Levobetaxolol (Betaxon) and other beta-adrenergic antagonists: preclinical pharmacology, IOP-lowering activity and sites of action in human eyes.

The pharmacological characteristics of levobetaxolol, a single active isomer of betaxolol, were determined and compared with activities of other beta-adrenoceptor antagonists. Levobetaxolol (43-fold beta1-selective) exhibited a higher affinity at cloned human beta1 (Ki = 0.76 nM) than at beta2 (Ki = 32.6 nM) receptors, while dextrobetaxolol was much weaker at both receptors. Levobetaxolol potently antagonized functional activities at cloned human beta1 and beta2 receptors, and also at guinea pig atrial beta1, tracheal beta2 and rat colonic beta3 receptors (IC50s = 33.2 nM, 2970 nM and 709 nM, respectively). Thus, levobetaxolol was 89-times beta1-selective (vs beta2). Levobetaxolol (Ki = 16.4 nM) was more potent than dextrobetaxolol (Ki = 2.97 microM) at inhibiting isoproterenol-induced cAMP production in human non-pigmented ciliary epithelial cells. Levobunolol and (l)-timolol had high affinities at beta1 and beta2 receptors but were considerably less beta1-selective than levobetaxolol. Levo-, dextro- and racemic-betaxolol exhibited little or no affinity, except at sigma sites and Ca2+-channels (IC50s > 1 microM), at 89 other receptor/ligand binding sites. Levobetaxolol exhibited a micromolar affinity for L-type Ca2+-channels. In conscious ocular hypertensive cynomolgus monkeys, levobetaxolol was more potent than dextrobetaxolol, reducing intraocular pressure by 25.9+/-3.2% at a dose of 150 microg/eye (n = 15-30). Quantitative [3H]-levobetaxolol autoradiography revealed high levels of binding to human ciliary processes, iris, choroid/retina, and ciliary muscles. In conclusion, levobetaxolol is a potent, high affinity and beta1-selective IOP-lowering beta-adrenoceptor antagonist.

The effect of immunotherapy on the cutaneous late phase response to antigen.

BACKGROUND: This study used the skin chamber model to evaluate prospectively the effect of immunotherapy (IT) on the cutaneous early and late phase response (LPR) to epicutaneous antigen challenge. METHODS: Nine subjects with allergic rhinitis were studied at three time points: before starting IT, after 3 months of IT, and after 6 months of IT. Skin chamber histamine content was measured hourly for 12 hours, and cell counts performed hourly during hours 6 to 12. An intradermal skin test was placed, and the reaction was measured hourly for 12 hours. Skin biopsy specimens were obtained 8 hours after intradermal placement and evaluated for cellular infiltrate and major basic protein deposition. Serum antigen-specific IgG and IgE levels were measured at each time point to confirm physiologic effect of IT. RESULTS: Six months of IT significantly (p < 0.05) decreased both early and LPR skin test reactivity and skin chamber histamine for hours 1 to 3, 4 to 6, and 9 to 12. Skin chamber LPR cellular influx decreased significantly (p < 0.05) for neutrophils only. Decrease in LPR histamine after 6 months of IT was significantly correlated with both decrease in mononuclear cells (R2 = 0.817, p = 0.002) and decrease in neutrophils (R2 = 0.813, p = 0.009). Also significantly correlated were decrease in LPR skin test reactivity, with percent change in skin chamber mononuclear cells (R2 = 0.800, p = 0.009) and decrease in early skin test reactivity (R2 = 0.675, p = 0.01). Biopsy specimens showed no consistent change in either dermal cellular infiltrate or deposition of major basic protein. CONCLUSION: IT significantly attenuates cutaneous histamine release and skin test reactivity and is accompanied by a decrease in skin chamber LPR neutrophil influx without significantly altering the dermal infiltrate at 8 hours.

Constitutents of Magnolia Grandiflora. III. Toxic principle of the wood.

The alcoholic extract of the wood of Magnolia grandiflora exhibited toxicity to mice when injected by the ip route. The toxic principle was found to be a phenolic quaternary alkaloid and was obtained as a colorless crystalline solid. Analytical and spectral data showed that it was identical with menisperine (also called chakranine and isocorydinium cation) which has not been previously isolated from the genus Magnolia.