Antihistamines mixtures

Of the several syntheses available for the phenothiazine ring system, perhaps the simplest is the sulfuration reaction. This consists of treating the corresponding diphenylamine with a mixture of sulfur and iodine to afford directly the desired heterocycle. Since the proton on the nitrogen of the resultant molecule is but weakly acidic, strong bases are required to form the corresponding anion in order to carry out subsequent alkylation reactions. In practice such diverse bases as ethylmagnesium bromide, sodium amide, and sodium hydride have all been used. Alkylation with (chloroethyl)diethylamine affords diethazine (1), a compound that exhibits both antihista-minic and antiParkinsonian activity. Substitution of w-(2-chloroethyl)pyrrolidine in this sequence leads to pyrathiazine (2), an antihistamine of moderate potency. 

Rubbing the site of the sting with a crushed dock leaf is a simple yet rapid way of decreasing the extent of the pain. In common with many other weeds, the sap of a dock leaf contains a mixture of natural amines (e.g. urea (III) above), as well as natural antihistamines to help decrease any inflammation. The amines are solvated and, because the sap is water based, are alkaline. Being alkaline, these amines react with methanoic acid to yield a neutral salt, according to... 

NA, not avaiiabie IV, intravenous IM, intramuscuiar. antimuscarinic and moderate antiserotonin actions. Chiorphenamine causes iess sedation than some other antihistamines. Transient CNS stimuiant effects may be seen when injected intravenously. Chiorphenamine is a racemic mixture, with the antihistamine action residing mainly in the (+) laevo isomer (dexchiorphenamine). This isomer is aiso commerciaiiy avaiiabie. 

Cyclodehydration. The commercial preparation of an antihistamine (Lorata-dine, 3) requires cyclodehydration of the ketone 1. Use of the usual reagent for this reaction, polyphosphoric acid at 190°, leads to a mixture of two products in about 45% yield. The most useful and reasonably priced reagent is HF and BF3 at -30°, which gives 2 in >90% yield. 

Figure 9.16. Separation of a mixture of antihistamines and decongestants by ion pair chromatography. Courtesy of Millipore Corp., Waters Chromatography Division.

Kirchner s book 1127 gave an overview on the TLC of antihistamines, and Boonen 1128] also dealt with the separation of various antihistamines using plain silica and a mixture of ethanol/acetic acid/water (5 3 2). Recent experiments used metal ion impregnated silica layers to improve the separation of antihistamines 1129-1311. Antihistamines are easily visualised by iodine vapour. Separation of seven antihistamines on plain silica as well as metal ion impregnated silica with a benzene/butanol/acetic acid/water (7 8 5 2) mixture is shown in Table 10.18. Metal ion impregnation improved the separation of these antihistamines, especially when two or more stationary phases were used for parallel separations. 

Thus administration of an aldehyde invariably results in the appearance of the corresponding acid as an excreted metabolite, although in some instances both the acid and alcohol are formed. Thus the aldehyde formed by deamination of the antihistamine chlorpheniramine is metabolized to a mixture of the corresponding acid and alcohol. 

Carbinoxamine is a potent antihistaminic and is available as the racemic mixture. Carbinoxamine differs structurally from chlorpheniramine only in having an oxygen atom separate the asymmetric carbon atom from the aminoethyl side chain. The more active leva isomer of carbinoxamine has the (5) absolute configuration and can be superimposed on the more active dextro isomer (S configuration ) of chlorpheniramine. 

Lithium amide has been used in place of sodamide for the preparation of heterocyclic amines with antihistaminic activity. For example, a mixture of 2-amiuo-pyridine, /3-dimethylaminoethyl bromide hydrobromide, and 2 equivalents of lithium amide is refluxed in toluene for 22 hrs. Kaye, who notes that lithium amide... 

The enantiomeric separation of some racemic antihistamines and antimalar-ials, namely (+/-)-pheniramine, (+/-)-bromopheniramine, (+/-)-chlorophen-iramine, (+/-)-doxylamine, and (+/-)-chloroquine, were investigated by capillary zone electrophoresis (CZE). The enantiomeric separation of these five compounds was obtained by addition of 7 mM or 1 % (w/v) of sulfated P-cyclo-dextrin to the buffer as a chiral selector. It was found that the type of substituent and degree of substitution on the rim of the cyclodextrin structure played a very important part in enhancing chiral recognition (174). The use of sulfated P-cyclo-dextrin mixtures as chiral additives was evaluated for the chiral resolution of neutral, cyclic, and bicyclic monoterpenes. While there was no resolution of the monoterpene enantiomers with the sulfated P-cyclodextrin, the addition of a-cyclodextrin resulted in mobility differences for the terpenoid enantiomers. Resolution factors of 4-25 were observed. The role of both a-cyclodextrin and sulfated P-cyclodextrin in these separations was discussed (187). The enantiomeric separation of 56 compounds of pharmaceutical interest, including anesthetics, antiarrhythmics, antidepressants, anticonvulsants, antihistamines, antimalarials, relaxants, and broncodilators, was studied. The separations were obtained at pH 3.8 with the anode at the detector end of the capillary. Most of the 40 successfully resolved enantiomers contained a basic functionality and a stereogenic carbon (173). 

STPs are found to be the major contributor of pharmaceuticals in the Ebro River water. Compounds more frequently detected in the Ebro River basin were analgesics (diclofenac, naproxen, ibuprofen), lipid regulators (gemfibrozil, bezafibrate), antibiotics (azythromycin, trimethoprim, erythromycin, sulfamethoxazole), the antiepileptic carbamazepine, the antihistaminic ranitidine, and the 6-blockers atenolol and sotalol, which are the ones of major consumption in Spain as well as the ones excreted at higher percentages as parent drugs. Concentrations detected in both waste and surface waters are from 100 to 1000 times lower than the levels reported to cause acute toxicity. However, with respect to chronic effects, for some of the most ubiquitous compounds the margin of safety is narrow. As a wide spectrum of pharmaceuticals has been detected in natural waters, effects of mixtures should also be taken into account. 

Two- or three-component mixtures from decongestant-antihistamine combinations ingredients of which included phenylpropanol- ... 

One of the common side effects of taking antihistamines for colds or allergies is drowsiness. Again, this is the result of the fact that antihistamines are mixtures of enantiomers. One causes drowsiness the other is a good decongestant. 

DEPT spectra of the antihistamine phenindamine in base form are shown as an example (Figure 5.14) the data reveal the base to be a mixture of the two positional isomers shown in the Figure 5.14. The six methylene carbons (three for each compound), two methines and A -methyl resonances (44.8,44.7 ppm, seen resolved at high expansion) are clearly identified from amongst the many closely placed lines of the normal decoupled spectrum (a), while all the Cq lines (2 x 5) may be found in the low-field region of the spectrum [54]. 

RESPIRATORY TRACT These drugs reduce secretion in both the upper and lower respiratory tracts. This effect in the nasopharynx may provide symptomatic relief of acute rhinitis associated with coryza or hay fever. The contribution of antihistamines employed in cold mixtures is likely due to their antimuscarinic properties, except in conditions with an allergic basis. 

Newton DW, Murray W] and Lovell MW, pKg determination of benzhydrylpiperazine antihistamines in aqueous and aqueous methanol solutions, /. Pharm. Set, 71(12), 1363-1366 (1982). NB Attempted to measure pKa for meclizine by extrapolation of apparent pKa values in cosolvent-water mixtures to 0% cosolvent, but found diat meclizine could only be titrated in >47.8% methanol solutions, which was too hi. ... 

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