摘要:

ObjectiveTo determine abstinence rates and to obtain safety data during the use of integrated therapy with acamprosate and the main established psychotherapeutic intervention programmes in the treatment of alcohol dependence.DesignNon-blind, parallel-group, multicentre, phase IV study.SettingNaturalistic setting reflecting the clinical use of acamprosate in outpatient treatment of alcoholics in Germany.Patients753 patients meeting the DSM-III-R criteria for alcohol dependence. At study entry, patients had to be abstinent for 1 to 4 weeks, and those who relapsed within the first 14 days of treatment were withdrawn from the study.InterventionsAll patients received acamprosate 1332 to 1998 mg/day according to bodyweight and were assigned to one of the following treatment groups: individual psychotherapy, group psychotherapy, behavioural therapy, brief intervention or family therapy. The patients were followed for 24 weeks.Outcome measuresThe principal outcome criterion was the time to the first drink. Secondary outcome measures were cumulative abstinence duration and craving. Adverse events were recorded systematically and classified according to World Health Organization adverse reaction terminology.ResultsThe mean time to first drink was 81.5 days. 236 (33.5%) patients were continuously abstinent during the study. The discontinuation rate in the study was 49%, and the cumulative abstinence duration was 61%. Abstinence and discontinuation rates in this study were similar to those found in placebo-controlled clinical trials. Craving fell to scores of less than 50 on the Lübecker Craving Scale within 2 weeks of treatment initiation. There were no significant differences between the different psychosocial support treatment arms concerning time to first relapse or abstinence rates. Linear regression analysis showed severity of alcohol dependence according to DSM-III-R criteria to be associated with treatment outcome (p = 0.003). The most common adverse clinical events during the first 2 weeks of treatment were diarrhoea (69 patients), pruritus (37 patients), headache (28 patients) and fatigue (16 patients). Acamprosate was discontinued in nine patients (1%) because of severe adverse events; only two cases were clearly linked to treatment (diarrhoea and dermatitis). One death occurred during the study (status asthmaticus).ConclusionsAbstinence rates with integrated acamprosate and psychosocial support in a naturalistic setting are similar whatever the psychosocial support used, and similar to those seen in placebo-controlled clinical trials of acamprosate. The safety profile of acamprosate was good.

ISSN:1174-5886    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

Acamprosate [calcium acetylhomotaurinate] is a GABAminergic compound that was originated by Meram for the treatment of alcohol dependence. Merck KGaA has licensed the compound. It has been launched in 25 countries. In most European countries it is marketed as Campral®, for instance, Spain. In Spain it is also marketed as Zulex®. In France it is marketed as Aotal®by Merck Lipha (Merck KGaA). It is licensed to Almirall-Prodesfarma in Spain and is marketed as Zulex®. Phase III trials involving 600 patients are underway in the USA. Forest Laboratories have entered into a distribution, marketing, trademark licence and supply agreement with Merck Lipha for rights to acamprosate in the US. Merck Lipha expects to submit an NDA in the US in late 2001/early 2002 for the use of acamprosate in the treatment of alcohol dependence. Acamprosate should be used as part of an organised alcohol withdrawal programme in patients who are motivated to give up alcohol and who have agreed to undergo detoxification. Acamprosate does not appear to have addictive potential itself.[1] It significantly increases the probability of maintained abstinence and does not change ethanol toxicity.[2]Figure. Acamprosate

ISSN:1174-5886    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

Merz + Co's neramexane [MRZ 2/579], an amino-alkyl-cyclohexane, is a noncompetitive NMDA receptor antagonist. It is currently in phase II clinical development in Germany, and may be developed for alcohol-dependence, chronic pain and neuroprotection. In July 2001, it was announced that Forest Laboratories has entered into a license agreement with Merz + Co for the development and marketing of neramexane in the USA.Figure. Neramexane

ISSN:1174-5886    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

Biogen has developed a LFA-3/IgG fusion protein,alefacept [BG 9273, LFA 3, LFA 3/CD2, human LFA-3/IgG fusion protein, LFA 3 TIP, AmeviveTM], that is a fusion protein consisting of the first LFA-3 extracellular domain fused to the hinge CH2 and CH3 regions of human IgG1 which is targeted to the CD2 molecule. It has immunomodulatory properties because it recognises the CD2 ligand on the surface of T lymphocytes, thus interfering with the costimulatory role of CD2 in T cell activation. It also appears to block cell adhesion to blood vessel walls and the migration of immune cells into tissue.Psoriasis:Biogen has completed phase III trials of intravenous and intramuscular alefacept as a treatment for patients with chronic plaque psoriasis in the US and Europe. The company submitted simultaneous regulatory filings to the FDA and EMEA in August 2001. Biogen filed a Common Technical Document in Europe and the US under new guidelines implemented in July 2001 at the International Conference on Harmonisation (ICH). In October 2001, Biogen anounced that the FDA and EMEA had both completed initial reviews and had accepted the regulatory filing for full review.Other indications:alefacept was in phase I trials for the treatment ofautoimmune disorders, inflammatory diseases and tissue transplant disorders. Biogen has selected rheumatoid arthritis and scleroderma from this set of indications for further development of alefacept. The drug is currently in phase II clinical trials in rheumatoid arthritis. Biogen stated in June 2001 that a pilot study of Amevive®has been initiated in scleroderma.

ISSN:1174-5886    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

Aripiprazole [OPC 14597, Abilitat®] is a quinolinone derivative under development as a potential antipsychotic agent. In November 2001, Otsuka announced that an NDA has been submitted to the US FDA for aripiprazole. The compound is undergoing phase III clinical testing with Otsuka in Japan and the UK.Figure. Aripiprazole [OPC 14597, Abilitat®]Aripiprazole is thought to act as a presynaptic dopamine D2 autoreceptor agonist and as a postsynaptic dopamine D2 receptor antagonist. The pharmacological profile of aripiprazole suggests that it may be effective against both the positive and negative symptoms of schizophrenia. In September 1999, Otsuka and Bristol-Myers Squibb entered a licensing partnership for aripiprazole. Under the agreement, the companies will jointly market and promote the drug, under Otsuka's trademark, in the US and European Union, and will collaborate on the completion of clinical trials. Bristol-Myers Squibb will have exclusive rights to aripiprazole in all other markets, excluding Japan and certain Asian and Middle Eastern countries. Bristol-Myers Squibb plans to conduct additional trials of new forms of aripiprazole, and in new indications.

ISSN:1174-5886    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

Bevacizumab [rhuMAb-VEGF, anti-VEGF monoclonal antibody, Avastin™] is a humanised endothelial growth factor antagonist. It is undergoing development with Genentech in the USA for the treatment of relapsed metastatic breast cancer, and solid tumours, including advanced lung cancer. The FDA granted fast track status for bevacizumab, for the treatment of metastatic breast cancer, in April 2001.Clinical studies: the antibody is in phase I for diabetic retinopathy. It is thought to cut off the blood supply to tumours and prevent excess blood vessel growth at the retina in diabetic patients.Genentech announced in December 1999 that its phase II clinical trials of bevacizumab in combination with chemotherapy had met their primary objectives in colourectal and non-small cell lung cancer. A phase III trial in metastatic colourectal cancer is underway and compares the combination of bevacizumab + irinotecan + flourouracil/leucovorin with irinotecan + flourouracil/leucovorin and bevacizumab + flourouracil/leucovorin. A phase III trial in metastatic breast cancer is also underway in the US. Genentech is sponsoring the colorectal trial, and is in discussions with the NCI’s cooperative oncology group, ECOG regarding sponsorship for the proposed phase III lung cancer trial. Recruitment into the renal cancer trial was stopped in October 2001 because the NCI’s Data and Safety Monitoring Board determined that the trial had reached its pre-specified efficacy endpoint at the second interim analysis. A phase II/III trial is also underway which will evaluate bevacizumab in combination with carboplatin and paclitaxel, in patients with advanced non-squamous non-small cell lung cancer. is currently underway in the US, as is another phase II trial in patients with renal cancer.

ISSN:1174-5886    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

Atrix Laboratories has developed a topical gel formulation of the antibiotic dapsone, Atrisone™, using the Solvent-Micropartical (SMPTM) delivery technology. It is being developed for the treatment of acne, pruritis associated with burns, and atopic dermatitis.Results from phase I/II trials in patients with moderate to severe acne have been positive, with Atrisone™ reducing inflammatory and non-inflammatory lesions by about one-half over a short time period. A phase III study for this indication was initiated in the US in March 2001 and enrolment was completed in October 2001. Atrix Laboratories is conducting a small proof-of-concept trial of topical dapsone for the treatment of chronic itch (pruritus) associated with healing burn wounds in the USA. Atrix announced in October 2001 that initial results from this study had indicated that the product had significant efficacy. Atrix Laboratories submitted an IND application to the FDA seeking permission to conduct clinical trials in patients with atopic dermatitis in May 2001.An oral formulation of dapsone is already marketed for the treatment of leprosy and dermatitis herpetiformis.Atrix Laboratories licensed exclusive North American marketing and distribution rights for topical dapsone to Fujisawa in October 2001. Under this agreement, Fujisawa will pay up to $US25 million in licensing fees, milestone payments and funding for research and development. Atrix will be responsible for manufacturing of Atrisone™ on behalf of Fujisawa, which will also have rights to develop the product for additional indications.The Solvent-Microparticle (SMPTM) delivery system is a means of delivering water-insoluble drugs to the skin. It is a 2 stage system which combines dissolved drug with a microparticle suspension of the drug in a single formulation. The dissolved drug permeates into the epidermal layer of the skin, and the microparticle drug is maintained at a high level above the outermost layer of the skin for later delivery.

ISSN:1174-5886    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

Daptomycin [LY 146032, Cidecin™, Dapcin®] is an acidic lipopeptide injectable antibacterial derived from Streptomyces roseospors. It has excellentin vitroactivity against Gram-positive bacteria, including methicillin-resistantStaphylococcus aureus(MRSA),Enterococcus faecalisand vancomycin intermediately susceptibleStaphylococcus aureus(VISA). The compound acts on the cytoplasmic membrane of bacteria by collapsing the membrane potential and interfering with cell wall peptidoglycan biosynthesis. The US FDA has given daptomycin fast-track status. Cubist has filed a Clinical Trial Exemption for daptomycin in the UK.Figure. Daptomycin [LY 146032, Cidecin., Dapcin®]Daptomycin for injection:Cubist Pharmaceuticals acquired exclusive worldwide rights from Eli Lilly to develop, manufacture and market daptomycin to treat infectious diseases. In January 2001, Cubist Pharmaceuticals and Gilead Sciences announced the signing of a licensing agreement for the exclusive rights to commercialise IV and oral daptomycin in 16 European countries. Gilead has agreed to pay Cubist an up-front fee of $US13 million and Cubist is entitled to receive additional cash payments of up to $US31 million upon achievement of certain clinical and regulatory milestones. In April 2001 Cubist Pharmaceuticals announced the achievement of the first milestone in its collaboration with Gilead Sciences. Gilead has agreed to pay Cubist $US1.25 million for meeting the primary endpoint of Cubist's phase III trial examining the safety and efficacy of Daptomycin in the treatment of complicated skin and soft tissue infection caused by Gram-positive bacteria. Gilead will also pay Cubist a fixed royalty on net sales. Cubist will continue to be responsible for worldwide clinical development of CidecinTM, while Gilead will be responsible for any regulatory filings in the covered territories.Cubist Pharmaceuticals is investigating the efficacy of daptomycin in phase III clinical trials in the European Union, Israel, South Africa, Australia and the US for the treatment of complicated skin and soft-tissue infections [Evaluation of Daptomycin in Gram-positive entities (EDGESST)]. The company has completed its first pivotal phase III trial (study 9901), in which the primary endpoint was achieved. Daptomycin is being compared to vancomycin, oxacillin or nafcillin and will be required to show equivalence to the comparator agents. Cubist announced in October 2001 that a second pivotal phase III US trial (study 9801) had been completed. This study achieved its primary endpoint of demonstrating equivalence to comparator antibiotics. Achievement of this endpoint resulted in a $US1.25 million milestone payment from Gilead. Regulatory filings are planned for mid-2002.An open-label phase II trial using Daptomycin for the treatment of bacteraemia has been completed, and future trials are planned in the treatment of endocarditis and certain resistant infections, including vancomycin-resistant enterococcal infections.Cubist initiated global phase III clinical trials for community-acquired pneumonia (EDGECAP) in the fourth quarter of 2000. Enrolment in the first study (CAP1) was completed in September 2001. The study enrolled 729 patients, mainly in the northern hemisphere. Completion of enrolment resulted in a $US3.0 million milestone payment to Cubist from Gilead Sciences. A second study (CAP2) is also being conducted, predominantly in the southern hemisphere, and uses the same protocol as CAP1. Cubist expects to seek approval for daptomycin in the treatment of community-acquired pneumonia in mid-2002.Cubist also initiated global phase III clinical trials for complicated urinary tract infection (EDGEUTI) in the fourth quarter of 2000. Enrolment in a phase II/III feasibility study of daptomycin in the treatment of complicated urinary tract infections caused by Gram-positive pathogens has been completed. The outcome of this study will determine whether Cubist will pursue complicated urinary tract infections as a follow-on indication, should daptomycin receive initial marketing approval.Oral daptomycin:Cubist Pharmaceuticals has entered into a research and development collaboration with Emisphere Technologies to utilise Emisphere's oral drug delivery technology for Cubist's daptomycin and other lipopeptides. Under the terms of agreement, Emisphere could receive fees, research funding and milestone payments totalling $US30 million, should a product be successfully commercialised. Emisphere would also receive a royalty on sales of any product resulting from the collaboration, while Cubist would be responsible for drug development and would receive exclusive worldwide commercialisation rights to any oral products. If successfully developed, oral daptomycin would enable Cubist to compete in the market for step-down therapy from IV to oral, should the IV formulation also receive FDA approval. The ability to treat infected patients with daptomycin on an outpatient basis, could be an important contributor to a reduction in healthcare costs. Preclinical testing of oral daptomycin is ongoing. If development continues with positive results, an IND to begin human clinical trials will be filed in the first half of 2002.

ISSN:1174-5886    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

Genentech (a subsidiary of Roche) and XOMA are collaborating in the development of efalizumab [HU 1124], a humanised anti-CD11a monoclonal antibody that prevents T cell activation. Following promising results in earlier clinical trials, two phase III clinical trials in patients with moderate-to-severe psoriasis are underway at about 80 sites in the US and Canada. Enrolment in these trials (ACD2058g and ACD2059g) has been completed, with more than 1000 patients being evaluated.Genentech and Xoma originally intended to apply for FDA approval toward the end of 2001, or in the first quarter of 2002. However, in October 2001, the companies announced that the filing would be delayed until mid-2002 as an initial pharmacokinetic study was being conducted. This study is to confirm the equivalence of efalizumab used in clinical trials, and a slightly modified product resulting from large-scale manufacturing processes.Genentech had been paying XOMA to develop its drug through to phase II clinical trials. An agreement was subsequently reached between the two companies to continue their collaboration for the remaining clinical development and regulatory filings for efalizumab in plaque psoriasis. XOMA will share development costs, as well as future US profits, with Genentech on a 25%/75% basis. XOMA will receive a royalty on sales inside the US while Genentech will fund XOMA’s share of development costs. Based on encouraging results in psoriasis patients, Xoma and Genentech are considering expanding the development of efalizumab to include additional autoimmune indications.XOMA and Genentech have decided to expand the efalizumab product development programme to include organ transplant rejection. The programme is currently focusing on kidney transplant recipients, and enrolment in a phase I/II trial has been completed. The antibody targets the CD11a receptor on the surface of T cells to inhibit rejection without inhibiting the entire immune response.

ISSN:1174-5886    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

G 3139 [GC 3139; Genasense™, BCL2 antisense oligonucleotide, augmerosen] is an antisense oligonucleotide developed by Genta in the USA. It is targeted towards the Bcl-2 protein, which is a potent inhibitor of apoptosis and is overexpressed in many cancers including, follicular lymphomas, breast, colon and prostate cancers, and intermediate/high-grade lymphomas.In August 2000, Genta received Orphan Drug status from the FDA for the use of G 3139 in the treatment of patients with advanced malignant melanoma. G 3139 already has ’fast track’ status with the FDA for this indication in combination with dacarbazine. In September 2001, G 3139 received Orphan Drug status from the FDA for a further three indications: multiple myeloma, acute myelocytic leukaemia, and chronic lymphocytic leukaemia, as well as fast track status for the use of G 3139 in the treatment of multiple myeloma. The company also received approval in Europe for its submitted clinical trial exemption, and the European Medicines Evaluation Agency (EMEA) has accepted Genta's new Orphan Drug Filings. G 3139 now has Orphan Drug status in Europe for the treatment of multiple myeloma and chronic lymphocytic leukaemia.Genta signed a 2-year manufacturing agreement, in December 2000, with Avecia Ltd., to supply it with quantities of G 3139.Clinical studies updateMalignant melanoma:A phase III trial of G 3139 in combination with dacarbazine is underway in patients with malignant melanoma, with the target number for patient enrolment of 270. A phase I/IIa trial of G 3139 and dacarbazine in the treatment of advanced malignant melanoma expressing Bcl-2 is nearing completion at the University of Vienna, Austria.Leukaemia:Genta is planning to pursue additional studies with G 3139 in other indications including chronic lymphocytic leukaemia, acute myelocytic leukaemia. Two trials were initiated in January 2001 in chronic lymphocytic leukaemia (as monotherapy) and acute myeloid leukaemia (in combination with gemtuzumab ozogamicin) at the MD Anderson Cancer Center in the US. Both trials involve patients who have relapsed from front-line therapy. Preclinical studies of G 3139 + gemtuzumab ozogamicin have confirmed the rationale behind this combination therapy. The addition of G 3139 to gemtuzumab ozogamicin greatly increases the number of leukaemia cells undergoing apoptosis compared with gemtuzumab ozogamicin alone. A phase III trial of G 3139vsstandard second-line chemotherapy with fludarabine and cyclophosphamide was initiated in February 2001 in 200 patients with chronic lymphocytic leukaemia. The study will be conducted at 60 centres in the US, Canada and Europe. A phase I study is underway in the US in patients with acute leukaemia who have relapsed or were refractory to standard chemotherapy. The study is being conducted under a NCI Cooperative Research and Development Agreement (CRADA) at Ohio State University. In this study, G 3139 is being used in combination with fludarabine and cytarabine.Multiple myeloma:Genta is conducting a phase III pivotal trial of G 3139 in combination with dexamethasone in the US.Non-Hodgkin's lymphoma:A phase I/II clinical trial (n = 20) has been completed at the Royal Marsden Hospital, London in collaboration with the Institute of Cancer Research, United Kingdom, for the treatment of non-Hodgkin's lymphoma. Genta has initiated a phase II study of the safety and efficacy of G 3139 in combination with conventional chemotherapy drugs at the aforementioned locations in the UK. This trial will enrol patients with non-Hodgkin's lymphoma that were resistant to a standard chemotherapy programme. A phase I/IIa study of G 3139 (administered in combination with cyclophosphamide) in patients with relapsed follicular non-Hodgkin's lymphoma began in 1999.Prostate cancer:Two phase I/IIa clinical trials of G 3139, at Memorial Sloan-Kettering Cancer Center and Sidney Kimmel Cancer Center, USA, are underway for the treatment of prostate cancer. Genta announced the initiation of two additional prostate cancer trials in the US in July 2000. The trials are to be conducted at the Institute for Drug Development, Cancer Therapy Research Center in San Antonio, Texas, and the Memorial Sloan-Kettering Cancer Center in New York. Both will evaluate the use of G 3139 in combination with docetaxel in men with advanced prostate cancer. Two phase I/IIa trials are also in progress at the BC Cancer Agency Vancouver Cancer Centre in Canada, for hormone-resistant metastatic prostate cancer (in combination with mitoxantrone) and relapsed follicular non-Hodgkin's lymphoma (in combination with cyclophosphamide).Other cancers:A phase I/II trial of G 3139, in combination with docetaxel, has been initiated at the Lombardi Cancer Center, Georgetown University Medical Center, Washington DC, USA, for the treatment of breast cancer. A phase I/II study of G 3139 in combination with paclitaxel is also underway at the University of Chicago Medical Center and Ohio State University Hospital, USA, in patients with small cell lung cancer. Genta and the NCI have signed a letter of intent to enter into a Cooperative Research and Development Agreement (CRADA) for the development of G 3139 in cancer. The collaboration will investigate the use of G 3139 in the treatment of colorectal and small cell lung cancers and relapsed or resistant leukaemia. In December 1999, Genta announced that the NCI had begun a phase I/II study of G 3139 in combination with irinotecan in patients with relapsed colorectal cancer. In October 2001, Genta announced that a preclinical trial conducted at the University of Vienna showed enhanced activity of cisplatin, in mice implanted with human stomach cancer, when it was used in combination withG 3139. A 50% increase in survival, and 70% larger antitumour effect was observed in the mice treated with cisplatin in combination with G 3139, compared to those treated with cisplatin only.A patent has been issued providing protection for the composition of G 3139 and its analogues.

ISSN:1174-5886    

出版商:ADIS    

年代:2002

数据来源: ADIS