摘要:

Neisseria meningitidiscauses a wide range of human disease and remains a common cause of septicaemia and meningitis. Meningococcal serogroups A, B, C and Y cause the majority of cases of invasive disease in the US and throughout the world, with epidemics usually caused by serogroups A and C. Most patients with meningococcaemia, with or without meningitis, respond to standard antimicrobial therapy with either penicillin or ampicillin, but the recent emergence of meningococcal strains that are intermediately resistant to penicillin may alter these recommendations in the future. Given the devastating nature of meningococcal disease and emergence of these resistant strains, prevention (specifically through vaccination) remains the best approach to control this serious infection. A polysaccharide meningococcal vaccine is efficacious against disease caused by serogroups A, C, Y and W135, but is not effective in infants and children aged <2 years, and the duration of efficacy decreases markedly during the first 3 years after a single dose of the vaccine. Conjugate meningococcal vaccines have been developed to address these concerns. Initial studies with the meningococcal C conjugate vaccine have shown that the vaccine is safe and immunogenic and provides a T cell-dependent antigen that can be boosted by further doses of vaccine, or following exposure to the homologous organism or cross-reacting antigens. The UK recently implemented routine vaccination with the meningococcal C conjugate vaccine to all infants, and to all persons aged >1 year in a catch-up programme to immunise all school-aged children and young adults up to 20 years of age. Early postlicensure data indicate that this vaccine has shown significant efficacy in reduction of invasive meningococcal disease in these age groups. The full impact of vaccination will be determined once all age groups are immunised.

ISSN:1173-8804    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

The sequencing of entire bacterial genomes is becoming increasingly routine, promising to revolutionise approaches to identifying putative antimicrobial drug targets.In silicomethods can be used to identify putative gene products by comparing sequences of biochemically characterised enzymes and proteins with data produced by sequencing projects. Comparative genomics between a pathogenic bacterium versus nonpathogen as well as pathogen versus host can identify molecular targets that would be ideal for future investigation. The aim of these comparisons would be to identify genes that code for pathogenicity factors in the bacterium or genes essential for bacterial survival. The latter set of genes includes those that are nonfunctional or redundant in the host as well as genes absent from the host but essential in the pathogen. The products of these genes would be ideal targets for antimicrobial compounds. If compounds could be generated that disrupt the pathogen's ability to thrive but not affect the host, since there is a lack of the targeted protein, they could prove to be powerful therapeutics. An elegant example illustrating the power of comparative genomics involves comparison of the pathways of bacterial and eukaryotic aminoacyl-tRNA synthesis. Comparison of pathogenic bacterial genomes shows that many bacteria lack the genes encoding either one or two specific aminoacyl-tRNA synthetases, enzymes involved in ensuring correct aminoacylation of tRNA for subsequent translation of the genetic code. Bacteria have an alternative pathway by which amide aminoacyl-tRNAs are formed. Comparative genomics has demonstrated that this pathway is uniquely prokaryotic/archaeal and also relatively widely found in pathogenic bacteria, indicating the potential of the catalytic enzymes of the pathway as targets for novel antimicrobial drugs.

ISSN:1173-8804    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

Transdermal iontophoresis is the administration of ionic therapeutic agents through the skin by the application of a low-level electric current. This article presents an overview of transdermal iontophoretic delivery of drugs, including peptides and oligonucleotides. Recent advances in the area of iontophoretic delivery, including devices, hydrogel formulations, safety, clinical relevance and future prospects, are discussed. Electroporation, another method of electrically assisted drug delivery, is also briefly reviewed.Transdermal iontophoresis appears to be a promising technique for the delivery of a variety of compounds in a controlled and preprogrammed manner. Transdermal iontophoresis would be particularly useful in the delivery of hydrophilic drugs produced by biotechnology (peptides and oligonucleotides). However, because of the complex physicochemical properties of peptides, many factors must be carefully considered for the proper design of an iontophoretic drug delivery system for peptides. Iontophoresis has been successfully used in the delivery of small peptides, such as leuprolide and calcitonin analogues, in humans. However, it appears that transdermal iontophoresis may not be a suitable method for the systemic delivery of larger peptides (>7000D). The combined use of iontophoresis and electroporation may be more effective in the delivery of peptides, proteins, genes and oligonucleotides.The long-term safety of iontophoresis, patient compliance with the technique and the commercial success of this technology are yet to be demonstrated. Iontophoretic delivery of drugs would be beneficial in the treatment of certain skin disorders such as skin cancer, psoriasis, dermatitis, venous ulcers, keloid and hypertrophic scars. Investigations on reverse iontophoresis may yield interesting results that would be useful in the noninvasive measurement of clinically important molecules in the body.

ISSN:1173-8804    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

The second part of this review examines the use of recombinant interferon-α (rIFNα) in the following solid tumours: superficial bladder cancer, Kaposi's sarcoma, head and neck cancer, gastrointestinal cancers, lung cancer, mesothelioma and ovarian, breast and cervical malignancies.In superficial bladder cancer, intravesical rIFNα has a promising role as second-line therapy in patients resistant or intolerant to intravesical bacille Calmette-Guérin (BCG). In HIV-associated Kaposi's sarcoma, rIFNα is active as monotherapy and in combination with antiretroviral agents, especially in patients with CD4 counts >200/mm3, no prior opportunistic infections and nonvisceral disease. rIFNα has shown encouraging results when used in combination with retinoids in the chemoprevention of head and neck squamous cell cancers. It is effective in the chemoprevention of hepatocellular cancer in hepatitis C−seropositive patients. In neuroendocrine tumours, including carcinoid tumour, low-dosage (≤3MU) or intermediate-dosage (5 to 10MU) rIFNα is indicated as second-line treatment, either with octreotide or alone in patients resistant to somatostatin analogues. Intracavitary IFNα may be useful in malignant pleural effusions from mesothelioma. Similarly, intraperitoneal IFNα may have a role in the treatment of minimal residual disease in ovarian cancer. In breast cancer, the only possible role for IFNα appears to be intralesional administration for resistant disease. IFNα may have a role as a radiosensitising agent for the treatment of cervical cancer; however, this requires confirmation in randomised trials.On the basis of current evidence, the routine use of rIFNα is not recommended in the therapy of head and neck squamous cell cancers, upper gastrointestinal tract, colorectal and lung cancers, or mesothelioma. Pegylated IFNα (peginterferon-α) is an exciting development that offers theoretical advantages of increased efficacy, reduced toxicity and improved compliance. Further data from randomised studies in solid tumours are needed where rIFNα has activity, such as neuroendocrine tumours, minimal residual disease in ovarian cancer, and cervical cancer. A better understanding of the biological mechanisms that determine response to rIFNα is needed. Studies of IFNα-stimulated gene expression, which are now feasible, should help to identify molecular predictors of response and allow us to target therapy more selectively to patients with solid tumours responsive to IFNα.

ISSN:1173-8804    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

All drugs appearing in the Adis Profile Summary table have been selected based on information contained inR&D Insight™1, a proprietary product of Adis International. The information in the profiles is gathered from the world's medical and scientific literature, at international conferences and symposia, and directly from the developing companies themselves. The emphasis of this section inBioDrugsis on the clinical potential of new drugs, and selection of agents for inclusion is based on products in late phase clinical development that have recently had a significant change in status.

ISSN:1173-8804    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

Virulizin, a biological response modifier, is a mixture of proteins and peptides that have been extracted from bovine reticuloendothelial tissue that activates macrophages.1It is being developed by Lorus Therapeutics (formerly Imutec Pharma) for the treatment of various cancers and had completed phase II clinical trials in Canada for the treatment of pancreatic cancer and advanced malignant melanoma. The commencement of phase III clinical trials in Canada, for the treatment of pancreatic cancer, was delayed due to quality control problems with batches of virulizin and all clinical trials of virulizin were suspended as Lorus underwent a major restructuring programme. However, phase I/II clinical trials are now underway again in Canada in HIV-positive patients with Kaposi's sarcoma and for the treatment of pancreatic cancer. A phase I/II clinical trial is also underway in patients with pancreatic cancer in the USA. Lorus announced in June 2000 that it had completed a meta analysis of three phase I/II studies of virulizin that showed the drug increased survival and improved quality of life for pancreatic cancer patients. Based on these positive results, Lorus initiated a phase III trial to be conducted at 40 sites in North America in November 2001. The study aims to enrol 350 patients with advanced pancreatic cancer and will test the effectiveness of virulizin as first- and second-line treatment of pancreatic cancer. The study will compare virulizin + gemcitabine with gemcitabine alone as first-line therapy, while second-line treatment will involve patients who have failed to respond to gemcitabine. Some of these patients will receive virulizin + fluorouracil while another group will receive only fluorouracil. The study is scheduled to complete in 2004 or early 2005. Virulizin received orphan drug status for this indication from the US FDA in February 2001. Lorus received fast track designation from the FDA in June 2002 for virulizin for the treatment of pancreatic cancer.Virulizin is registered for the treatment of malignant melanoma in Mexico and is due to be launched there in 2002. Lorus has entered into an exclusive 7-year distribution agreement with Faulding Canada Inc., giving Faulding (now part of Mayne Group) the right to market and sell virulizin in Mexico for the treatment of melanoma. Lorus will receive royalties from sales of the product and will be responsible for its manufacture. In April 2002, Mayne exercised its option to acquire the distribution rights for virulizin in Brazil.Lorus Therapeutics has signed a collaborative agreement with NaPro BioTherapeutics, USA, to study the efficacy of virulizin in combination with paclitaxel for the treatment of lung adenocarcinoma.Lorus is conducting preclinical studies of virulizin in human breast cancer, lung, ovarian and prostate cancer, and has reported successful activity of the agent in these indications.Lorus was awarded a patent by the US Patent and Trademark Office to protect the only known process used to create virulizin. This patent, in conjunction with the patents issued in Australia, South Africa, New Zealand, Korea and Singapore, broadens and strengthens the protection of Lorus' intellectual property rights regarding the process, composition and use of virulizin.

ISSN:1173-8804    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

Genetics Institute (Wyeth) is collaborating with Medtronic-Sofamor Danek (which specialises in spinal reconstruction) and Integra Life Sciences to develop a BMP 2 product [INFUSE Bone Graft] for use in spinal reconstruction in North America.1The INFUSE Bone Graft product has been approved for use in lumbar interbody spinal fusion procedures in the USA and is in phase III trials for use in lumbar posterolateral spinal fusion procedures.During the procedure, damaged disc is replaced with a collagen sponge (Integra's Absorbable Collagen Sponge) soaked with BMP 2, which is held in place within an implanted cage device (LT-CAGE™ Lumbar Tapered Fusion Devise); the fusion process subsequently requires several months to complete. However, the patient is able to leave hospital the day after the operation, whereas in conventional spinal surgery a longer recovery time is required. The procedure supersedes the use of autograft bone as it uses a recombinant human bone morphogenic protein, rhBMP-2, which induces the body to grow its own bone where required.Genetics Institute has cloned and expressed bone morphogenic proteins 1-7 and established manufacturing processes by recombinant DNA technology. Bone morphogenic proteins may be useful in the treatment of osteoporosis and orthopaedic trauma.BMP 2 is also being developed for bone regeneration as an implanted device and as an injectable formulation. Genetics Institute is also collaborating with Integra LifeSciences to develop a formulation of BMP 2 with Integra's absorbable collagen-based structures for fracture treatment, which is awaiting approval in the USA.

ISSN:1173-8804    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

Amediplase [CGP 42935, MEN 9036, K2tu-PA] is a recombinant chimeric plasminogen activator, consisting of the kringle 2 domain from the A-chain of tissue plasminogen activator (t-PA) and the carboxy terminal region of pro-urokinase.1Amediplase was the outcome of a collaborative project with Ciba Geigy (now Novartis), but subsequent preclinical and clinical development has been completed by Menarini.Menarini is currently investigating amediplase in phase III clinical trials in Europe as a thrombolytic given as a single bolus to patients with myocardial infarction.In June 2002, Prometic Life Sciences announced that its collaboration with Menarini Biotech had resulted in the discovery of a scaleable manufacturing process for amideplase, based on Prometic's Mimetic Ligand− technology; amideplase manufactured by this process is expected to be used in the phase III studies.

ISSN:1173-8804    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

Omalizumab [anti-IgE monoclonal antibody E25, E25, humanised anti-IgE MAb, IGE 025, monoclonal antibody E25, olizumab, rhuMAb-E25, Xolair™] is a chimeric monoclonal antibody. It binds specifically to the Cε3 domain of immunoglobulin E (IgE). Cε3 is the site of high-affinity IgE receptor binding. IgE plays a major role in allergic disease by causing the release of histamine and other inflammatory mediators from mast cells. Omalizumab binds to and neutralises circulating IgE by preventing IgE from binding to its high-affinity mast-cell receptor. In addition, omalizumab does not bind to or induce histamine release from basophils, nor does it bind to or recognise IgG. The immune complexes formed between IgE and omalizumabin vivoare relatively small (molecular weight <1 million) and are therefore unlikely to cause organ damage.Collaboration between Genentech, Novartis and Tanox:omalizumab is very similar to the Tanox product CGP 51901. Genentech (Roche), Novartis and Tanox (formerly Tanox Biosystems) were developing both antibodies in phase II studies, with an agreement to collaborate on phase III development of the most promising one. The Genentech product, omalizumab, was selected for further development. Tanox has marketing rights to the drug in some Asian markets. Novartis and Genentech have marketing rights in the USA. Roche has an option to participate in the commercialisation of omalizumab and other anti-IgE products of the collaboration in Japan and Europe. Roche may exercise this option if specific events relating to commercialisation of the product occur; Roche has waived this option for omalizumab in Japan. If Genentech withdraws from the collaboration, Roche has an option to assume its place. Either Novartis or Genentech may withdraw from the collaboration on short notice, in which case rights to omalizumab revert to Tanox and the remaining collaborator unless Roche exercises its option in the event of withdrawal by Genentech.Patents:Protein Design Labs holds fundamental antibody humanisation patents. Protein Design Labs stated in its Annual Report for 2000 that Genentech may elect to take a patent licence for Xolair™ under a 1998 patent rights agreement.Clinical trials:Phase III clinical trials of omalizumab for the treatment of allergic rhinitis and allergic asthma were in progress with Genentech (Roche) in the USA, Canada, Europe and Japan, and are now completed. In New Zealand, the antibody was investigated in clinical trials for the treatment of allergic asthma at the Wellington School of Medicine. In the phase III trials, omalizumab was administered as a subcutaneous injection. It may also be administered intravenously. In additional phase I and II studies, the safety and efficacy of aerosol administration for allergic asthma was tested. Initial results of these studies indicated that aerosol administration is less effective than intravenous or subcutaneous administration.Temporary suspension of trials:In September 2000, the US FDA requested that Genentech and Novartis suspend new trials of omalizumab. Existing long-term trials, however, could continue. The hold on new trials was due to concerns about the preclinical toxicity of omalizumab and the follow-up antibody E26. Thrombocytopenia was reported in studies in monkeys for omalizumab at 5−27 times the maximum clinical dose and for E26 at 3−15 times the maximum dose. In response to FDA requests, Novartis and Genentech carried out additional preclinical trials so that a specific explanation of the toxicity could be obtained; Novartis suspected a species specificity for the adverse events, as no thrombocytopenic events occurred in the completed phase III clinical trials. The supplementary data were submitted to the FDA and the hold on clinical trials was lifted in November 2000.Regulatory filings:in June 2000, Genentech, Novartis and Tanox submitted a Biologics Licence Application (BLA) to the US FDA for approval of omalizumab for the treatment of allergic asthma and allergic rhinitis. Novartis filed for marketing approval of omalizumab in the European Union, Switzerland, Australia and New Zealand.Indication narrowed to adult allergic asthma:In July 2001, the FDA requested additional data, both preclinical and clinical, for Xolair™, as well as more detailed information concerning the effect of prolonged action of the drug. Genentech is to satisfy the FDA's request with data from the ALTO platelet monitoring safety study and with ongoing open-label studies. Genentech, Novartis and Tanox believe that substantial information can be provided from continuing trials, but additional trials on specific subgroups may be necessary. The new data will be submitted to both the US FDA and the EMEA in the European Union. The application for approval of Xolair™ that was submitted to the EMEA was withdrawn when it became clear that there would be a delay in approval in the USA. Tanox had originally anticipated that Xolair™ would be launched in mid-2001 in the USA and Europe. In November 2001, Genentech and Novartis stated that an amended BLA would be submitted to the FDA in the fourth quarter of 2002. The amended approval application will focus on the use of Xolair™ in adults only with allergic asthma. The original application was for treatment of both adults and children, and included allergic rhinitis. Genentech has stated that it will first pursue the narrower indication before filing supplemental BLAs. Approval of the drug in the USA may now be delayed until as late as the end of 2003. In Europe, Novartis is planning to develop Xolair™ for use only in asthmatic patients who are classed as being ‘at risk’, i.e. those who have been hospitalised or have visited an emergency department. Clinical studies are to be carried out, with submission for regulatory approval planned for 2003.Approval in Australia:In June 2002, Xolair™ was approved by the Therapeutic Goods Administration in Australia for the treatment of adults and adolescents with moderate allergic asthma. This is the first marketing approval for Xolair™.

ISSN:1173-8804    

出版商:ADIS    

年代:2002

数据来源: ADIS