摘要:

Executive SummaryHigh blood pressure (hypertension) is known as a ‘silent killer’ since it results in few symptoms by itself but is a major risk factor for other cardiovascular diseases such as stroke, heart attacks and congestive heart failure. Hypertension is the most prevalent of all cardiovascular diseases in the developed world. According to the American Heart Association (AHA), about 50 million Americans aged 60 years or older have high blood pressure. The most common biochemical systems and mediators responsible for hypertension are the renin/angiotensin system, the adrenergic system, endothelial-derived relaxing factor (EDRF) – now known to be nitric oxide (NO) – and endothelin, a powerful vasoconstrictor that is derived from the endothelium.Risk-factor modification and lifestyle changes can aid significantly in the control of hypertension, but are usually insufficient alone and pharmacological intervention is required. However, although an impressive array of pharmacotherapies is available for treatment of hypertension, effective control is not achieved for most patients. The major classes of hypertension drugs licensed for use are:angiotensin-converting enzyme (ACE) inhibitorsangiotensin-II receptor antagonists (colloquially referred to as angiotensin-II receptor blockers)calcium channel antagonists (colloquially referred to as calcium channel blockers)α-blockersβ-blockersdiuretics.Many, but not all, experts in this field feel there is a need for new and more effective treatments. The most important new drug classes in development are:vasopeptidase inhibitorsendothelin receptor antagonistsvasopressin antagonists.Adis Business Intelligence forecasts that ACE inhibitors, calcium channel antagonists and combinations with diuretics will continue to be the major technologies utilized in the hypertension market through until at least 2012. Angiotensin-II receptor antagonists will continue to be moderately utilized and β-blockers will continue to play a minor-to-moderate role throughout the next decade. The technology that will make the most significant market impact is endothelin receptor antagonists, which should be launched around 2004; endothelin receptor antagonists will become moderately used by 2006 and will begin to be of major utility about 2008–2009. Vasopeptidase inhibitors, another new technology, will soon begin to be of minor utility and should become moderately utilized from about 2004 onwards.The US hypertension market has a well-balanced pipeline that should produce a steady stream of introductions throughout the decade, mainly novel calcium channel antagonists and a variety of novel drugs from minor technology platforms. However, it is not clear how significant a market impact these new products will have, given the emphasis on technology platforms of only minor or moderate utility. In the immediate future, pricing will be the driving force for market growth. Nearly 30 branded pharmaceuticals face patent expiration over the next 10 years. This is likely to produce significant generic upheaval and may retard pricing for years. Overall, sales in the US hypertension market are forecast to grow to $US15 billion in 2012, an increase of 56% over year 2002 sales of $US9.8 billion.

ISSN:1061-2270    

出版商:ADIS    

年代:2003

数据来源: ADIS

摘要:

Executive SummaryThe proteasome is the cellular complex responsible for disposing of proteins that are either abnormal or old. Proteins that are destined for destruction by the proteasome are tagged with ubiquitin, a small polypeptide that enables proteins to enter the proteasome and be degraded. Because it helps regulate the level of proteins with important roles in cellular functions, the proteasome plays a key role in important processes such as DNA repair, cell cycle control, antigen processing and cellular differentiation.Academic researchers and the pharmaceutical industry have become increasingly interested in targeting the proteasome for therapeutic purposes. The rationale for this is that the proteasome helps regulate proteins that play important roles in pathogenesis of inflammatory diseases and cancer. One of the most important such proteins is nuclear factor-kappa B (NF-κB), a transcription factor that switches on genes for pro-inflammatory cytokines and also promotes cancer growth. The proteasome also regulates proteins that control the cell cycle, including cyclins, cell cycle inhibitors and p53. So, inhibiting the proteasome would be a way to inhibit NF-κB and cell cycle proteins as a strategy for therapy of inflammatory diseases – such as asthma, arthritis and psoriasis – and cancer. One further reason for targeting the proteasome for therapeutic purposes is that blocking proteasome activity causes an accumulation of ubiquitinylated misfolded proteins. This triggers the heat-shock response – a cellular defense mechanism that allows cells to withstand a volatile environment; this response could be useful in prevention of ischemic/reperfusion injury (tissue damage caused by sudden lack of blood flow).Boston-basedMillennium Pharmaceuticalsis leading the way in commercializing proteasome inhibitors for pharmaceutical use with two drugs in clinical trials – bortezomib and MLN-519. Bortezomib is a peptide boronate compound that is in phase III clinical trials for multiple myeloma and has received fast-track status from the US FDA. Millenium filed for US FDA approval of bortezomib in January 2003. MLN-519 is a lactacystin-type proteasome inhibitor that is in early clinical development for treatment of reperfusion injury, stroke and other neurological conditions. Millennium has out-licensed development of MLN-519 toPAION GmbH, a German biotech company, but retains an option to become reinvolved in development. Pennsylvania-basedCephalonand the Italian companyNovuspharmaare collaborating to discover and develop proteasome inhibitors for cancer therapy.

ISSN:1061-2270    

出版商:ADIS    

年代:2003

数据来源: ADIS

ISSN:1061-2270    

出版商:ADIS    

年代:2003

数据来源: ADIS

摘要:

Executive SummaryDrug-resistant infectious agents – those that are not killed or inhibited by antimicrobial compounds – are an increasingly important healthcare concern. Tuberculosis, gonorrhea, malaria and childhood ear infections are just a few of the diseases that have become more difficult to treat due to the emergence of drug-resistant pathogens. Many physicians are concerned that several bacterial infections soon may be untreatable. A key factor in the development of antimicrobial resistance (AR) is the ability of infectious organisms to adapt quickly to new environmental conditions. Microbes generally are unicellular creatures that, compared with multicellular organisms, have a small number of genes. Even a single random gene mutation can have a large impact on their disease-causing properties; and since most microbes replicate very rapidly, they can evolve rapidly. The innate adaptability of microbes is complemented by the widespread and sometimes inappropriate use of antimicrobials.Against this backdrop,Pharmaceutical Innovationinterviewed experts from the pharmaceutical and diagnostic industries for their views on the problem of AR and what steps need to be taken to manage the situation.Pharmaceutical Innovationoutlines some of the issues raised by these opinion leaders. A better understanding of the microbiology and genetics of infectious microorganisms is the future key to managing AR according to many of the experts. The application of genomics will play a key role in new drug discovery, based on the premise that the novel targets selected are essential to the viability of the organism. Many of the experts interviewed agreed that vaccines are underutilized to prevent infection and that increasing their use could result in far less antibiotic therapy being needed.Pharmaceutical Innovationalso spoke with executives from three companies with interesting strategies for developing new antibiotics:Paratek Pharmaceuticalsis tackling the heart of antibiotic resistance;Microbiais battling bacterial biofilms; andStructural GenomiXis focussing on using the 3-dimensional structure of bacterial proteins for drug discovery.

ISSN:1061-2270    

出版商:ADIS    

年代:2003

数据来源: ADIS

摘要:

Executive SummaryThe HIV pandemic represents a new challenge to biomedical research. What began as a handful of recognized cases among homosexual men in the US has become a global pandemic of such proportions that it clearly ranks as one of the most destructive viral scourges in history. In the past few years new treatments and drugs have been developed and tested, but the development of a new generation of therapies remains a major priority, because of the lack of chemotherapeutic drugs or vaccines that show long-term efficacyin vivo.Recently, gene therapy strategies for the treatment of patients with HIV infection have received increased attention because they are able to offer the possibility of simultaneously targeting multiple sites in the HIV genome, thereby minimizing the production of resistant virus.Recombinant genes for gene therapy can be classified as expressing interfering proteins (intracellular antibodies, dominant negative proteins) or interfering RNAs (antisense RNAs, ribozymes, RNA decoys). The latter group offers the advantage of avoiding the stimulation of host immune response which might progressively decrease the efficacy of proteins. The stumbling block to achieving lasting antiviral effects is still represented by the lack of efficient gene transfer techniques capable of generating persistent transgene expression and a high number of transduced cells relative to untransduced cells. Novel delivery vectors, such as lentiviruses, might overcome some of these shortcomings.The use of recombinant genes to generate immunity is a very promising concept that is rapidly expanding. Since the immune system can significantly amplify the response to tiny amounts of antigen, DNA vaccines can indeed be delivered by exploiting traditional gene therapy approaches without the need of high transduction efficiency.

ISSN:1061-2270    

出版商:ADIS    

年代:2003

数据来源: ADIS

ISSN:1061-2270    

出版商:ADIS    

年代:2003

数据来源: ADIS

ISSN:1061-2270    

出版商:ADIS    

年代:2003

数据来源: ADIS

ISSN:1061-2270    

出版商:ADIS    

年代:2003

数据来源: ADIS

ISSN:1061-2270    

出版商:ADIS    

年代:2003

数据来源: ADIS