Small Pharmaceutical Companies Research Articles

New Disturbing Trend in Antimicrobial Resistance of Gram-Negative Pathogens

Gram-negative bacteria-producing extended-spectrum β-lactamases (ESBLs) are found to be truly multiresistant pathogens causing severe clinical problems. In our investigations, fifteen class C β-lactamases with extended substrate spectra have been reported in Gram-negative pathogens. Because of the emergence and dissemination of these enzymes, we propose that these enzymes be recognized as class C ESBLs (cESBLs), although most of the known ESBLs are class A and D β-lactamases. To decrease the selective pressure of antimicrobial drugs and minimize antimicrobial resistance, it is necessary for health-care professionals to recognize the presence of emerging cESBLs as a new and disturbing trend in antimicrobial resistance of Gram-negative pathogens. Because there is currently no drug development against cESBL-producing Gram-negative pathogens in progress and large pharmaceutical companies have largely withdrawn from research and development of new antimicrobial drugs, there is a tremendous need for the development of new β-lactams (or β-lactamase inhibitors) by focused cooperation between academia and small pharmaceutical companies, using the similar structural mechanism (a potential therapeutic target) of the extended substrate spectrum shown in most cESBLs. The consensus view about antimicrobial resistance is that severe clinical problems arise from the emergence of antibiotic resistance in Gram-negative pathogens causing nosocomial infections, and from the lack of new antimicrobial agents to challenge the threat [1]. There are four disturbing trends (extending substrate spectra) in the increasing antimicrobial resistance of Gram-negative pathogens [1]: (i) class B β-lactamases (metallo-β-lactamases) conferring resistance to almost all β-lactam antibiotics [2]; (ii) a bifunctional aminoglycoside-modifying enzyme [3]; (iii) the evolution of a fluoroquinolone-modifying enzyme from an aminoglycoside acetyltransferase [4]; and (iv) a new plasmid-borne fluoroquinolone efflux determinant [5]. These disturbing trends indicate that options for the treatment of health-care–associated Gram-negative infections are perilously limited as the organisms expand their ability to evade existing antimicrobial agents [1],[6]. Here we wish to draw attention to a new disturbing trend (the recently emerging class C extended-spectrum β-lactamases [ESBLs]), and to the antimicrobial drug development for class C ESBLs. We suggest also that the category of ESBLs has to be expanded.

Psychopharmacology: concepts and opinions about the use of stimulant medications

Psychopharmacology: concepts and opinions about the use of stimulant medications

The Dawn of Anxiolytics: Frank M. Berger, 1913–2008

Back to table of contents Previous article Next article Images in PsychiatryFull AccessThe Dawn of Anxiolytics: Frank M. Berger, 1913–2008Richard Balon M.D.Richard Balon M.D.Search for more papers by this authorPublished Online:1 Dec 2008https://doi.org/10.1176/appi.ajp.2008.08040552AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail The discovery that ushered in the era of tranquilizers and other anxiety medications was Frank Berger’s discovery of meprobamate. Frank Berger, M.D. , was a microbiologist of Czech origin working in the United Kingdom during World War II. Shortly after Florey and colleagues purified penicillin, Berger was looking for a substance that would preserve penicillin by inhibiting penicillinase-producing bacteria. One of these substances, mephenesin (Myanesin) met this criterion. While performing toxicity studies, Berger noted that large doses of mephenesin produced tranquilization in laboratory animals. He published his findings in 1946 in the British Journal of Pharmacology(1) . Shortly after this discovery, Berger moved to the United States and worked at Carter Products (later Carter-Wallace), a small pharmaceutical company. There he continued working with mephenesin, investigating why it was metabolized rapidly. He and his co-workers found that mephenesin’s rapid deactivation by oxidation of its terminal hydroxy groups was best blocked by carbamates. They synthesized a few hundred carbamates. Meprobamate (2) seemed to be “the best one.” Several clinical trials with meprobamate were conducted, one by Berger himself. To convince hesitant executives about meprobamate’s properties, Berger produced a short documentary showing the drug’s effect on rhesus monkeys. The brand name “Miltown,” after a small village near New Brunswick, N.J., was selected (meprobamate was also later distributed as “Equanil”). Meprobamate became extremely popular during the 1950s and opened the market to other “tranquilizing” drugs (e.g., chlordiazepoxide). Meprobamate relieved anxiety, relaxed muscles, and induced mild euphoria and “inner peace.” Some even suggested that it should be added to drinking water so the masses would be less anxious. Thus, it is interesting that the Associated Press reported in March 2008 that traces of meprobamate were found in water supplies of Los Angeles and several other places. Only a few years after its introduction, it became obvious that meprobamate could be habit forming, its sudden withdrawal could be dangerous, and overdose could be lethal. Its use decreased, especially after the arrival of benzodiazepines, but it never totally faded away. Generic meprobamate is still available. Frank Berger continued his research and development of carbamates (e.g., the pain reliever carisoprodol) and later returned to bacteriology and immunology. Berger is an example of an alert observer and astute researcher from the golden era of serendipity in psychopharmacology research, along with R. Kuhn, J. Delay, P. Deniker, and others. Recently, Donald Klein (3) reminded us of “a seismic shift in psychiatry between 1950 and 1970,” the Age of Serendipitous Psychopharmacology Discoveries. During those times, lithium, chlorpromazine, iproniazid, meprobamate, chlordiazepoxide, haloperidol, and other psychotropic drugs were “discovered” mostly because of “chance observations of unexpected clinical benefits or as inadvertent outcomes of blind pharmaceutical searches” (3) . Address correspondence and reprint requests to Dr. Balon, UPC-Jefferson, 2751 East Jefferson #200, Detroit, MI 48207; [email protected] (e-mail). Photograph used by permission of Christine Berger. Image accepted May 2008 (doi: 10.1176/appi.ajp.2008.08040552). The author thanks Thomas Ban, M.D., for providing information about Frank Berger.

Update on emerging drugs for sarcopenia – age-related muscle wasting

Sarcopenia – the progressive loss of muscle mass with advancing age is characterised by a deterioration of muscle quantity and quality leading to a gradual slowing of movement and a decline in strength and power. Sarcopenia is a highly significant public health problem. Frail elders often require assistance for accomplishing even basic tasks of independent living, and they are also at increased risk of serious injury from sudden falls and subsequent fractures. Since these age-related changes are largely attributed to the complex interaction of factors affecting neuromuscular transmission, muscle architecture, fibre composition, excitation-contraction coupling, and metabolism, the mechanisms responsible for these deleterious changes present numerous therapeutic targets for novel drug discovery. Objective: This review provides an update on some of the emerging drugs for sarcopenia that have been in development during 2005 – 2008. Methods: This is a review of the current status of emerging therapies and novel approaches for sarcopenia. Results: Considerable research and development in academic and research institutions and in large and small pharma is being directed to sarcopenia and related health issues; specifically the development and evaluation of novel therapeutic strategies to attenuate, prevent, or ultimately reverse age-related muscle wasting and weakness. Conclusions: Few, if any, drugs have been developed for sarcopenia specifically, but there are many existing and emerging drugs that have potential application for tackling age-related muscle wasting, particularly drugs for neurodegenerative diseases.

In memoriam: Dr. Herbert Falk (1924-2008)

In memoriam: Dr. Herbert Falk (1924-2008)

The ever-changing role of information professionals in pharmaceutical R&D

The role of the information professionals in the pharmaceutical industry is explored with particular reference to the author’s current role leading a team at a small pharmaceutical company. Particular emphasis is placed on the importance of establishing a good relationship with the customers for the searches, but topics such as time management, training and resource allocation for example are also covered.

Treatment of health-care-associated infections caused by Gram-negative bacteria: a consensus statement

This consensus statement presents the conclusions of a group of academic and industrial experts who met in London in September, 2006, to consider the issues associated with the treatment of hospital infections caused by Gram-negative bacteria. The group discussed the severe clinical problems arising from the emergence of antibiotic resistance in these bacteria and the lack of new antibacterial agents to challenge the threat. The discovery of new drugs active against hospital-acquired Gram-negative bacteria is essential to prevent a future medical and social catastrophe. An important strategy to promote drug discovery will be the development of focused cooperations between academic institutions and small pharmaceutical companies.

Early phase studies in India: Are we too early to explore?

Early phase studies in India: Are we too early to explore?

FDA and the Antibiotic Breakpoint Updating Process

We read with interest the Current Topics article prepared by Jeffrey L. Fox, “FDA reasserts authority over antibiotic breakpoint updating process,” in the May 2007 issue of Microbe (p. 222). We were disappointed that such an important article did not present a more balanced view of all stakeholders, including interviews with additional clinical microbiologists or clinicians including those specializing in infectious diseases. However, Fox accurately points out the key regulatory requirements of the Food and Drug Administration (FDA) and the patient safety benefits of regular updates to breakpoints in the face of emerging bacterial resistance. FDA and Clinical and Laboratory Standards Institute (CLSI, formerly NCCLS) share common interests in establishing breakpoints for interpretation of antimicrobial susceptibility tests. CLSI convened a special meeting in January, which included representatives from FDA, CDC, large and small pharmaceutical companies, diagnostic devices companies, clinical microbiologists, and infectious diseases clinicians from the United States and abroad, to discuss how CLSI and FDA can best work together on the issue of antibiotic susceptibility test interpretive breakpoints. The group recommended that CLSI publish the initial FDA breakpoints of newly approved antimicrobial agents following a brief presentation to CLSI by the drug's sponsor. If the CLSI Subcommittee on Antimicrobial Susceptibility Testing (AST) does not agree with the FDA breakpoints, the drug will not be included in the CLSI susceptibility testing publications. Further, CLSI would not propose any alterations of the FDA breakpoints for at least two years following approval of the official drug label. If, after that time, emerging resistance or other issues arise that suggest the need to revise the breakpoints, the subcommittee would review all relevant data to determine if a change would be warranted. These recommendations have been endorsed by CLSI's AST Subcommittee, Area Committee on Microbiology, and Board of Directors. This new approach should assuage the concerns of pharmaceutical companies that the FDA and CLSI breakpoints might differ for their new drugs. It should also better serve clinical microbiology laboratories and diagnostic device manufacturers because there will not be conflicting breakpoint recommendations for new drugs in the United States.

Emerging drug treatments for cystic fibrosis

Although the gene for cystic fibrosis was discovered in 1989, a definitive cure remains elusive for this deadly orphan disease. Advances in nutritional rehabilitation, antibiotics, mucolytics and delivery of care have improved survival to a median age of 37.5 years; however, the psychosocial, personal and financial burdens of this lifelong chronic illness remain considerable. The current portfolio of investigational therapeutics is explored here and placed in a context of therapeutic target and predicted clinical benefit. Partnership between large and small pharma, the Cystic Fibrosis Foundation and academia should be fostered to accelerate therapeutic development.

Mergers and Acquisitions Dynamics in the Biotechnology Industry

This article aims to provide an explanation of the driving forces of consolidation involving genomics-based biotechnology and small pharma companies with large pharma. The factors that lead firms to choose acquisitions over alliances have set forth the foundation for a new form of governance of technological change. The synergies resulting from internally coherent and mutually supportive resources along the drug discovery value chain totally justifies much of the mergers and acquisitions (M&A) activity. As such, M&A can help firms become more competitive through the reconfiguration of their resources, skills and capabilities in the face of changing business environments. There is clearly an awareness that finding a gene or protein target does not automatically lead to a new therapeutic drug. As such, many of the genomics companies have gone through a reality check and realised that they do not have the necessary expertise, intellectual property and resources for securing their long-term survival. Consequently, acquisitions have multiplied over the last years, mainly fuelled by such requirements as managing product portfolios, accessing critical capabilities, entering new markets, building critical mass, accelerating research and development, and reducing costs.

Is the pharmaceutical industry responding to the challenge of increasing bacterial resistance?

There is general agreement that bacterial resistance is a growing problem that needs immediate attention, especially when one considers that the current antibacterial pipeline is probably inadequate to meet future needs. To complicate this problem, many large pharmaceutical companies are either leaving the anti-infective field or decreasing commitments to new antibacterial drug discovery. The purpose of this brief report is to focus on some of the more important issues involved and to examine the roles of biotechnology companies and small pharmaceutical companies in addressing this growing problem. There is a definite need for innovative solutions involving new paradigms that include roles for biotechnology companies, small and big pharmaceutical companies, and possible innovative governmental support to adequately address the need for novel antibacterial agents in the future.

The Pharmaceutical Medicine Year That Was

It is probably fair to say that 2006 has not been a radically different year in the US; let us briefly survey the landscape. As we knew a year ago, large pharma is beset with its problems of relatively empty development pipelines and imminently expiring patents. The latter has led to a steady stream of patent litigation between large pharma and the generic manufacturers. The complexity of these cases has attracted the attention of the federal authorities because of the anticompetitive aspects involved; in some cases, the short legal deadlines seem to make litigation automatic. Large pharma’s response to these fundamental problems has been to continue to license early-stage products from small pharma (or even to buy these small companies, lock, stock and barrel). Thus, the year has been punctuated by these occasional, high-valued deals that have featured elsewhere in this volume of the International Journal of Pharmaceutical Medicine (see the Summary of Recent Deal Activity section in each issue). There is still no evidence that large pharma has lost its mega-merger orientation and rumours of yet further transactions between the few large and famous companies continue to circulate from time to time. For small companies, the financial situation was a bit brighter during 2006 than in the previous year. By mid-year, there were several venture capital firms who had accomplished impressive fundraising and, thus, ‘the window has been opened’ a bit for small companies seeking investment. When added to the money coming from large pharma, the small pharma environment has improved during the year, even if it is not like the halcyon days of the early

Management effects on quality‐policy implementation

PurposeThis paper aims to review the levels of management commitment and involvement in four small (fewer than 500 employees) pharmaceutical companies and the nature and extent of structured programs for policy implementation.Design/methodology/approachIn each of the companies, the comparative success of policy implementation was assessed by the extent of management commitment to the process. Assessments were based on the review of 40 attributes of a four‐part implementation cycle. A lack of a structured process, lack of support and involvement of management and the degree to which management was subsequently involved in the overall implementation were commonly observed problems. The degree of management involvement was a prominent factor in the overall success of the policy implementation.FindingsQuality policies play an important role in the understanding of a company's operational principles and practices. The most successful policy implementation in the companies studied relied on policies being drafted internally with the cooperation of not only the nominated quality management but also the supporting non‐quality management functions. The use of a structured and predetermined implementation plan that is shared across all sectors of the company and the development of supporting systems to monitor progress were also observed to benefit employee involvement and effective policies.Originality/valueThe study of these companies and their comparative abilities to follow a structured process for quality system policies provides valuable guidance for quality practitioners facing similar processes of change within their own organizations. A structured process for implementing policies is also provided.

Small Pharmaceutical Companies

Small Pharmaceutical Companies

Antibacterial drug discovery: is small pharma the solution?

Although antibacterial research has declined in many larger pharmaceutical companies, small companies have begun to fill in the gap. Antibacterial discovery research is currently being conducted in at least 35 small companies. One successful approach taken by small pharma has been to continue clinical programmes that were abandoned by large companies. Issues surrounding these activities, as well as proposed changes, are outlined.

Barriers to Alzheimer Disease Drug Discovery and Development in Academia

The drug discovery and the drug development processes represent a continuum of recursive activities that range from initial drug target identification to final Food and Drug Administration approval and marketing of a new therapeutic. Drug discovery, as its name implies, is more exploratory and less focused in many cases, whereas drug development has a clinically defined endpoint and a specific disease goal. Academia has historically made major contributions to this process at the early discovery phases. However, current trends in the organization of the pharmaceutical industry suggest an expanded role for academia in the near future. Megamergers among major pharmaceutical corporations indicate their movement toward a focus on end-stage clinical trials, manufacturing, and marketing. There has been a parallel increase in outsourcing of intermediate steps to specialty small pharmaceutical, biotechnology, and contract service companies. The new paradigm suggests that academia will play an increasingly important role at the proof-of-principle stage of basic and clinical drug discovery research, in training the future skilled work force, and in close partnerships with small pharmaceutical and biotechnology companies. However, academic drug discovery research faces a set of barriers to progress, the relative importance of which varies with the home institution and the details of the research area. These barriers fall into four general categories: (1) the historical administrative structure and environment of academia; (2) the structure and emphasis of peer review panels that control research funding by government and private agencies; (3) the organization and operation of the academic infrastructure; and (4) the structure and availability of specialized resources and information management. Selected examples of barriers to drug discovery and drug development research and training in academia are presented, as are some specific recommendations designed to minimize or circumvent these barriers. In some cases, precedents established by other disease-focused areas may be relevant to Alzheimer disease and related disorders, but the overall impact of any changes requires adaptation at the top of the administrative structures in academia and funding agencies to support and encourage cooperative efforts among faculty investigators.

Drug discovery 2001

Differing views were heard at the Drug Discovery Technology 2001 conference held in August in Boston, MA, USA on how to identify new drug targets through genomics (bmn.com, 16 August). Speakers from large and small pharmaceutical companies discussed the merits of parallel processing and automated high-throughput testing versus ‘one-at-a-time’ gene screening. Pfizer, inc (Groton, NJ, USA) reported some success in targeting a family of phosphodiesterase genes in search of new treatments for respiratory illness and erectile dysfunction, but experienced very high failure rates in phase 1 trials. MJD

Epidemiology in the pharmaceutical industry

A survey assessing the practice of epidemiology in the pharmaceutical industry was sent to all member companies and research affiliates of the Pharmaceutical Research and Manufacturers of America (PhRMA) and to six non-member companies. Eighty-three companies were surveyed. Screening questions established whether or not a company employed epidemiologists, had an epidemiology department, or contracted work to epidemiologists outside the company. The survey included questions about organizational structure, functional role of epidemiologists, epidemiology department activities within the company, and collaboration with external partners. The response rate was 90.4%. Of the responding companies, 40% employed epidemiologists, 20% had epidemiology departments, and 36% utilized epidemiologists contracted outside the company. Eighty per cent of companies that employed epidemiologists also contracted epidemiology services outside of the company, while 6.7% of companies that did not employ epidemiologists utilized outside epidemiology services. Among all companies 42.7% employed or utilized epidemiologists. Differences were found in the extent to which large, medium and small pharmaceutical companies employ and utilize epidemiologists. The survey demonstrates that epidemiologists perform many roles within the pharmaceutical industry; that there are many potential opportunities for epidemiologists in this industry and that increased emphasis on safety will require more epidemiology training and recruitment efforts. Copyright (c) 2000 John Wiley & Sons, Ltd.

Protein—drug complexes important for immunoregulation and organ transplantation

Recently, two structures of the Ser/Thr phosphorylase calcineurin in complex with FK506 and its cognate immunophilin, FKBP12, have been reported, both solved by small pharmaceutical companies focused on structure-based drug design. A realization, however, that the toxicities associated with calcineurin-mediated immunosuppressants might be mechanism based has driven the current interest in alternative approaches to autoimmunity prophylaxis and preventing transplant rejection. Regulatory approval in 1995 of the immunosuppressant prodrug mycophenolate mofetil, whose active metabolite, mycophenolic acid, inhibits inosine monophosphate dehydrogenase, has focused attention on the potential significance of the de novo purine-biosynthesis pathway as a target for immunosuppressive drugs, leading ultimately to the solution of enzyme structure as a drug design target. As this and other clinically relevant targets are discovered, elaborated and refined via the activity of their cognate agents (as was the case for the phosphatase calcineurin via the activity of cyclosporin), a critical opportunity should ensue for structural biology to exert a profound effect on the future development of these therapies.