摘要:

Severe combined immunodeficiencies (SCID) are rare disorders that represent paediatric medical emergencies, as the outcome for affected patients can easily be fatal unless proper treatment is performed. The only curative treatment for SCID is reconstitution of the patient's immunity. For more than 30 years, allogeneic bone marrow transplantation (BMT) has been extremely successful for SCID. However, BMT often results in only incomplete restoration of B cell function in treated patients, especially when haploidentical donors are used. In addition, BMT can be associated with severe complications such as graft-versus-host disease (GVHD). Alternative forms of therapy for SCID are therefore desirable. Genetic correction of peripheral T lymphocytes and/or haematopoietic stem cells (HSCs) by retrovirally mediated gene transfer has been attempted for patients with SCID due to adenosine deaminase deficiency, the first genetic disease targeted in clinical gene therapy trials with very limited success, overall. After these pioneer trials, recent progress has led to significant improvement of gene transfer techniques and better understanding of HSC biology which has culminated in the recent success of a gene therapy trial for patients affected with X-linked SCID (X-SCID). In this trial, patients with X-SCID received autologous bone marrow stem/progenitor cells which had been retrovirally transduced with a therapeutic gene. Based on the current follow-up, the overall efficacy of this gene therapy procedure is to be considered similar to or even better than that achievable by allogeneic BMT, because patients were not exposed to the risks of GVHD. Although these exciting results have clearly demonstrated that gene therapy is a feasible therapeutic option for X-SCID, they have also raised important questions regarding the long-term outcome of this experimental procedure and the possibility of translating this success into applications for other forms of SCID.

ISSN:1173-8804    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

Radiopharmaceuticals used forin vivoimaging of inflammatory conditions can be conveniently classified into six categories according to the different phases in which the inflammatory process develops. The trigger of an inflammatory process is a pathogenic insult (phase I) that causes activation of endothelial cells (phase II); there is then an increase of vascular permeability followed by tissue oedema (phase III). Phase IV is characterised by infiltration of polymorphonuclear cells, and a self-limiting regulatory process called apoptosis is observed (phase V). If the inflammatory process persists, late chronic inflammation takes place (phase VI). In some pathological conditions, such as organ-specific autoimmune diseases, chronic inflammation is present early in the disease.The aim of nuclear medicine in the field of inflammation/infection is to develop noninvasive tools for thein vivodetection of specific cells and tissues. This would allow early diagnosis of initial pathophysiological changes that are undetectable by clinical examination or by other diagnostic tools, and could also be used to evaluate the state of activity of the disease during therapy. These potential applications are of great interest in clinical practice.In this review, we describe the various approaches that have been developed in the last 25 years of experience. Recent advances in the diagnosis of inflammatory processes have led to the development of specific radiopharmaceuticals that are intended to allow specific stage-related diagnosis.

ISSN:1173-8804    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

Interferon-α (IFNα) is a pleiotropic cytokine with direct and indirect antitumour effects. These include prolongation of the cell cycle time of malignant cells, inhibition of biosynthetic enzymes and apoptosis, interaction with other cytokines, and immunomodulatory and antiangiogenic effects. The first clinical trials in solid tumours used crude preparations of natural IFNα and demonstrated that tumour regressions in solid tumours and haematological malignancies were possible. Since the advent of genetic engineering technology, recombinant (r) IFNα has been widely evaluated in solid tumours. This review discusses the use and potential of rIFNα in solid tumours; the first part focuses on malignant melanoma and metastatic renal cell carcinoma (RCC).In the adjuvant treatment of malignant melanoma, rIFNα has been tested in randomised trials in more than 6000 patients. High-dosage IFNα (≥10MU) prolongs disease-free survival (DFS) but not overall survival (OS). Low-dosage IFNα (≤3MU) has not been shown to prolong DFS or OS, and current data do not support its use outside clinical trials. The latest United Kingdom Co-ordinating Committee on Cancer Research meta-analysis of ten randomised trials that used adjuvant rIFNα has shown that there is a benefit in DFS but not OS. No conclusions can be reached for intermediate-dosage IFNα (5 to 10MU) until the mature results of the European Organization for Research and Treatment of Cancer (EORTC) study 18952 are available. In RCC, current evidence does not support the use of adjuvant IFNα.In metastatic malignant melanoma and RCC, reported response rates to rIFNα are approximately 15%. In a minority of responding patients, however, these responses can be long-standing. In metastatic malignant melanoma, IFNα combined with other cytotoxic agents with or without interleukin-2 has achieved high response rates but has not improved survival. In metastatic RCC, intermediate dosages of rIFNα should be used and therapy should probably be prolonged (>12 months); response depends on prognostic factors such as good performance status, whereas survival is affected by factors such as low tumour burden. Nephrectomy should therefore be considered in patients with good performance status prior to IFNα immunotherapy in advanced RCC, even in patients with metastatic disease.The toxicity of high-dosage IFNα and the lack of definite benefit on OS with high- or low-dosage IFNα do not support its use outside clinical trials. Data from the ongoing US Intergroup studies, the ongoing EORTC 18991 study (long-term therapy with pegylated IFNα) and mature data from EORTC 18952 (intermediate-dosage IFNα) will help establish the role of IFNα as adjuvant therapy in malignant melanoma.

ISSN:1173-8804    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

Over the past decade the potential for delivering targeted therapy against malignant disease by the use of monoclonal antibodies (MAbs) has begun to be realised. Haematological malignancies, because of the relative accessibility of the malignant cell in blood and bone marrow and the understanding of haemopoietic lineage-specific antigens, have provided a successful testing ground for this therapy. There have been many technical developments which have allowed the safe delivery of more potent antibody constructs. The development of human or chimeric antibodies has largely overcome the problems associated with host immune responses to rodent-derived MAbs. Protein engineering to combine MAbs with other biologically active molecules such as radioisotopes, toxins, chemotherapy and cytokines, has made available a new range of agents with clinical activity.The purpose of this review is not to give a catalogue of all therapeutic antibodies but rather to outline the principles of this approach, the current state of knowledge, and possible directions for future development. First, the general requirements and strategies for use of both unmodified and conjugated MAbs are discussed, followed by a summary of the trial data in specific lymphoid and myeloid haemopoietic malignancies. The focus is on MAbs that now have an accepted use in clinical practice, with some discussion of newer MAbs under development. Vaccination strategies and the role of MAbs in bone marrow transplantation are not discussed in detail.The trials of the next decade will address issues such as: whether clinical activity translates into improved survival; the optimal strategies and timing for clinical use; whether increasing potency of MAbs (as in radio- and immunoconjugates) will increase toxicity and, finally, what other potential molecules, such as those influencing cell growth and death, may be targeted.

ISSN:1173-8804    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

▴ Anakinra, a recombinant human interleukin-1 (IL-1) receptor antagonist, is the first biological agent approved to block the pro-inflammatory effects of IL-1 in patients with rheumatoid arthritis.▴ In a double-blind, randomised trial in 472 patients with active, severe or very severe rheumatoid arthritis, recipients of subcutaneous anakinra 150 mg/day achieved higher response rates [assessed using the American College of Rheumatology (ACR) composite score] and accumulated more mean productivity days after 6 months than placebo recipients.▴ However, the response rates and accumulated productivity days of patients receiving subcutaneous anakinra 30 or 75 mg/day for 6 months were similar to those of placebo.▴ With respect to the total Genant radiographic scores, the same study showed that all anakinra treatment regimens slowed disease progression after 6 months to a greater extent than placebo.▴ In double-blind, randomised trials in patients with rheumatoid arthritis, combined treatment with anakinra and methotrexate was associated with higher ACR 20, 50 and 70 response rates than with methotrexate alone.▴ Anakinra, used alone or in combination with methotrexate, was generally well tolerated, with the most frequent adverse event being a mild injection-site reaction of transient duration. Infections requiring antibacterial therapy or hospitalisation occurred more commonly in anakinra recipients than in placebo recipients, but were a rare cause for discontinuation of anakinra therapy (≈1%) in clinical trials.Table.Features and properties of anakinra (recombinant human interleukin-1 receptor antagonist, rhIL-1ra)Figure. Anakinra

ISSN:1173-8804    

出版商:ADIS    

年代:2002

数据来源: ADIS

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:

BioMarin Pharmaceutical is developing laronidase, recombinant α-L-iduronidase enzyme replacement therapy for the treatment of mucopolysaccharidosis I (MPS-I) [the most severe form of this is called Hurler syndrome].1The company has received US and European orphan drug designation for the enzyme and has fast-track review status with the FDA.In 1998, BioMarin Pharmaceutical and Genzyme General formed a joint venture for development and marketing of laronidase. A Phase I trial in 10 patients with a range of disease severity of MPS-I required for US and European filing was completed at the Harbor-UCLA Medical Center in California. This open label trial involved weekly infusions with laronidase. The two-year follow-up data revealed sustained and, in certain parameters, improved clinical results recorded at the end of 1 year of therapy. BioMarin and Genzyme General have completed a pivotal, Phase III trial in the centres in the USA, Canada and Europe, including patients with Hurler-Scheie and Scheie syndromes. In a multicentre, double-blind, placebo-controlled study, all 45 patients with MPS-I have received at least their initial weekly infusion of laronidase. Patients are being evaluated over a 6-month period.BioMarin Pharmaceutical and Genzyme General have filed on 15 April 2002 the first portion of a ‘rolling’ BLA with the US FDA for use of laronidase in the treatment of MPS-I. The companies are planning to complete the BLA filing in Q3 2002. The application will include 6-month data from the ongoing open-label Phase III extension study and also the 6-month data from the placebo-controlled part of the Phase III study. In the open-label extension study, patients from both the treatment and placebo arms of the Phase III trial received weekly infusions of laronidase for at least 6 months. The response from the US FDA is anticipated during the H1 of 2003.Both companies plan to initiate two new clinical trials in patients with MPS-I. One study will enrol patients with MPS-I under 5 years old. Another study will investigate laronidase in patients with advanced clinical symptoms of MPS-I. Additionally, patients from the ongoing Phase III study will continue to receive treatment with laronidase.On 1 March 2002, BioMarin and Genzyme filed a marketing approval application with European regulatory authorities for AldurazymeŒ for the treatment of MPS-I.Mucopolysaccharidosis I is a rare autosomal recessive lysosomal storage disorder caused by α-L-iduronidase deficiency. Its manifestations in children can include growth and developmental delay, enlargement of spleen and liver, skeletal deformity, cardiac and pulmonary impairment, vision or hearing loss and mental dysfunction. At present, bone marrow transplantation is the only available treatment.

ISSN:1173-8804    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

LeuTech®is a sterile, lyophilised kit-packaged diagnostic system containing murine anti-CD15 IgM monoclonal antibody proprietary radiolabelled with technetium 99m (99mTc) for infection imaging.1After intravenous injection of LeuTech®, diagnostic imaging can be obtained within 1h with conventional planar γ camera techniques. LeuTech®binds to neutrophilsin vivoat the infection site. LeuTech®is a fast (1h to obtain image), convenient (one-step injection), safe, effective (bright, clear images) and cost-effective diagnostic for existing and new nuclear imaging markets including chronic and acute indications such as appendicitis, ischaemic bowel, post-surgical infection and nosocomial infection.Palatin Technologies has successfully completed a Phase III trial with LeuTech®in 203 patients at 10 sites in the USA for the detection of equivocal appendicitis. A BLA with the US FDA for LeuTech®has been filed for the diagnosis of equivocal appendicitis. The US FDA has recommended LeuTech®for approval for the diagnosis of appendicitis in patients with equivocal signs and symptoms. On 28 September 2000 Palatin received a ‘complete review’ letter from the FDA regarding the BLA for LeuTech®. While, there were no further data requested on the safety and clinical efficacy of LeuTech®’, FDA requested some manufacturing, quality control and validation steps and data to be completed prior the approval of LeuTech®. Palatin plans to finalise the amendments to BLA in the H2 of 2002.LeuTech®is also being investigated in Phase II clinical trials for the diagnosis of osteomyelitis in 45 patients at four sites. Positive interim results from a Phase II clinical study conducted in 19 patients with diabetic foot ulcers and suspected osteomyelitis were announced at the Society of Nuclear Medicine Annual Meeting, Toronto, Canada, in June 2001. Imaging with LeuTech®provided a diagnostic image within 1 hour compared with the 24 hours required to obtain an image using standard-of-care diagnostic, Indium oxide-labelled white blood cells. Walter Reed Army Medical Center is evaluating LeuTech®for early detection of inhalation anthrax. LeuTech®is planned to be evaluated for the detection of osteomyelitis secondary to joint replacements (such as hip replacement), postoperative abscesses, ulcerative colitis and other intra-abdominal infections (colitis, spleen or urinary tract).Palatin Technologies has exclusive rights to murine anti-CD15 IgM monoclonal antibody from The Wistar Institute of Biology and Anatomy.LeuTech®has been licensed to Mallinckrodt worldwide, except for Europe. In October 2000, Mallinckrodt was acquired by Tyco International.On 15 May 2002, Palatin Technologies announced that its agreement with Tyco/Healthcare/Mallinckrodt regarding LeuTech®marketing was amended to require Mallinckrodt to pay an additional $3.2 million to cover half of Palatin's expenses for the completion of the FDA's review. The additional funding is conditional upon reaching of certain milestones with Palatin receiving $800 000 within ten days of the signing of the amendment. Under the terms of the original agreement (1999), Palatin received a licensing fee of $500 000 and $13 million for the stock. All expenses prior to FDA approval were equally shared. Palatin will manufacture LeuTech®and will receive a transfer price per unit and also royalties on net sales.

ISSN:1173-8804    

出版商:ADIS    

年代:2002

数据来源: ADIS