihydrate form, thus rendering GSK's patent invalid for lack of novelty. The Federal Circuit's decision strengthens the inherent anticipation doctrine, particularly for acts of infringement based on the so-called ‘disappearing polymorph’ or ‘natural’ conversion theories. Generics companies seeking to practise expired patents and prepare prior art products thus have added protection against charges of ‘inevitable infringement’.
Raman piezospectroscopic evaluation of intergrowth ferroelectric polycrystalline ceramic in biaxial bending configuration
Authors: Ge Wanyin , Zhu Wenliang , Deluca Marco , Wan Keshu , Yi Zhiguo , Li Yongxiang , Pezzotti Giuseppe
Published: February 2007

The piezospectroscopic (PS) effect was studied in an intergrowth bismuth layer-structure ferroelectric ceramic Bi5TiNbWO15 according to a micro-Raman spectroscopic evaluation. By using a ball-on-ring flexure configuration, a biaxial stress was generated in a Bi5TiNbWO15 plate-like specimen and in situ collected Raman spectra were acquired and analyzed under several loading conditions. As the observed spectral line contained signals arising from the whole illuminated in-depth region, the laser probe information was deconvoluted (by means of an in-depth probe response function obtained according to the defocusing method) in order to deduce biaxial PS coefficients for the three Raman bands of Bi5TiNbWO15 located at 763, 857, and 886 cm−1, respectively. The biaxial PS coefficients of these bands were derived to be −1.74±0.16, −2.51±0.16, and -2.64±0.31 cm−1/GPa, respectively, and should be referred to the c axis of the Bi5TiNbWO15 crystal.
Energy conversion efficiency of a thermoelectric generator under the periodically alternating temperature gradients
Authors: Yamashita Osamu , Odahara Hirotaka , Satou Kouji
Published: February 2007

The thermo-emf ΔV and thermoelectric current ΔI generated by imposing the temperature gradient (TG) alternating at a period of T on a thermoelectric (TE) generator were measured as a function of t, where t is the lapsed time and T was varied from 8s to ∞. The alternating TG was produced by switching a voltage of 2.6V across two Peltier modules (20×20×4.0mm3) connected in series. Two different types of TE generators were employed as a generator and sandwiched between Peltier modules. The dimensions of the generators (1) and (2) were 15×15×4.0 and 20×20×3.8mm3, respectively. The input power Winput fed to two Peltier modules increases abruptly with an increase of 1∕T, but the effective temperature difference ΔTeff produced between two Peltier modules has a local maximum at 1∕T=1∕240s−1 for the generator (1) and at 1∕120s−1 for the generator (2), whose maximum values are 2.59 and 3.65 times as large as those obtained at 1∕T=0s−1. The local maxima of ΔVeff, ΔIeff, and ΔWeff, generated by a generator, appeared at the period T giving the local maximum ΔTeff. The maximum energy conversion efficiency ΔW∕Winput obtained at an optimum period is 0.37% for the generator (1) and 0.27% for the generator (2), which are 3.54 and 5.66 times as high as those obtained at 1∕T=0s−1, respectively. The application of the periodically alternating TG to a TE generator was thus found to be very effective to enhance the energy conversion efficiency of a generator. However, the present low conversion efficiency is attributed not only to both the small ΔTeff (<22K) and low ZT of generators (<0.76 at 298K) and two Peltier modules (=0.75 at 298K) but also to much heat transfer to or from the surroundings other than at the hot and cold sides of a TE generator or two Peltier modules.
Effect of annealing temperature on structural and bonded states of titanate nanotube films
Authors: Kim Gil-Sung , Ansari S. G. , Seo Hyung-Kee , Kim Young-Soon , Shin Hyung-Shik
Published: February 2007

A conversion from commercial titania (TiO2) nanoparticles to nanotubes was achieved by a hydrothermal method. The titanate nanotube (titanate) film was then deposited on a Si (001) substrate using an electrophoretic deposition (EPD) technique. The post hydrothermal treatment was then carried out by annealing the films at 300–1000°C for 30min in the static air. A major amount of intercalated sodium (Na) in as-synthesized titanate nanotubes was removed during the electrodeposition process. The collapse of the tubular structure can be seen clearly when annealed above 500°C. X-ray diffraction data indicate a significant increase in the anatase phase peak intensity with annealing temperature. O 1s peak is found to be built up of subpeaks of H2O, −OH, and Ti–O. Annealing results in an increase of the Ti–O peak intensity while other peaks disappear. Clear changes in the O 1s peak positions, symmetry, and shift towards lower energy (0.8eV) are evident with the increasing annealing temperature. The doublet spectral lines of Ti 2p were found separated by an energy of 5.6eV. Photoelectron spectroscopy show that during the annealing treatment, the chemical bonds such as H2O and −OH are removed from the titanate films as well as converting the bonded states of titanate to that of titania.
Magnetic field anomaly detector using magnetoelectric composites
Authors: Bergs Richard , Islam Rashed A. , Vickers Michael , Stephanou Harry , Priya Shashank
Published: February 2007

This study reports the low frequency magnetoelectric (ME) response of the sintered composites comprising of a piezoelectric phase Pb(Zr0.52Ti0.48)O3 (PZT) and magnetostrictive phases NiFe1.9Mn0.1O4 (NFM) and Ni0.8Zn0.2Fe2O4 (NZF) with varying ferrite contents of 3, 5, 10, 15, and 20mol%. It was found that the ME coefficient for the PZT-NZF samples shows considerably less scattering as a function of frequency and the composition 0.8PZT-0.2NZF exhibited a flat response in the range of 10–100Hz with a magnitude of 220mV∕cmOe. This composition was used to design the magnetic field anomaly detector mounted in front of a global positioning system (GPS) controlled vehicle. The results from the vehicle test clearly demonstrate the feasibility of using sintered ME composites for magnetic field detection in the noisy environment.
Efficient blue upconversion emission in Tm3+ via energy transfer from Yb3+ doped in lithium modified tellurite glass
Authors: Giri Neeraj Kumar , Singh Anant Kumar , Rai S. B.
Published: February 2007

Intense blue and red upconversion emissions were obtained in Tm3+ doped tellurite glass when codoped with Yb3+ ions on pumping with 798nm radiation. The highest intensity of the blue emission was found for glasses with 0.5mol% Tm3+ and 6.0mol% Yb3+. From a study of the dependence of the upconversion intensity on excitation intensity, it is concluded that emissions are due to Tm3+ ions and involve cooperative energy transfer as well as energy transfer from Yb3+ to Tm3+ ions. Lifetime of the Tm3+ level, which is responsible for the intense blue emission, has been measured for various concentrations of Yb3+.