摘要:

The incidence of cytomegalovirus (CMV) retinitis appears to be declining with improved treatment protocols for HIV and prophylaxis protocols for other high risk patients. Despite this, CMV retinitis remains a major cause of visual loss in patients who are severely immunocompromised. Treatment options are evolving in the light of viral resistance, new methods of drug delivery, new drugs, and the increased potential for improvement of immune function that modern antiretroviral therapy provides. In this article, we review the changing options available for the management of CMV retinitis and discuss possible therapeutic agents for the future.

ISSN:1174-5886    

出版商:ADIS    

年代:1999

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 InsightTM, a proprietary product of Adis International. As the emphasis ofDrugs in R&Dis on the clinical potential of new drugs, selection of agents for full profile is based on the extensiveness of available data. Information on all drugs in clinical development, as identified fromR&DInsightTM, is included in the summary table. Information and/or profiles of agents in preclinical development may be included as appropriate.

ISSN:1174-5886    

出版商:ADIS    

年代:1999

数据来源: ADIS

摘要:

&NA;Adefovir dipivoxil (GS 840, bis-POM PMEA, Piv2PMEA) is an ester prodrug of the nucleoside reverse transcriptase inhibitor adefovir, the prototype compound of the acyclic nucleosides phosphonates (ANP) class. Unlike other ANP analogues, unmodified adefovir displays poor oral bioavailability whereas adefovir dipivoxil is rapidly and completely converted to adefovir after oral administration.Adefovir has demonstrated antiviral activity not only against HIV, but also against other viruses frequently observed in HIV-infected individuals, such as cytomegalovirus and hepatitis B virus. It has the convenience of oral, once daily administration, and available clinical data suggest high-level drug resistancemay not be a factor limiting long term use. The most prominent adverse event of adefovir dipivoxil is nephrotoxicity. However, in on-going clinical trials, the frequency and severity of renal abnormalities was reduced at a daily dose of 60mg.

ISSN:1174-5886    

出版商:ADIS    

年代:1999

数据来源: ADIS

摘要:

&NA;Benzimidavir (BW 1263W94, 1263W94, GW 1263) is a novel, orally bioavailable benzimidazole compound selected for development by Glaxo Wellcome for the treatment of cytomegalovirus (CMV) infection. Glaxo Wellcome investigated benzimidavir in the early stages of development in collaboration with the University of Michigan (Department of Medicinal Chemistry). Phase I/II clinical studies are underway in the EU and the US.Although its mechanism of action is not fully understood, benzimidavir appears to interfere with CMV DNAsynthesis by blocking a virus-specific process that is a novel antiviral target.This possibly novel mechanism of action against CMV indicates that benzimidavir may be active against strains resistant to current therapies. Studies in volunteers have indicated good oral bioavailability and acceptable tolerance and it appears not to interfere with anti-HIV activity of antiretroviral drugs. Clinical trials will assess further the efficacy of benzimidavir for treatment of CMV infections.

ISSN:1174-5886    

出版商:ADIS    

年代:1999

数据来源: ADIS

摘要:

Although they are highly immunogenic, live attenuated cytomegalovirus (CMV) vaccines have the potential for latency, reactivation and oncogenicity. The feasibility of an inert subunit vaccine which mimics the immunogenic capacity of the live whole vaccine is therefore being investigated. The most promising vaccine candidates appear to be based on CMV glycoprotein B (gpB).Chiron Vaccines is developing a recombinant gpB subunit vaccine formulated in either alum or MF59, although MF59 appears to be the most effective adjuvant. US phase II trials of the vaccine have been completed and phase III trials are planned.Chiron had signed an agreement in principle with Univax Biologics covering the development of immunotherapeutics based on Chiron's vaccines. The first programme was to involve CMV immune globulin prepared from individuals immunised with the recombinant gpB/MF59 vaccine. Univax had intended to commence phase I/II trials with this product. However, Univax subsequently merged with Nabi and it is unclear if this agreement still exists.

ISSN:1174-5886    

出版商:ADIS    

年代:1999

数据来源: ADIS

摘要:

Live attenuated cytomegalovirus (CMV) vaccines appear to be highly immunogenic with low reactogenicity in healthy seronegative volunteers. However, the potential for latency, reactivation and oncogenicity remains a concern with these live vaccines.The live attenuated Towne strain CMV vaccine was first developed in the late 1970s and is now being tested in phase II clinical trials by Pasteur Mérieux Connaught in the US. The vaccine has been shown to reduce the severity of CMV disease in renal transplant recipients, but it had no effect on the incidence of CMV infection in seronegative mothers.Pasteur Mérieux Connaught and Virogenetics are investigating a combined vaccination strategy consisting of priming with a canarypox virus expressing CMV glycoprotein B (gpB) followed by vaccination with Towne strain CMV. This strategy elicited protective humoral immune responses in a clinical study.

ISSN:1174-5886    

出版商:ADIS    

年代:1999

数据来源: ADIS

摘要:

GEM 132 (Gene Expression Modulator 132) is a genetic antisense compound developed by Hybridon for the treatment of human cytomegalovirus (CMV) infection and CMV retinitis. The compound is comprised of the DNA sequence complementary to that of the intron-exon boundary between 2 genes required for CMV replication (UL-36 and UL-37), and is chemically modified for increased metabolic stability and greater binding affinity for its target.Hybridon is developing 2 formulations of GEM 132; an IV injection for the treatment of systemic CMV infection and an intravitreal injection for the treatment of CMV retinitis. In Europe and the US, GEM 132 is undergoing phase I/II clinical trials for the treatment of CMV retinitis in AIDS patients and phase II trials for the treatment of systemic CMV infection. European clinical trials are being conducted in Paris for both indications. Hybridon's strategic plans are to develop GEM 132 concurrently in 2 continents to take advantage of data sets interchange and comparison.Based on preclinical studies, this advanced chemistry antisense compound may demonstrate improved potency and less toxicity in the clinical setting compared with available therapies for CMVinfections. Results from ongoing clinical trials will determine the therapeutic efficacy of this compound in relation to other antisense molecules under development.

ISSN:1174-5886    

出版商:ADIS    

年代:1999

数据来源: ADIS

摘要:

Sevirumab (Protovir®, MSL 109, EV2 7, SDZ MSL 109) is a human anticytomegalovirus (CMV) monoclonal antibody directed to a conformational epitope of the envelope glycoprotein H (gpH). In 1993, Novartis who originally developed sevirumab, licensed North American and Asian rights to Protein Design Laboratories. Novartis and Protein Design Laboratories share certain copromotion and co-marketing rights in these countries. The compound was exclusively licensed to Corange (Boehringer Mannheim) for Europe and the rest of the world; however, rights have now returned to Protein Design Labs.Phase II trials for CMV retinitis have been completed in Switzerland and the US. A further phase II study, sponsored by the National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group (ACTG), has been halted as the use of higher doses of sevirumab were indicated. The study,which was evaluating sevirumab as an adjunctive treatment to ganciclovir or foscarnet in AIDS patients with newly diagnosed CMV retinitis, had enrolled approximately half of the anticipated 167 patients. The ACTG had reportedly recommended the trial continue, but with higher doses of sevirumab than the 15 and 60mg doses originally used. A phase II/III study being conducted by the Studies of the Ocular Complications of AIDS (SOCA), a study group affiliated to the National Eye Institute in the US, was also halted because of lack of efficacy. The sevirumab dose used in that study was 60mg. A previous study demonstrated a delay in disease progression of 60 to 100 days.Aphase II/III trial is being conducted to investigate the effect of sevirumab in the prevention of CMV infection in patients undergoing bone marrow transplantation.Results from phase II trials show sevirumab to have potential in the treatment of CMV disease in combination with foscarnet or ganciclovir. Compared with foscarnet and ganciclovir, sevirumab appears to have a wider margin of safety and is well tolerated with no anti-monoclonal antibody immune responses.

ISSN:1174-5886    

出版商:ADIS    

年代:1999

数据来源: ADIS

摘要:

&NA;Valganciclovir (RS 79070, Cymeval) is an oral prodrug of ganciclovir under investigation in phase III clinical trials with F. Hoffmann-La Roche for the treatment of cytomegalovirus (CMV) retinitis in HIV-infected patients. Valganciclovir can be absorbed orally and is then metabolised to ganciclovir. It has the potential to replace ocular implants or intravenous treatments for CMV retinitis with a once daily oral treatment (or twice per day for the first 3 weeks in the induction phase). Comparative studies between valganciclovir and the intravenous formulation of ganciclovir (Cytovene®) are also underway as induction therapy for the treatment of CMV retinitis in patients with AIDS.

ISSN:1174-5886    

出版商:ADIS    

年代:1999

数据来源: ADIS

摘要:

Fusion of HIV with its host cell requires the interaction of the viral envelope glycoprotein 120 (gp120) with the chemokine receptor CXCR4 [T cell-tropic (T-tropic) or X4 HIV strains] or CCR5 [macrophage-tropic (M-tropic) or R5 HIV strains] followed by a ‘spring-loaded’ action of the glycoprotein 41 (gp41) that ensures fusion of the viral and cellular lipid membranes and permits the viral nucleocapsid to enter the cell. The overall fusion process can be blocked by a number of compounds. These include siamycin analogues, SPC 3 (a synthetic peptide derived from the V3 domain of gp120), pentafuside (T 20, DP 178) [a synthetic peptide corresponding to amino acid residues 127 to 162 of gp41], the betulinic acid derivative RPR 103611, TAK 779 (a low molecular weight nonpeptide CCR5 antagonist) and a number of compounds (T 22, T 134, ALX40-4C, CGP64222 and AMD3100) that are targeted at the CXCR4receptor. In particular, the bicyclam AMD 3100 has proved highly potent and selective as a CXCR4 antagonist that blocks the infectivity of X4 HIV strains in the nanomolar concentration range. The proof-of-concept that fusion inhibitors should be able to suppress viral replicationin vivohas been demonstrated with pentafuside. Pentafuside and AMD 3100 have now proceeded to phase II clinical trials.

ISSN:1174-5886    

出版商:ADIS    

年代:1999

数据来源: ADIS