1. 1. HL-60 human leukemia cells are a widely employed model system for the analysis of signal transduction processes mediated via regulatory heterotrimeric guanine nucleotide-binding proteins (G-proteins). HL-60 promyelocytes are pluripotent and can be differentiated into neutrophilic or monocytic cells. 2. 2. HL-60 cells express formyl peptide-, complement C5a-, leukotriene B4 (LTB4)- and platelet-activating factor receptors, receptors for purine and pyrimidine nucleotides, histamine H1- and H2-receptors, β2-adrenoceptors and prostaglandin receptors. 3. 3. The major G-proteins in HL-60 cells are pertussis toxin (PTX)-sensitive Gi-proteins (Gi2 > Gi3). Gs-proteins and G-proteins of the Gq-family (e.g., G16) are expressed, too. 4. 4. G-protein-regulated effector systems in HL-60 cells are adenylyl cyclase and phospholipase C-β2 (PLC-β2) and, possibly, phospholipase D (PLD), nonselective cation (NSC) channels and NADPH oxidase. 5. 5. The expression of signal transduction pathways in HL-60 cells strongly depends on the differentiation state of cells. 6. 6. Formyl peptides, via Gi-proteins, mediate activation of PLC, PLD, NSC channels, NADPH oxidase and azurophilic granule release and are referred to as full secretagogues. In dibutyryl cAMP (Bt2cAMP)-differentiated HL-60 cells, C5a and LTB4 are partial and incomplete secretagogues, respectively. There are substantial differences in the Gi-protein activations induced by formyl peptides, C5a and LTB4. 7. 7. In HL-60 promyelocytes, purine and pyrimidine nucleotides mediate activation of PLC and NSC channels largely via PTX-insensitive G-proteins and induce functional differentiation. In Bt2cAMP-differentiated HL-60 cells, they additionally activate PLD, NADPH oxidase and granule release via PTX-sensitive and -insensitive pathways. ATP and UTP are partial secretagogues. Multiple types of receptors (i.e., P2Y- and P2U-receptors and pyrimidinocyeptors) may mediate the effects of nucleotides in HL-60 cells. 8. 8. Bt2cAMP- and 1α,25-dihydroxycholecalciferol-differentiated HL-60 cells express Hl-receptors coupled to Gi-proteins and PTX-insensitive G-proteins. In the former cells, histamine mediates activation of PLC and NSC channels, and in the latter, activation of NSC channels. Histamine is an incomplete secretagogue in these cells. 9. 9. HL-60 promyelocytes express H2-receptors coupled to adenylyl cyclase, PLC, and NSC channels. There are substantial differences in the agonist/antagonist profiles of H2-receptor-mediated cAMP formation and rises in cytosolic Ca2+ concentration, indicative of the involvement of different H2-receptor subtypes. H2-receptors mediate functional differentiation of HL-60 cells. 10. 10. Certain cationic-amphiphilic histamine receptor ligands (i.e., 2-substituted histamines, lipophilic guanidines, and a histamine trifluoromethyl-toluidide derivative) show stimulatory effects in HL-60 cells that are attributable to receptor-independent activation of Gi-proteins.

G-protein-coupled receptors in HL-60 human leukemia cells.

The sedative and antihistamine effects of diphenhydramine were assessed in relation to plasma concentration after placebo, diphenhydramine 50 mg intravenously, and diphenhydramine 50 mg orally to each of 6 healthy volunteers on three separate occasions. Diphenhydramine plasma elimination t1/2 was 3.0 to 4.3 hr, volume of distribution was 188 to 336 L, and clearance was 637 to 1,014 ml/min. Systemic bioavailability of the oral preparation ranged from 0.26 to 0.60. The sedative effect of intravenous diphenhydramine differed from that of placebo only during the first 3 hr. Antihistamine effect, as measured by reduction of histamine provoked skin wheal diameter, was significantly different from that of placebo for at least 8 hr. There was a positive correlation between plasma diphenhydramine level and sedative and antihistamine effects, but wide variation in the extent and rate of change of these effects were observed between the subject. There appears to be a concentration range of 25 to 50 ng/ml, within which there is significant antihistamine effect without significant sedation.

Correlation between Plasma Diphenhydramine Level and Sedative and Antihistamine Effects

Molecular pharmacolōgy : the mode of action of biologically active compounds

Eine der haufigsten chronischen Erkrankungen des Kindesalters ist das Asthma bronchiale. Obwohl die klassische Verlaufsform des Status asthmaticus keine diagnostischen Schwierigkeiten bereitet, werden haufig die abortiv verlaufenden Formen, die sich gerade bei Kleinkindern oft nur in Form von rezidivierendem oder chronischem Husten ausern, verkannt.

https://edoc.ub.uni-muenchen.de/1086/1/Mamblekos_Georgios.pdf

Asthma bronchiale im Kindesalter

For many years, the use of antihistamines in dermatological conditions has been closely linked to the treatment of urticarias and to the symptomatic relief of pruritus. H1- receptor antagonists are the first-line drugs for urticarias. Those urticarias of type I immunological origin respond better than physical urticarias. H2-receptor antagonists may be added for refractory patients but are rarely effective alone. Conventional H1-blockers are frequently associated with somnolence and anticholinergic effects. Therefore, new antihistamines without depressive effects on the central nervous system have recently been introduced.

Rational Use of Antihistamines in Allergic Dermatological Conditions

H1-antihistamines have been used in treatment of allergic disorders for more than 30 years. However, many of them have been employed in a less than systematic fashion. Most of the antihistamines show an apparent dual mechanism of action on isolated organs, consisting of a competitive and a non-competitive component. To induce non-competitive antagonism, higher concentrations are usually required, but for dimethindene the dose ratios for competitive and non-competitive activities differed only by less than one log unit. For therapeutic guidelines it should be considered that some antihistamines loose their effectiveness under long-term treatment and that patients may complain about the sedative side-effects. Thus, for maximum benefit it sometimes appears necessary to change the preparation before a choice for the individual dose is finally made. Under this condition they will cause relief from many allergic symptoms. Nevertheless, the classical antihistamines are without effect in bronchial asthma. The search for new drugs has been successful in this direction, as it has shown the antihistaminic/antiallergic drug Ketotifen to be able to prevent and control bronchial asthma. Many commercial preparations used in the treatment of common cold, vomitus or rhinitis contain an additive in combination with the antihistamines. Some of the additives appear to be of some value since they are used to reduce the side-effects of antihistamines. Secondary pharmacological properties of the antihistamines however provide also additional uses. This holds especially for effects on the CNS. Together with the search for the role played by histamine in the central cell-to-cell communication, new drugs might be found which will inhibit more selectively the action of histamine in the CNS.

D. Reinhardt

Papers

H1-receptor antagonists: comparative pharmacology and clinical use.