The objective of the present study was to estimate the therapeutic efficacy of rinopront used to treat inflammatory diseases of the nasopharynx in the children. The study included 32 patients at the age between 12 and 14 years presenting with various forms of acute and chronic rhinitis. The children with infectious inflammatory rhinitis with concomitant catarrhal maxillary sinusitis and pronounced symptoms of rhino-conjunctival syndrome recovered within 4-5 days after the initiation of rhinopront therapy. The patients presenting with vasomotor and all-the-year-round allergic rhinitis needed two courses of treatment (5 days each) to recover. The duration of treatment of mild seasonal rhinitis was 4 days whereas the moderately severe disease required the second 5-day course of therapy to be performed to arrest the disease activity.

This work expanded the knowledge of the use of chemometric experimental design in optimizing of six antihistamines separations by capillary electrophoresis with electrochemiluminescence detection. Specially, central composite design was employed for optimizing the three critical electrophoretic variables (Tris-H(3)PO(4) buffer concentration, buffer pH value and separation voltage) using the chromatography resolution statistic function (CRS function) as the response variable. The optimum conditions were established from empirical model: 24.2mM Tris-H(3)PO(4) buffer (pH 2.7) with separation voltage of 15.9 kV. Applying theses conditions, the six antihistamines (carbinoxamine, chlorpheniramine, cyproheptadine, doxylamine, diphenhydramine and ephedrine) could be simultaneous separated in less than 22 min. Our results indicate that the chemometrics optimization method can greatly simplify the optimization procedure for multi-component analysis. The proposed method was also validated for linearity, repeatability and sensitivity, and was successfully applied to determine these antihistamine drugs in urine.

A liquid chromatographic method was applied for the analysis of two sustained-release mixtures containing dextromethorphane hydrobromide, carbinoxamine maleate with either phenylephrine hydrochloride in pharmaceutical capsules (Mix 1) or phenyl-propanolamine, methylparaben, and propylparaben, which bonds as a drug base to ion exchange resin in pharmaceutical syrup (Mix 2). The method was used for their simultaneous determination using a CN column with a mobile phase consisting of acetonitrile-12 mM ammonium acetate in the ratio of 60:40 (v/v, pH 6.0) for Mix 1 and 45:55 (v/v, pH 6.0) for Mix 2.

An anionic rearrangement of 2-benzyloxypyridine is described. Pyridine-directed metalation of the benzylic carbon leads to 1,2-migration of pyridine via a postulated associative mechanism (addition/elimination). Several aryl pyridyl carbinols were obtained in high yields. A formal synthesis of carbinoxamine, an antihistamine drug used for the treatment of seasonal allergies and hay fever, emerges from this methodology.

With the effort to discover new chemotypes blocking L-type calcium channels (LTCCs), ligand-based virtual screening was applied with a specific interest toward the diltiazem binding site. Roughly 50000 commercially available compounds served as a database for screening. The filtering through predicted pharmacokinetic properties and structural requirements reduced the initial database to a few compounds for which the similarity was calculated toward two template molecules, diltiazem and 4-chloro-Ncyclopropyl- N-(4-piperidinyl)benzene-sulfonamide, the most interesting hit of a previous screening experiment. For 18 compounds, inotropic and chronotropic activity as well as the vasorelaxant effect on guinea pig were studied "in vitro", and for the most promising, binding studies to the diltiazem site were carried out. The procedure yielded several hits, confirming in silico techniques to be useful for finding new chemotypes. In particular, N-[2-(dimethylamino)ethyl]-3-hydroxy-2-naphthamide, N,Ndimethyl- N'-(2-pyridin-3-ylquinolin-4-yl)ethane-1,2-diamine, 2-[(4-chlorophenyl)(pyridin-2-yl)methoxy]- N,N-dimethylethanamine (carbinoxamine), and 7-[2-(diethylamino)ethoxy]-2H-chromen-2-one revealed interesting activity and binding to the benzothiazepine site.

An important topic in the drug discovery and development process is the role of drug binding to plasma proteins. In this paper the characterization of the interaction between antihistamines (cationic drugs) towards human serum albumin (HSA) and alpha(1)-acid glycoprotein (AGP) under physiological conditions by capillary electrophoresis-frontal analysis is presented. Furthermore, the binding of these drugs to all plasma proteins is evaluated by using ultrafiltration and capillary electrophoresis. Antihistamines present a wide-ranging behaviour with respect to their affinities towards plasma proteins. Orphenadrine, phenindamine, tripelenamine and tripolidine principally bind to HSA; carbinoxamine, dimetindene and etintidine principally bind to AGP; brompheniramine, chlorpheniramine and ranitidine present an important binding to lipoproteins and/or globulins and finally, chlorcyclizine, cinarizine, cyclizine, doxylamine, hydroxyzine, perphenazine and terfenadine do not bind to lipoproteins and/or globulins but bind to HSA and AGP in different extension. The interaction of antihistamines with HSA is determined by the hydrophobicity (direct relationship) and the polar surface area (indirect relationship) of the compounds. The steric parameters and hydrogen bonding character of compounds seems to be related with the binding of antihistamines to AGP. The antihistamine-HSA affinity constants were evaluated and the K(1) values ranged from 7 x 10(2)M(-1) (for doxylamine) to 4 x 10(4)M(-1) (for phenindamine).

The Philadelphia Medical Examiners Office has reported a series of 15 deaths between February 1999 and June 2005 of infants and toddlers 16 months and younger in which drugs commonly found in over-the-counter (OTC) cold medications were present. A total of 10 different drugs were detected: pseudoephedrine, dextromethorphan, acetaminophen, brompheniramine, carbinoxamine, chlorpheniramine, ethanol, doxylamine and the anticonvulsants, phenobarbital, and phenytoin. The drugs were confirmed and quantified by gas chromatography (GC)-mass spectrometry, with the exception of ethanol, which was analyzed by headspace GC and of phenobarbital and phenytoin that were quantified by GC with a nitrogen phosphorus detector. The most predominant drug was pseudoephedrine, which was found in all of the cases (blood concentration, n=14, range=0.10-17.0 mg/L, mean=3.34 mg/L) and was the sole drug detected in three cases. Acetaminophen was detected in blood from each of the five cases with sufficient sample. Other drugs (with frequency of detection) were dextromethorphan (five cases), carbinoxamine (four cases), chlorpheniramine (two cases) and brompheniramine, doxylamine, and ethanol (one case each). In the majority of the cases, toxicity from drugs found in easily available OTC medications was listed either as the direct cause of death or as a contributory factor. The manner of death was determined to be natural in only two of the cases. This postmortem study supports previous evidence that the administration of OTC cold medications to infants may, under some circumstances, be an unsafe practice and in some cases may even be fatal. The treating physicians and the general public need to be made more aware of the dangers of using OTC cold medications to treat very young children so that these types of tragedies might be avoided.

Chemical reactivity of homocysteine thiolactone (HTL) has been implicated in cardiovascular disease. Owing to its aminoacyl-thioester character, HTL undergoes facile electrophilic and nucleophilic reactions at its amino and activated-carboxyl group, respectively. To gain insight into the mechanism of the reactions involving its amino group, the kinetics of the condensation of homocysteine thiolactone with formaldehyde, acetaldehyde, and pyridoxal phosphate, were analyzed in the pH range from 5 to 10. The reactions were first order with respect to HTL, aldehyde, and hydroxide ion concentrations. Of the two ionic species of HTL (pKa=6.67+/-0.05), the acid form HTL+ was approximately 100-fold more reactive than the base form HTL(0). The reactions of HTL with aldehydes involve intermediate adducts. The conversion of the intermediate carbinolamine to a product, 1,3-tetrahydrothiazine-4-carboxylic acid or its 2-substituted analogue, occurs in a two-step reaction. The first step involves hydrolysis of the thioester bond in the intermediate, facilitated by anchimeric assistance by the oxygen of the carbinolamine group of the intermediate. The second step involves an attack of the liberated thiolate on the aldehyde-derived carbon of the intermediate, affording 1,3-tetrahydrothiazine-4-carboxylic acid or its 2-substituted analogue. An unusual feature of these reactions is that the formation of the carbinolamine group increases the reactivity of the thioester bond of HTL approximately 10(4)-fold. The facile formation of tetrahydrothiazines may contribute to HTL elimination from the human body.

A simple and sensitive spectrophotometric method was developed for the determination of carbinoxamine maleate in pharmaceutical formulations. The method is based on the formation of a ternary complex, extractable with chloroform, between copper(II), eosin, and carbinoxamine maleate. The absorption spectra of the ternary complexes shows, under optimum conditions, a maxima at 538 nm, with apparent molar absorptive 6.1690 x 10(4) mol(-1) cm(-1), Sandell's sensitives 6.75 x 10(-3) microg cm(-2), and linearity in the concentration range 0.75-10.0 microg ml(-1). The method can be achieved with high accuracy (recovery values, 100 +/- 2%) and precision (with standard deviation 0.029-0.155 and relative standard deviation 3.87-1.55%). The method was again successfully applied, with high accuracy and good precision, for the determination of carbinoxamine maleate in various pharmaceutical formulations (syrup, drops, and tablets).

The Montgomery County Coroner's Office has encountered a series of 10 infant deaths over an 8-month period in infants under 12 months old with toxicology findings that include a variety of drugs commonly found in over-the-counter (OTC) cold medications. The drugs detected were ephedrine, pseudoephedrine, dextromethorphan, diphenhydramine, chlorpheniramine, brompheniramine, ethanol, carbinoxamine, levorphanol, acetaminophen, and the anti-emetic metoclopramide. Toxicology findings were confirmed in 2 different matrices in 9 of the 10 cases and by 2 different analytical methods. The blood concentrations of the drugs and the case histories, as well as the cause of death for each infant, if available, will be given. The majority of these deaths were either toxicity from the OTC cold medications directly or as a contributory factor in the cause of death. Only two of the cases were the result of possible child abuse. Caregivers may be under the mistaken notion that OTC cold medications formulated for children are also safe for use in infants. These cases demonstrate that not only is administration of some OTC cold medications not safe, but use of OTC cold medications in infants can result in toxicity that can lead to death.