Intravenous delivery of adenovirus vectors requires that the virus is not inactivated in the bloodstream. Serum neutralizing activity is well documented, but we show here that type 5 adenovirus also interacts with human blood cells. Over 90% of a typical virus dose binds to human (but not murine) erythrocytes ex vivo, and samples from a patient administered adenovirus in a clinical trial showed that over 98% of viral DNA in the blood was cell associated. In contrast, nearly all viral genomes in the murine bloodstream are free in the plasma. Adenovirus bound to human blood cells fails to infect A549 lung carcinoma cells, although dilution to below 1.7 x 10(7) blood cells/ml relieves this inhibition. Addition of blood cells can prevent infection by adenovirus that has been prebound to A549 cells. Adenovirus also associates with human neutrophils and monocytes ex vivo, particularly in the presence of autologous plasma, giving dose-dependent transgene expression in CD14-positive monocytes. Finally, although plasma with a high neutralizing titer (defined on A549 cells) inhibits monocyte infection, weakly neutralizing plasma can actually enhance monocyte transduction. This may increase antigen presentation following intravenous injection, while blood cell binding may both decrease access of the virus to extravascular targets and inhibit infection of cells to which the virus does gain access.
Stable transfection of the human neuroblastoma cell line SH‐SY5Y with the human 5‐hydroxytryptamine2A (5‐HT2A) or 5‐HT2C receptor cDNA produced cell lines demonstrating ligand affinities that correlated closely with those for the corresponding endogenous receptors in human frontal cortex and choroid plexus, respectively. Stimulation of the recombinant receptors by 5‐HT induced phosphoinositide hydrolysis with higher potency but lower efficacy at the 5‐HT2C receptor (pEC50 = 7.80 ± 0.06) compared with the 5‐HT2A receptor (pEC50 = 7.30 ± 0.08). Activation of the 5‐HT2A receptor caused a transient fourfold increase in intracellular Ca2+ concentration. Whole‐cell recordings of cells clamped at −50 mV demonstrated a small inward current (2 pA) in response to 10 µM 5‐HT for both receptors. There were no differences in potency or efficacy of phosphoinositide hydrolysis among four hallucinogenic [d‐lysergic acid diethylamide (LSD), 1‐(4‐iodo‐2,5‐dimethoxyphenyl)‐2‐aminopropane (DOI), 5‐methoxy‐N,N‐dimethyltryptamine, and mescaline] and three nonhallucinogenic drugs (m‐chlorophenylpiperazine, quipazine, and ergotamine). Comparison of equipotent doses producing 20% of the maximal response induced by 5‐HT revealed selective activation of the 5‐HT2A receptor by LSD and to a lesser degree by DOI, mescaline, and ergotamine. Quipazine and 5‐methoxy‐N,N‐dimethyltryptamine were relatively nonselective, whereas m‐chlorophenylpiperazine selectively activated the 5‐HT2C receptor. It is unlikely therefore that hallucinosis is mediated primarily by activity at the 5‐HT2C receptor, whereas activity at the 5‐HT2A receptor may represent an important but not unique mechanism associated with hallucinogenic drug action.
A double-blind, placebo controlled clinical trial was conducted to assess the clinical and physiological effects of 'epostane', a progesterone synthesis inhibitor, in mid-trimester prostaglandin termination of pregnancy. Mean peripheral progesterone levels had fallen by 74% after 72 h in the patients treated wtih epostane. The mean induction-abortion interval in the treatment group was 490 (SD 271) min, comparcd with 1432 (SD 640) min in the control group. Intrauterine pressure recording demonstrated increased sensitivity to prostaglandin E2 after epostane treatment but no change in oxytocin sensitivity. The clinical implications of facilitated induction of abortion are discussed.
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