The recently introduced H1 receptor antagonists ebastine, fexofenadine and mizolastine, and the relatively new H1 antagonists acrivastine, astemizole, azelastine, cetirizine, levocabastine and loratadine, are diverse in terms of chemical structure and clinical pharmacology, although they have similar efficacy in the treatment of patients with allergic disorders. Acrivastine is characterised by a short terminal elimination half-life (t1/2,β) [1.7 hours] and an 8-hour duration of action. Astemizole and its metabolites, in contrast, have relatively long terminal t1/2,β values; astemizole has a duration of action of at least 24 hours and is characterised by a long-lasting residual action after a short course of treatment. Azelastine, which has a half-life of approximately 22 hours, is primarily administered intranasally although an oral dosage formulation is used in some countries. Cetirizine is eliminated largely unchanged in the urine, has a terminal t1/2,β of ∼7 hours and a duration of action of at least 24 hours. Ebastine is extensively and rapidly metabolised to its active metabolite; carebastine, has a half-life of ∼15 hours and duration of action of at least 24 hours. Fexofenadine, eliminated largely unchanged in the faeces and urine, has a terminal t1/2,β of ∼14 hours and duration of action of 24 hours, making it suitable for once or twice daily administration. Levocabastine has a terminal t1/2,β of 35 to 40 hours regardless of the route of administration, but is only available as a topical application administered intranasally or ophthalmically in patients with allergic rhinoconjunctivitis. Loratadine is rapidly metabolised to an active metabolite descarboethoxyloratadine and has a 24-hour duration of action. Mizolastine has a terminal t1/2,β of ∼13 hours and duration of action of at least 24 hours. Most orally administered new H1 receptor antagonists are well absorbed and appear to be extensively distributed into body tissues; many are highly protein-bound. Most of the new H1 antagonists do not accumulate in tissues during repeated administration and have a residual action of less than 3 days after a short course has been completed. Tachyphylaxis, or loss of peripheral H1 receptor blocking activity during regular daily use, has not been found for any new H1 antagonist. Understanding the pharmacokinetics and pharmacodynamics of these new H1 antagonists provides the objective basis for selection of an appropriate dose and dosage interval and the rationale for modification in the dosage regimen that may be needed in special populations, including elderly patients, and those with hepatic dysfunction or renal dysfunction. The studies cited in this review provide the scientific foundation for using the new H1 antagonists with optimal effectiveness and safety.

Clinical pharmacology of new histamine H1 receptor antagonists.

Determination of factors controlling the particle size in nanoemulsions using Artificial Neural Networks.

Cherry-picked ligands at histamine receptor subtypes.

The reactions of aryl-stabilized sulfonium ylides with trialkyl/triarylboranes have been investigated. Clean monohomologation of the boranes with only a small amount of the higher homologation products ( 95% ee) was observed in all cases. The ylide−borane reaction was applied to short syntheses of the anti-inflammatory agents neobenodine and cetirizine, both of which contain a chiral diarylmethylalkoxy and diarylmethylamino moiety, respectively.

Synthesis and applications of chiral organoboranes generated from sulfonium ylides.

Rats are commonly used in anaphylaxis models, mainly in intestinal anaphylaxis. Hypersensitivity mechanisms are complex and they are not clearly defined. Ovalbumin (OVA) is commonly used for studies on the hypersensitivity mechanism. However, the potential pro-inflammatory mediators induced by this antigen in the model of paw oedema in immunized rats are still not completely understood. This work examines the pharmacological modulation of several mediators involved in rat hind paw immune oedema induced by OVA. Wistar rats were previously immunized (14-18 days) with OVA (30 microg, intraperitoneally) or sham-sensitized with aluminum hydroxide (control). The paw volumes were measured before the antigenic stimuli and 1, 2, 3 and 4 h after the intraplantar injection of OVA (10 microg/paw). Subcutaneous injection of dexamethasone, diphenhydramine, cyproheptadine, chlorpromazine or methysergide significantly inhibited (p < 0.05) the allergic paw oedema. The dual inhibitor of cyclooxygenase and lipoxygenase (NDGA), the cyclooxygenase inhibitor (indomethacin), the lipoxygenase inhibitor (MK-886), the PAF antagonist (WEB 2086), the mast cell stabilizer (ketotifen), and the anti-histamine (meclizine) did not inhibit the immune oedema. In addition, thalidomide and pentoxifylline (anti-tumour necrosis factor drugs) were ineffective against OVA-induced oedema. The fact that indomethacin, MK-886, NDGA and WEB 2086 are unable to inhibit this allergic oedema indicates that the dexamethasone action seems not to be via phospholipase A2, but possibly due to the synthesis and/or the inhibitory activity of cytokines. The paw oedema inhibition by diphenhydramine, but not by meclizine, may suggest a different mechanism, which is independent of the effect of histamine. These data indicate that allergic oedema is more sensitive to anti-serotonin drugs, mainly anti-5-HT2, suggesting that the principal mediator of this inflammatory response is serotonin.

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The pharmacological profile of ovalbumin-induced paw oedema in rats.

The classical histamine H1-receptor antagonists diphenhydramine (3a) and cyproheptadine (9) and their derivatives (3b-d, 10) were connected with a 2-guanidinothiazole containing structure (28) derived from the H2-receptor antagonist tiotidine in order to obtain combined H1-/H2-receptor antagonists. The two moieties were not directly linked together, but were separated by a polymethylene spacer and a polar group (nitroethenediamine or urea). Thus 12 compounds were obtained that proved in vitro to possess high H1- and H2-receptor antagonist activity at the isolated guinea-pig ileum (H1) and the isolated guinea-pig right atrium (H2), respectively. The incorporation of the diphenhydramine as well as the cyproheptadine component provides high affinity to H1-receptors. The tricyclic cyproheptadine and its 10,11-dihydro derivative (30-32, 34), however, cause a decrease of H2-receptor antagonist potency compared to the diphenhydramines (29a-d, 33a-d). Using nitroethenediamine as the polar group is apparently more favourable to H1- and H2-receptor affinity as the urea function. All compounds elicit a dual mode of competitive and noncompetitive antagonism. Among the novel compounds the nitroethenediamines with 4-fluoro- or 4-methyl-substituted diphenhydramine as H1-receptor antagonist moiety (29c, d) display the most potent H1- and H2-receptor antagonist effects. The presented concept is a very promising way to combine H1- and H2-receptor antagonist properties in one molecule.

Synthesis and Pharmacology of Combined Histamine H1‐/H2‐Receptor Antagonists Containing Diphenhydramine and Cyproheptadine Derivatives

Combined histamine H1/H2 receptor antagonists: Part II.

Synthesis and Pharmacology of Combined Histamine H1-/H2-Receptor Antagonists Containing Diphenhydramine and Cyproheptadine Derivatives.

Durch Pd-C-katalysierte Doppelbindungsisomerisierung werden aus den Allylamiden 3 die Enamide 4 dargestellt. 4a-d und 10 werden in einer elektrophilen α-Amidoalkylierungsreaktion mit dem Silylenolether 6 zu den Amidoketonen 8a-d und 12 umgesetzt. Die Enamide werden dabei durch Umsetzung mit O,O′-Dimethyldithiophosphorsaure (5) und SnCl4 aktiviert.



Electrophilic α-Amidoalkylation with Enamides According to a New Activation Procedure Using O,O′-Dimethyldithiophosphoric Acid



The allylic amides 3a-d are rearranged to give enamides 4a-d using Pd-C as a catalyst. 4a-d and 10 are employed in an electrophilic α-amidoalkylation reaction with silyl enol ether 6 yielding the amido ketones 8a-d and 12. The enamides are activated for this reaction by treatment with O,O′-dimethyldithiophosphoric acid (5) and SnCl4.

/pdf/elektrophile-a-amidoalkylierungen-mit-enamiden-nach-einem-16preu0394.pdf

Cornelia Wolf

Papers

Synthesis and Pharmacology of Combined Histamine H1‐/H2‐Receptor Antagonists Containing Diphenhydramine and Cyproheptadine Derivatives

Combined histamine H1/H2 receptor antagonists: Part II.

Synthesis and Pharmacology of Combined Histamine H1-/H2-Receptor Antagonists Containing Diphenhydramine and Cyproheptadine Derivatives.

Elektrophile α-Amidoalkylierungen mit Enamiden nach einem neuen Aktivierungsverfahren mit O,O'-Dimethyldithiophosphorsäure