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Toll-like receptors (TLR) are critical mediators of the immune system with their activation linked to infection, inflammation and the pathogenesis of immune diseases including autoimmunity and cancer. For this reason, over the last 2 decades, TLR and their associated signalling pathways have been targeted therapeutically to enhance innate and adaptive immunity. Several TLR ligands, both endogenous and synthetic are at various phases of clinical testing, and new ligands are continually emerging. Agonists of TLR7 are known immune response modifiers, simultaneously stimulating several cell types, resulting in immune cell activation and cytokine and chemokine release. The immune stimulating properties of the TLR7 agonist Imiquimod has also been exploited for use in the treatment of malignant superficial tumours of the skin. Here, we investigated a novel TLR7 agonist UC-1V150 and demonstrate it activates both human and mouse myeloid cells in vitro and in vivo, to deliver potent FcγR-mediated engulfment of opsonized target cells.

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The impact of electrode corrosion behaviour, reactor geometry and current density on electrocoagulation efficiency were investigated for the treatment of molasses process wastewater. Two laboratory-scale vertical plate electrocoagulation reactors were used for this investigation: the first being a low aspect ratio bath reactor with a low specific electrode area, while the other was a high aspect ratio column reactor with a high specific electrode area. Anomalous anodic dissolution and cathodic corrosion of the aluminium electrodes both contributed significantly to overall metal consumption. Increasing specific electrode area and aspect ratio each led to improved treatment efficiency, whereas the impact of current density was more complicated involving the combined influences of several competing effects. The space-time yields of coagulant and bubbles (both functions of specific electrode area, current density and current efficiency) were found to influence mixing within the reactor and thus treatment efficiency.

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Using the modified transmembrane migration method to measure sperm motility, it was shown that the surfactant nonoxynol-9 alone, was twice as potent as (+)-propranolol alone as a spermicidal agent. Addition of (+)-propranolol to nonoxynol-9 shifted the dose-response curve to the left of the curves for either component alone, and a surprising synergistic action was evident. These observations may form the basis for the development of a new advantageous topical contraceptive combination product.

PIP: Researchers from the Cambridge Research Institute in England conducted i vitro research on the effects of (+)-propranolol and nonoxynol-9, alone and in combination, on human sperm motility. They used modified transmembrane migration method of Hong et al since it allowed dose- response curves to be done on each semen sample from 7 donors. They also applied the PCONLIN computer program to more detailed data to define the shape of the curve more accurately. Nonoxynol-9 exhibited twice the potency of (+)-propranolol. Their drug concentrations at which 50% maximal inhibition occurred (IC50) were .156 mg mL-1 and .373 mg mL-1 respectively. Moreover, with the addition of 1-2.5 mM (+)- propranolol to nonoxynol-9, the dose-response curve moved to the left of the curves for either (+)-propranolol and nonoxynol-9 alone. Therefore the 2 agents exhibited a synergistic effect. Later they applied data from other experiments to a simple effect model and found a 3-10 fold increase in potency of nonoxynol-9 and 1 mM (+)-propranolol together compared to nonoxynol-9 alone. These results gave further credence to a synergistic action of the 2 drugs. The combination which resulted in the greatest inhibition of sperm motility (99.9%) included 1.6 mM nonoxynol-9 and 2.5 mM (+)-propranolol. Nevertheless they did not see a need to use 1 mM (+)-propranolol because the concentration of nonoxynol-9 causing total inhibition of sperm motility was similar. Therefore effective concentrations of each in a topical contraceptive agent can be .5 mg mL-1 nonoxynol-9 and .3 mg mL-1 (+)-propranolol (about 1 mM). This results in using about 1/10th of the nonoxynol-9 used in current contraceptive formulations which reduces the potential problems of sensitivity.

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Several beta-adrenoceptor blocking agents have been evaluated for spermicidal activity using a transmembrane migration method. The rank order of potency of the active compounds was: penbutolol greater than (+)-propranolol greater than bufuralol greater than (-)-alprenolol greater than oxprenolol greater than metoprolol. Atenolol, pindolol, practolol, tolamolol were without activity. The observed potencies of spermicidal activity are believed to be unrelated to beta-blocking activities, and we have shown that whilst they are not predictable from lipid solubility or nonspecific membrane properties of the compound alone, both these aspects appear to play a role in this pharmacological activity.

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1. The regulation of lung adenylate cyclase was investigated in guinea pigs sensitized with high dose (300-500 micrograms kg-1) ovalbumin to raise IgG(I) and low dose (2.8-4.0 micrograms kg-1) to raise to IgG/IgE (II) antibodies. 2. Basal activity of sensitized II (IgG/IgE antibodies) lung adenylate cyclase was approximately double that of the control values. 3. Guanosine 5'-triphosphate (GTP) was a potent activator of adenylate cyclase from the sensitized II (IgG/IgE) lung membranes. 4. The sensitivity of lung membrane adenylate cyclase to stimulation by beta-adrenoceptor agonists or VIP was reduced whereas no significant difference was observed with histamine or bradykinin on the sensitized II membranes. 5. Possible mechanisms involved in the increase in basal activity and in the decreased sensitivity to beta-adrenoceptor- and VIP-mediated stimulation of adenylate cyclase by ovalbumin sensitization of guinea-pig lung membranes are discussed.

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The transmembrane migration technique, a simple method in-vitro for quantitatively assessing the effects of a drug on human sperm motility, has been evaluated. The original method has been modified to include a preincubation step, and the incubation time has been reduced to 90 min. In semen samples possessing sperm concentrations of less than 75 x 12(6) spermatozoa mL-1 the volume of the lower reservoir has been reduced to 1 mL. This modified method has been used to compare the spermicidal potency of the widely employed non-ionic surfactant nonoxynol-9, with nonoxynol-5 and nonoxynol-15 (containing, respectively, fewer and more ethylene oxide units per molecule). The rank order of spermicidal potency of the compounds evaluated was nonoxynol-9 = nonoxynol-5 greater than nonoxynol-15.

PIP: A modified transmembrane migration method was used to evaluate the spermicidal potency of nonoxynol-9 and to make comparisons with 2 other water-soluble nonoxynols -- nonoxynol-5 and nonoxynol-15. The proportion of sperm which moves across the membrane from the upper to the lower chamber was assessed and expressed as the transmembrane migration ratio (TMR). Semen samples were collected by masturbation after at least 3 days' sexual abstinence, from a pool of 8 healthy volunteers (18-35 years). The characteristics noted of each sample included spermatozoa concentration and sperm motility, the percentage dead sperm being assessed using ethidium bromide, and fluorescence microscopy. The rank order of potency of the nonoxynols examined was nonoxynol-5=nonoxynol 9, which was greater than nonoxynol-15. The varying potency of the nonoxynols with respect to their IC50 values corresponds to the pertinent lipophilic nature of each compound. An observed increase in the IC50 was related to an increase in the side-chain lengths: 5915. This relationship indicates the importance of lipophilicity in the properties of these surfactants to diffuse into the sperm plasma membrane and disturb its conformation and semipermeable nature, preventing the occurrence of both sperm motility and ovum fertilization.

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Bradykinin receptors on normal lung membranes seem to be coupled to adenylate cyclase. Stimulation of the enzyme from sensitized lung membranes by adrenaline and vasoactive intestinal peptide was markedly reduced, whereas the ability of bradykinin and histamine to activate the sensitized adenylate cyclase was unaffected. Additional experiments are necessary in order to delineate the precise molecular events associated with activation of each of the two presently known bradykinin receptor types.

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