Biomedical subjects

Michael J Reiter

Publications and source records attributed to Michael J Reiter.

4 recordsLinked to original sources

PubMed2005

Synthesis and structure-activity-relationships of 1H-imidazo[4,5-c]quinolines that induce interferon production.

1H-Imidazo-[4,5-c]quinolines were prepared while investigating novel nucleoside analogues as potential antiviral agents. While these compounds showed no direct antiviral activity when tested in a number of cell culture systems, some demonstrated potent inhibition of virus lesion development in an intravaginal guinea pig herpes simplex virus-2 assay. We have determined that the in vivo antiviral activity can be attributed to the ability of these molecules to induce the production of cytokines, especially interferon (IFN), in this model. Subsequently, we found that the compounds also induce in vitro production of IFN in human peripheral blood mononuclear cells (hPBMCs). The in vitro results reported herein and the in vivo results reported previously led to the discovery of imiquimod, 26, which was developed as a topical agent and has been approved for the treatment of genital warts, actinic keratosis, and superficial basal cell carcinoma.

Aminoquinolines↗

PubMed2003

The immune response modifier and Toll-like receptor 7 agonist S-27609 selectively induces IL-12 and TNF-alpha production in CD11c+CD11b+CD8- dendritic cells.

IL-12 and TNF-alpha production by dendritic cells (DCs) is a critical step in the initiation of local inflammation and adaptive immune responses. We show in this study that a small molecule immune response modifier that is a Toll-like receptor 7 (TLR7) agonist induces IL-12 and TNF-alpha production from murine CD11c(+)CD11b(+)CD8(-) DCs, a subset not previously known for this activity. Stimulation of these DCs through TLR7 in vivo induces significant cytokine production even 12 h after initial stimulation, as well as migration of the DC into T cell zones of the lymphoid tissue. In contrast, stimulation through TLR4 and TLR9 induced IL-12 production predominantly from CD8(+) DCs, consistent with previously published data. All TLR stimuli induced the increase in surface expression of the activation markers B7-1, B7-2, and class II in both CD8(+) and CD8(-) DCs, demonstrating that CD8(+) DCs do respond to TLR7-mediated stimuli. To date this is the only known stimuli to induce preferential cytokine production from CD8(-) DCs. Given the efficacy of TLR7 agonists as antiviral agents, the data collectively indicate that stimulation of CD8(-) DCs through TLR7 most likely plays a role in the generation of antiviral immune responses.

Aminoquinolines↗

PubMed2002

Beta-adrenergic blocking drugs as antifibrillatory agents.

Beta-Adrenergic blockade is associated with a significant reduction in mortality in most patients with structural heart disease. Clinical trial data involving patients after myocardial infarction or with congestive heart failure demonstrate that a reduction in sudden death accounts for much of the observed mortality reduction. Beta-adrenergic blockade inhibits the proarrhythmic effects of both neural and humoral sympathetic stimulation and inhibits the vagal withdrawal that accompanies ischemia. Although it does not have a dramatic effect on spontaneous ectopy or inducible monomorphic ventricular tachycardia, experimental and clinical data suggest that it inhibits the development of ventricular fibrillation by several mechanisms.

Adrenergic beta-Antagonists↗

PubMedDate not supplied

Cardiovascular drug class specificity: beta-blockers.

Beta-adrenergic blockers are one of the most frequently prescribed cardiovascular drugs. Numerous beta-blockers are available for clinical use. Although these agents differ substantially, it is not clear whether (and which) differences are clinically relevant. Most of the important differences among agents reflect the relative specificity for beta1-, beta2-, and alpha-adrenergic receptors. Selection of a particular agent and target dose is probably best guided by available trial data, even though data are limited. Nonselective agents (with or without alpha-blocking properties) devoid of intrinsic sympathetic activity (ISA) are most appropriate postinfarction. Evidence exists demonstrating a mortality benefit postinfarction for propranolol, timolol, metoprolol, and, in the presence of left ventricular dysfunction, carvedilol. In the setting of heart failure, the selective agents metoprolol and bisoprolol as well as the nonselective agent carvedilol (which possesses alpha-blocking properties) have a demonstrated mortality benefit. Not all tolerated beta-blockers are associated with a survival benefit and it is probably not advisable to extrapolate benefits to all drugs with similar (although probably not identical) properties. Carvedilol may possess advantages over other beta-blockers and a possible survival advantage, suggested by the recent Carvedilol or Metoprolol European Trial (COMET), although these findings are not universally accepted. Ultimately, selection of a specific agent avoids obvious contraindications and uses trial data to guide selection and dose as long as side effects are absent or tolerable.

Adrenergic beta-Antagonists↗