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(S)-4-Chlorophenylpyridylmethanol and (R)-4-chlorobenzhydrol are key pharmaceutical intermediates for the synthesis of bepotastine and cloperastine, respectively. However, the biocatalytic approach to prepare these bulky diaryl ketones remains challenging because of the low activity of naturally occurring alcohol dehydrogenases (ADH). In the present study, ADH seq5, which has an adequate binding pocket volume and accepts bulky diaryl ketones, was further engineered with a binding pocket of increased hydrophobicity. Based on molecular simulation and binding free energy analyses, a small mutation library was constructed, and mutant seq5-D150I with a threefold increase in kcat and a low Km was obtained successfully. The comparison of kinetic parameters, binding free energy, docking conformation, and critical catalytic distances calculated by molecular dynamic simulations revealed the source of increased activity. To develop a practical approach with seq5-D150I, reaction conditions including pH, temperature, buffer, and metal ions were optimised and applied to synthesise (S)-4-chlorophenylpyridylmethanol and (R)-4-chlorobenzhydrol with high enantiomeric excess. The space-time yields for (S)-4-chlorophenylpyridylmethanol and (R)-4-chlorobenzhydrol increased dramatically to as high as 263.4 g∙L-1 day-1 and 150 g∙L-1 day-1, respectively, which, to our knowledge, is the highest reported yield to date. These results show that the biocatalytic approach with seq5-D150I may be practical for future industrial applications.Key points An alcohol dehydrogenase was engineered based on binding free energy analysis. The mutant seq5-D150I obtained a threefold increase in kcat and a low Km. Two important pharmaceutical intermediates were obtained with high space-time yield.

Esophageal squamous cell carcinoma (ESCC) is a major type of esophageal cancer. The prognosis of patients with ESCC remains poor because of the high morbidity and mortality of the disease. One strategy for drug discovery for ESCC treatment or prevention is screening FDA-approved drugs. In the present study, we found that the antitussive agent cloperastine can inhibit the proliferation of ESCC cells. However, the underlying mechanism was unclear. To determine the mechanism of this inhibitory effect, we performed proteomic analysis using KYSE150 cells treated with cloperastine and DMSO. The results identified several down-regulated signaling pathways included those of three key proteins (NADH dehydrogenase [ubiquinone] 1 alpha subcomplex 1, NADH ubiquinone oxidoreductase subunit S5, and cytochrome C oxidase subunit 6B1) involved in oxidative phosphorylation. Meanwhile, we observed that oxidative phosphorylation in mitochondria was inhibited by the drug. Importantly, cloperastine suppressed ESCC growth in a xenograft mouse model in vivo. Our findings revealed that cloperastine inhibits the proliferation of ESCC in vivo and in vitro by suppressing mitochondrial oxidative phosphorylation.

A new, simple and cost-effective method for the synthesis of sulfated beta-cyclodextrin (S-β-CD), one of the most widely used chiral mobile phase additive, using sulfamic acid as sulfonating agent has been described. The method was optimized and the acquired product was characterized and compared with a marketed Sigma Aldrich sulfated beta-cyclodextrin (S-β-CD1). Beta cyclodextrin (β-CD), hydroxypropyl beta-cyclodextrin (HP-β-CD), S-β-CD1 and S-β-CD2 were evaluated as chiral mobile phase additives (CMPAs) for the enantiomeric separation of cloperastine, an antitussive agent, using reversed-phase HPLC. Under the optimized conditions, a resolution of 3.14 was achieved within 15 minutes on an achiral Kromasil C8 (150 x 4.6 mm, 5 µ) column with a mobile phase of 5mM monopotassium phosphate containing 10mM S-β-CD3 pH 3 and 45% methanol with a run time of 15 min. The method utilizing S-β-CD3 as CMPA was validated as per ICH guidelines and applied for the quantitative determination of cloperastine enantiomers in active pharmaceutical ingredients and pharmaceutical formulations. The selectivity changes imparted by S-β-CD were proven to be beneficial for chiral separation. The chiral recognition mechanism and elution order of the reported enantiomers were determined by simulation studies. It was observed that inclusion complex formation and hydrogen bonding are the major forces for the chiral resolution.

The present study predicts a three-dimensional model for the histamine H1 receptor and the design of antihistamine inhibitors using cloperastine as the core molecule by docking studies. In this work, we predicted a three-dimensional structure of the histamine H1 receptor using the MODELLER9V7 software. The protein structure was developed based on the crystal structure of the histamine H1 receptor, the lysozyme chimera of Escherichia virus T4 (PDB ID: 3RZE_A) target collected from the PDB data bank. Using molecular dynamics simulation methods, the final predicted structure is obtained and further analyzed by VERIFY3D and PROCHECK programs, confirming that the final model is reliable. The drug derivatives of cloperastine were designed and docking was performed with the designed ligands along with the drug. The predicted model of the histamine H1 receptor structure is stable and confirms that it is a reliable structure for docking studies. The results indicate that MET 183, THR 184 and ILE 187 in the histamine H1 receptor are important determinant residues for binding as they have strong hydrogen bonding with cloperastine derivatives. The drug derivatives were docked to the histamine H1 receptor protein by hydrogen bonding interactions and these interactions played an important role in the binding studies. The molecule 1-{2-[(4-chlorophenyl) (phenyl) methoxy] ethyl}-4-methylenepiperidine showed the best docking results with the histamine H1 receptor. The docking results predicted the best compounds, which may act as better drugs than cloperastine and in the future, these may be developed for anti-allergy therapy.

The chiral separation of five antihistamine drugs including meclizine, cloperastine, azelastine, carbinoxamine and mequitazine was studied by HPLC combined with chiral stationary phases. The effect of chiral columns, the types and contents of organic modifiers, and the concentrations of basic additive on the chiral separation was evaluated and optimized in detail. The best enantioselectivity for these compounds was observed using Chiralpak IA and Chiralpak ID as chiral columns. In particular, baseline separation of carbinoxamine with the largest resolution of 3.82 was achieved using a Chiralpak ID column with the mobile phase of acetonitrile–water–ammonia solution (90 : 10 : 0.1, v/v/v). Based on this result, an enantioselective HPLC-MS/MS method was developed and validated for determination of carbinoxamine enantiomers in rat plasma. Also, this method was successfully applied in evaluating the pharmacokinetic profiles of carbinoxamine enantiomers. Good linearity (r > 0.99) for both enantiomers over a concentration range of 0.1–100 ng mL−1 was obtained. The accuracy ranged from 87.4% to 113.8%, and the intra-day and inter-day precisions were below 9.4% for (+)- and (−)-carbinoxamine at three quality control levels. The pharmacokinetic parameters demonstrated that the absorption and elimination processes of carbinoxamine enantiomers were not stereoselective, and chiral inversion did not occur either in rats.

Cancer therapy is often hampered by the disease’s development of resistance to anticancer drugs. We previously showed that the autonomously upregulated product of fibroblast growth factor 13 gene (FGF13; also known as FGF homologous factor 2 (FHF2)) is responsible for the cisplatin resistance of HeLa cisR cells and that it is likely responsible for the poor prognosis of cervical cancer patients treated with cisplatin. Here we show that cloperastine and two other histamine H1 receptor antagonists selectively kill HeLa cisR cells at concentrations that little affect parental HeLa S cells. The sensitivity of HeLa cisR cells to cloperastine was abolished by knocking down FGF13 expression. Cisplatin-resistant A549 cisR cells were similarly susceptible to cloperastine. H2, H3, and H4 receptor antagonists showed less or no cytotoxicity toward HeLa cisR or A549 cisR cells. These results indicate that histamine H1 receptor antagonists selectively kill cisplatin-resistant human cancer cells and suggest that this effect is exerted through a molecular mechanism involving autocrine histamine activity and high-level expression of FGF13. We think this represents a potential opportunity to utilize H1 receptor antagonists in combination with anticancer agents to treat cancers in which emergent drug-resistance is preventing effective treatment.

No vaccine against infection by SARS-CoV-2 yet exists. Treatment by hydroxychloroquine (HCQ) medication, among others, has been proposed. However, prophylactic HCQ medication has been little evaluated. We propose to use data from patients with rheumatic diseases (RA, SLR) who have been chronically taking HCQ medication since before the COVID-19 outbreak (hereafter: HCQpa), in order to evaluate the potential of HCQ for preventing infection with SARS-CoV-2. This can be achieved with relative ease by considering whether COVID-19 prevalence is significantly lower in HCQpa than in the general population (i.e., all people that are not HCQpa). Even if COVID-19 prevalence is truly significantly lower in HCQpa, some HCQpa may still present with COVID-19 (lower prevalence does not mean a prevalence of zero). However, given a value for COVID-19 prevalence in the general population and a number of available HCQpa, one may compute the maximum number of HCQpa for that total number of HCQpa considered that can have COVID-19 in order to still be able to conclude a lower COVID-19 prevalence in HCQpa (i.e., if there is one more case of COVID-19 than that maximum number, the COVID-19 prevalence in the HCQpa cannot be said to be lower than in the general population). Because the COVID-19 prevalence in the general population is not known with precision, we will consider different general population prevalence values. Among these contemplated prevalence values, one is derived from the official total number of confirmed cases, others by computing the total number of cases from the number of fatal COVID-19 cases so far and considering different case fatality rates per total cases. Our analyses show that systematic testing for COVID-19 in as few as 5,000 HCQpa is all that is needed for a test of whether HCQ has a prophylactic action against COVID-19, even for a COVID-19 prevalence value as low as 250 per 100,000, provided that test sensitivity is at least equal to its specificity. For higher COVID-19 prevalence values, the number of HCQpa needed is even lower.

Cloperastine hydrochloride, a piperidine derivative, is a drug substance with a central antitussive effect and widely used in cough treatment; and its impurities have not been reported. Herein we isolated and identified five impurities (named as impurity A, B, C, D and E) in cloperastine hydrochloride bulk drug and developed a quantitative HPLC method. First, impurity A, B, C were enriched by ODS column chromatography and isolated by semi-preparative HPLC, at the same time, impurity D was purified by ODS column chromatography. Then, impurity E was enriched by strong acid degradation and purified by semi-preparative HPLC. At last, their structures were characterized by a variety of spectral data (MS, 1H NMR, 13C NMR, HSQC, HMBC and 1H-1H COSY). Impurity A was confirmed as 1-[2-(diphenylmethoxy)ethyl]piperidine, which having one less chloro-substituent compared with cloperastine. Impurity B was confirmed as 1-[2-[(2-chlorophenyl)(phenyl)methoxy]ethyl]piperidine, which was the isomer of cloperastine with 2-chloro-substituent. Impurity C was confirmed as 1-[2-[(3-chlorophenyl)(phenyl)methoxy]ethyl]piperidine, which was the isomer of cloperastine with 3-chloro-substituent. Impurity D was confirmed as (4-chlorophenyl)(phenyl)methanone, which was the raw material for the synthesis of cloperastine. Impurity E was confirmed as (4-chlorophenyl)(phenyl)methanol, which was an intermediate in the synthesis of cloperastine, and it was also a hydrolysate of cloperastine. Finally, the developed method was validated in terms of specificity, linearity, sensitivity, precision and accuracy.

The current study was focused on establishing a novel ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS) method for the quantitative estimation of the co-formulated drugs; paracetamol (PAR), pseudoephedrine hydrochloride (PSD) and brompheniramine maleate (BRP) in human plasma to Egyptian volunteers. Additionally, the study aimed to recognize whether the co-administration of the target drugs to different ethnic population affects their pharmacokinetics. The drugs extraction involved liquid-liquid extraction technique with the aid of ethyl acetate. Reversed phase UPLC separation was accomplished on Agilent Zorbax SB C18 (50 mm × 2.1 mm, 1.8 μm) column using acetonitrile: 0.1% formic acid (70: 30 v/v) as the mobile phase. Positive electrospray ionization and multiple reaction monitoring were employed. The short analysis time (1 min/sample) was promising as it has allowed the analysis of many human plasma samples per day. The developed method displayed linear ranges of 0.05–20.0 μg/mL for PAR, 1.0–500.0 ng/mL for PSD and 0.1–50.0 ng/mL for BRP. A detailed validation of the developed method was performed in compliance with the FDA guidelines where all the validation parameters results were satisfactory. The UPLC-MS/MS method was utilized for studying the pharmacokinetics of the three drugs after the oral administration of their combined dosage form to Egyptian healthy volunteers. The pharmacokinetic study was accomplished after agreement of the ethics committee. The achieved pharmacokinetic results by the newly developed method were; Cmax (ng/mL) 8001.77, 127.76, 1.92, tmax (h) 0.75, 1.5, 4.0 and t½ (h) 3.3, 4.65, 16.26 for PAR, PSD and BRP, respectively, these results were compared with those obtained from other reported clinical trials done on other races. It was clear that the pharmacokinetic parameters of PAR and PSD were not affected when the same dose was given to volunteers from different ethnic populations. Additionally, the co-administration of PSD and BRP with PAR has not altered the pharmacokinetics of PAR. The pharmacokinetics of PSD when it was co-administered with PAR and BRP was almost similar to that when it was co-administered with benorylate and chlorpheniramine, however, the Cmax of PSD was greatly affected when it was co-administered with caffeine, chlorpheniramine and cloperastine.

This chapter describes methods of synthesis, pharmacological properties, and the use of derivatives of 1-phenyl-3-(piperidin-1-yl)propan- and butan-1-ol, such as trihexyphenidyl, biperiden, pridinol, cycrimine, and diphenidol, and pirmenol; derivatives of 2-(piperidin-1-yl)ethan-1-ol or 3-(piperidin-1-yl)propan-1-ols cloperastine, benproperine, pipazetate, and raloxifene; derivatives of 3-(piperidin-1-yl)propane-1,2-diol—diperodon and 3-(piperidin-1-yl)propane-1,1-diol—pipoxolan; derivative of 1-phenyl 3-(piperidin-1-yl)propan-1-one—dyclonine; and the derivative of 2,2-diphenyl-4-(piperidin-1-yl)butanamide—fenpiverinium bromide.

The classification of an impurity of a drug substance as genotoxic means that the "threshold of toxicological concern" (TTC) value of 1.5 μg/day intake, considered to be associated with an acceptable risk, should be the admissible limit in the raw material and that leads to new analytical challenges. In this study, reliable chromatographic methods were developed and applied as limit tests for the control of three genotoxic impurities (GTIs) in cloperastine fendizoate, drug widely used as an antitussive active pharmaceutical ingredient (API). In particular, GC-MS was applied to the determination of one alkyl halide (2-chloroethanol, 2-CE), while HPLC-DAD was selected for the analysis of two sulfonate esters (methyl p-toluenesulfonate, MPTS, and 2-chloroethyl p-toluenesulfonate, CEPTS). Regarding GC-MS, strong anion-exchange (SAX)-SPE was applied to remove fendizoate from the sample solutions, due its low volatility and its high amount in the raw material. The GC-MS analysis was performed on a Factor Four VF-23 ms capillary column (30 m × 0.25 mm I.D., film thickness 0.25 μm, Varian). Single ion-monitoring (SIM) detection mode was set at m/z 80. In the case of HPLC-DAD, a suitable optimization of the chromatographic conditions was carried out in order to obtain a good separation of the impurity peaks from the drug substance peaks. The optimized method utilizes a SymmetryShield RP(8) column (250 mm × 4.6 mm, 5 μm, Waters) kept at 50°C, with phosphate buffer (pH 3.0; 10 mM)-methanol (containing 10% ACN) (45:55, v/v) as the mobile phase, at the flow-rate of 1.7 mL/min and UV detection at 227 nm. The required sensitivity level was achieved by injecting 80 μL of sample solution, purified from fendizoate by SAX-SPE, followed by a 1:1 (v/v) dilution of the SPE eluate with water. For both GC-MS and HPLC-DAD, the method validation was performed in relation to specificity and limit of detection (LOD), as required by ICH guidelines in relation to limit assays. The developed methods were successfully applied for the determination of GTIs in five different batches of cloperastine fendizoate. In all the analyzed batches, the three target GTIs were below the concentration limit.

We previously reported that prenatal exposure to diethylstilbestrol (DES) impaired passive avoidance responses in mice. Apart from the above, we also found that cloperastine, a centrally acting antitussive, ameliorated depression-like and anxiety-like behaviors in rodents at antitussive-effective doses. In this study, we investigated whether or not cloperastine rescues impairment of passive avoidance responses in mice prenatally exposed to DES. Male DES-exposed mice were subcutaneously administered cloperastine at 10 or 30 mg/kg twice a day from 32 to 41 days after birth and subjected to behavioral testing 42 to 46 days after birth. Cloperastine at 10 and 30 mg/kg ameliorated DES-induced impairment of passive avoidance responses. In addition, cloperastine affected the levels of 5-HT1A receptors, GIRK and BDNF in the hippocampus of DES-exposed mice. However, the number of BrdU-positive cells in the hippocampus of DES-exposed mice was not changed by chronic administration of cloperastine. These findings suggest that the action of endocrine disruptors in the brain may not always be irreversible, and that the symptoms caused by endocrine disruptors might be curable with drugs such as cloperastine.

Clinically, both overactive bladder (OAB) and dysuria are known to occur in patients with cerebral infarction (CI). A few anticholinergic drugs are used to treat OAB in such patients, although the effect is not satisfactory. On the other hand, little or no therapeutic drug is available for dysuria after CI. We previously reported that dextromethorphan (DM) and cloperastine (CP), centrally acting antitussives, reduce the frequency of micturition reflex and increase the threshold pressure in anesthetized rats. In this article, we describe the effects of DM and CP on urinary disturbances at 24 h after CI, induced by occlusion of the left middle cerebral artery in conscious rats. We also briefly review the structure, function, and distribution of G-protein-coupled inwardly rectifying K(+) (GIRK) channels in the brain, since both drugs have potent inhibitory effect on GIRK channel-activated currents in brain neurons. Of the two drugs, CP at antitussive-effective doses ameliorated both OAB and dysuria 24 h after CI in rats. On the other hand, DM aggravated the dysuria, although it significantly ameliorated the OAB. These results suggest that CP may have some therapeutic value for the treatment of OAB and dysuria after CI. At the present time, mechanisms of the effect of CP are unknown. However, several lines of evidence including pharmacological findings support the idea that the effects of CP may be produced at least partly by an increase in the level of 5-HT in the brain through an inhibitory effect on GIRK channel-activating currents.

Tablets containing both paracetamol (PM) and cloperastine hydrochloride (CLH) in a combination formulation prepared by standard vertical granulation technology were found to have altered pharmaceutical properties. The hardness and disintegration time of tablets containing both PM and CLH gradually increased during storage, and the cross-screw did not operate smoothly during preparation of the mixed powder. The objective of the present study was to investigate the mechanism of formation of eutectic mixtures consisting of PM and CLH. Binary mixtures of PM and CLH in various proportions were prepared as physical mixtures and analyzed by DSC to study their thermal behavior. Phase diagrams obtained from the endothermic peaks due to melting of physical mixtures of PM and CLH demonstrated the formation of eutectic mixtures with eutectic temperatures of 86.9-110.2 degrees C depending on the ratio of constituents. The formation of the eutectic mixture was studied for a 50:50 mol.% ratio of PM and CLH. PXRD analysis revealed that the eutectic mixture of PM and CLH is structurally different from native PM and CLH. The most probable interaction sites between PM and CLH were demonstrated by DSC analysis of a binary mixture of PM and CLH prepared by melt quenching.

We have previously reported that centrally acting non-narcotic antitussives inhibited G protein-coupled inwardly rectifying potassium (GIRK) channel-activated currents, and that the antitussives had multiple pharmacological actions on various models of intractable brain diseases in rodents. In this study, the question of whether these antitussives inhibit drug-induced hyperactivity in mice was investigated. Antitussives, such as cloperastine and tipepidine, at cough suppressant doses, inhibited an increase in ambulation of mice neonatally treated with 6-hydroxydopamine. In addition, all antitussives studied inhibited an increase in methamphetamine-induced hyperactivity in mice. Methylphenidate, which is used for treatment of ADHD, inhibited 6-hydroxydopamine-lesion-induced, but not methamphetamine-induced, hyperactivity in mice. By the rota-rod test, the drugs had little effect on motor coordination of the hyperactive mice. Significant correlation was found between the ameliorating effects of antitussives on methamphetamine-induced hyperactivity and their inhibitory actions on GIRK channel currents (coefficient factor, 0.998). Furthermore, tertiapin, a GIRK channel blocker, prevented an increase in methamphetamine-induced hyperactivity of mice. These results demonstrated that antitussive drugs (cloperastine, tipepidine and caramiphen) possessing inhibitory action on GIRK channels inhibit drug-induced hyperactivity in mice, suggesting that such antitussives may potentially be therapeutic for patients with ADHD.

Background: Cough is one of the most common symptoms for which patients seek medical attention from primary care physicians and lung specialists. About 40% of the population at any one time report cough. Cough is associated with significantly impaired health-related quality of life. Levodropropizine is an effective and very well tolerated peripheral antitussive drug. We want to compare it to central cough suppressants efficacy (opioids and non-opioids) that may be associated with side effects limiting their use. Methods: After a comprehensive literature search, a meta-analysis of 7 clinical studies of levodropropizine vs. control, including a total of 1,178 patients, was performed with the aim to evaluate the overall comparative efficacy of levodropropizine in the pediatric and adult population. Three electronic databases and reference list were used to search for studies that assessed the efficacy of levodropropizine for treating cough in children and adults using as standardized efficacy parameters the cough frequency and severity, and number of night awakenings as outcome parameters. Results: The meta-analysis of all standardized efficacy parameters showed a highly statistically significant difference in the overall antitussive efficacy in favor of levodropropizine vs. control treatments (p = 0.0015). The heterogeneity test for the efficacy outcome was not statistically significant (p = 0.0534). Seven studies met out inclusion criteria. A meta-analysis of the eligible ones showed a statistically significant difference in the overall anti-tussive effect of levodropropizine versus control (p = 0.0015). Conclusions: This analysis indicates that levodropropizine is an effective antitussive drug in children and adults, with statistically significant better overall efficacy outcomes vs. central antitussive drugs (codeine, cloperastine, dextromethorphan) in terms of reducing cough intensity and frequency, and nocturnal awakenings. This result further reinforces the favorable benefit/risk profile of levodropropizine in the management of cough. The efficacy of levodropropizine in the treatment of cough in children and adults is higher than that of the common centrally-acting anti-tussive.

A new chemiluminescence (CL) reaction was observed when cloperastine hydrochloride was injected into the reaction mixture after the CL reaction of Ce(IV) and sodium sulfite finished. A new flow injection CL method for the determination of cloperastine hydrochloride was established based on the CL reaction. The relative standard deviation (RSD) for the determination of cloperastine hydrochloride was 1.3% (n=11, c=1.0×10−6 g/mL). The CL intensity responded linearly to the concentration of cloperastine hydrochloride in the range 2.0×10−7∼2.0×10−5 g/mL (r=0.9962). The detection limit was 5×10−8 g/mL cloperastine hydrochloride. The method had been applied to the determination of cloperastine hydrochloride in tablets with satisfactory results.

Ten antihistamine drugs, diphenhydramine, orphenadrine, chlorpheniramine, diphenylpyraline, triprolidine, promethazine, homochlorcyclizine, cyproheptadine, cloperastine and clemastine, have been found to be extractable from human plasma samples using MonoTip C18 tips, inside which C18-bonded monolithic silica gel was fixed. Human plasma (0.1 mL) containing the ten antihistamines was mixed with 0.4 mL of distilled water and 25 µL of a 1 M potassium phosphate buffer (pH 8.0). After centrifugation of the mixture, the supernatant fraction was extracted to the C18 phase of the tip by 25 repeated aspirating/dispensing cycles using a manual micropipettor. The analytes retained on the C18 phase were then eluted with methanol by five repeated aspirating/dispensing cycles. The eluate was injected into a gas chromatography (GC) injector without evaporation and reconstitution steps, and was detected by a mass spectrometer with selected ion monitoring in the positive-ion electron impact mode. The separation of the ten drugs from each other and from impurities was generally satisfactory using a DB-1MS column (30 m × 0.32 mm i.d., film thickness 0.25 µm). The recoveries of the ten antihistamines spiked into plasma were 73.8–105%. The regression equations for the ten antihistamines showed excellent linearity with detection limits of 0.02–5.0 ng/0.1 mL. The within-day and day-to-day coefficients of variation for plasma were not greater than 9.9%. The data obtained from determination of diphenhydramine and chlorpheniramine in human plasma after oral administration of the drugs are also presented. Copyright © 2006 John Wiley & Sons, Ltd.

Capillary electrophoresis (CE) with carboxymethylated beta- or gamma-cyclodextrins was used to achieve the rapid enantiomeric separation of a set of basic drugs. The enantiomers of 12 chiral amino-containing pharmaceutical compounds belonging to various therapeutic categories were analyzed by CE using an uncoated 60 cm x 75 microm I.D. silica capillary. Several experimental parameters such as the nature, concentration and pH of the buffer, nature and concentration of the anionic cyclodextrin and temperature were studied in order to optimize the enantiomeric separation. The variation of the solute partition coefficient for the chiral selector, the enantioselectivity and resolution factors are used to assess the quality of the chiral separation. It is shown that the solute affinity for the chiral selector is not related to its enantioresolution factor. None of the two cyclodextrin selectors used was able to separate the whole set of basic drugs.

Chemically oversulfated galactosaminoglycans with potential as therapeutic agents (inhibitors of human leukocyte elastase) were tested as chiral selectors in capillary electrophoresis of basic racemates. The high anionic character of these compounds provides them with anodic mobility in acidic buffer; using uncoated capillaries, the enantioresolution of racemic basic drugs was obtained at pH 2.5. Dimethindene, chloroquine and chlorpheniramine were enantioresolved applying negative voltage (-15 kV) while the other analytes (propranolol, pindolol, tetrahydrozoline and cloperastine) exhibited catodic migration. The addition of organic solvents to the running buffer was evaluated in order to increase the resolution; methanol provides the best results and in general, baseline separation of the analytes was reached. The studied oversulfated mucopolysaccharide, shows the same ionic character of heparin but presents different stereochemistry and sites of sulfation. A comparison with heparin, used in the same acidic conditions, may underline the role of ionic, spatial and steric features of glycosaminoglycans in the enantiorecognition.

Introducción: la tos es un motivo frecuente de consulta en Pediatría que conlleva un consumo importante de fármacos antitusígenos, bajo prescripción médica o como medicamentos de libre dispensación, pese a que su eficacia no esta claramente probada. Objetivos: conocer el perfil de prescripción de antitusígenos de los pediatras de Atención Primaria de la Comunidad Autónoma Vasca y la percepción del uso de medicamentos antitusígenos de libre dispensación. Material y métodos: encuesta estructurada, anónima, en la que participaron 77 pediatras del País Vasco (36 de Álava, 28 de Bizkaia y 13 de Gipuzkoa). Resultados: no usaban antitusígenos 25 pediatras (32,5%) y sí lo hacían 52 (67,5%). Los antitusígenos más prescritos fueron dextrometorfano, 41 (78,8%); codeína, 34 (65,4%), y cloperastina, 34 (65,4%). Los motivos de prescripción fueron catarro de vías altas, 47 (90,4%); laringitis, 14 (26,9%); rinitis 7 (13%), y bronquitis, 3 (6%). Otros tratamientos fueron miel, 16 (20,8%); fitoterapia, 6 (7,8%), y homeopatía, 6 (7,8%). Conclusiones: la prescripción de antitusígenos es frecuente en los pediatras de Atención Primaria del País Vasco. El dextrometorfano es el medicamento más recetado. El catarro de vías altas constituye la causa más frecuente para prescribir antitusígenos. Los antitusígenos de libre dispensación no parecen ser de uso frecuente. Introduction: cough is a frequent complaint in Pediatrics that carries a significant consumption of antitussives, by prescription or by over the counter (OTC) drugs, although the effectiveness of these drugs is not clearly proven. Objectives: to assess the prescription profile of cough medicines by primary care pediatricians of the Basque Country and the perception of the use of OTC cough medicines by families. Material and methods: structured survey. Took part 77 primary care pediatricians of the Basque Country (Alava 36, Bizkaia 28 and Gipuzkoa 13). Results: twenty-five (32.5%) pediatricians do not use antitussives and 52 (67.5%) use them normally. The most prescribed antitussives were: dextromethorphan 41 (78.8%), codeine 34 (65.4%) and cloperastine 34 (65.4%). The reasons for prescribing were colds 47 (90.4%), laryngitis 14 (26.9%), rhinitis 7 (13%) and bronchitis 3 (6%). Other treatments were honey 16 (20.8%), herbal therapy 6 (7.8%) and 6 homeopathy (7.8%). Conclusions: the prescription of antitussives is common in primary care pediatricians of the Basque Country. Dextromethorphan is the most prescribed medication. The cold is the most common cause for prescribing cough suppressants. OTC antitussive medications seems not be commonly used by families.

Cloperastine is an antitussive drug, which can be received as an over-the-counter cold medicine. The chemical structure of cloperastine is quite similar to that of the antihistamine drug diphenhydramine, which is reported to inhibit hERG K+ channels and clinically induce long QT syndrome after overdose. To analyze its proarrhythmic potential, we compared effects of cloperastine and diphenhydramine on the hERG K+ channels expressed in HEK293 cells. We further assessed their effects on the halothane-anesthetized guinea-pig heart under the monitoring of monophasic action potential (MAP) of the ventricle. Cloperastine inhibited the hERG K+ currents in a concentration-dependent manner with an IC50 value of 0.027 μM, whose potency was 100 times greater than that of diphenhydramine (IC50; 2.7 μM). In the anesthetized guinea pigs, cloperastine at a therapeutic dose of 1 mg/kg prolonged the QT interval and MAP duration without affecting PR interval or QRS width. Diphenhydramine at a therapeutic dose of 10 mg/kg prolonged the QT interval and MAP duration together with increase in PR interval and QRS width. The present results suggest that cloperastine may be categorized as a QT-prolonging drug that possibly induces arrhythmia at overdoses like diphenhydramine does. Keywords:: cloperastine, antitussive drug, hERG K+ channel, QT interval, monophasic action potential

Notwithstanding their key roles in therapy and as biological probes, 7% of approved drugs are purported to have no known primary target, and up to 18% lack a well-defined mechanism of action. Using a chemoinformatics approach, we sought to “de-orphanize” drugs that lack primary targets. Surprisingly, targets could be easily predicted for many: Whereas these targets were not known to us nor to the common databases, most could be confirmed by literature search, leaving only 13 Food and Drug Administration—approved drugs with unknown targets; the number of drugs without molecular targets likely is far fewer than reported. The number of worldwide drugs without reasonable molecular targets similarly dropped, from 352 (25%) to 44 (4%). Nevertheless, there remained at least seven drugs for which reasonable mechanism-of-action targets were unknown but could be predicted, including the antitussives clemastine, cloperastine, and nepinalone; the antiemetic benzquinamide; the muscle relaxant cyclobenzaprine; the analgesic nefopam; and the immunomodulator lobenzarit. For each, predicted targets were confirmed experimentally, with affinities within their physiological concentration ranges. Turning this question on its head, we next asked which drugs were specific enough to act as chemical probes. Over 100 drugs met the standard criteria for probes, and 40 did so by more stringent criteria. A chemical information approach to drug-target association can guide therapeutic development and reveal applications to probe biology, a focus of much current interest.

Maria Antonietta Catania1, Salvatore Cuzzocrea1,21Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina; 2IRCCS Centro Neurolesi “Bonino-Pulejo”, Messina, ItalyAbstract: Cough constitutes an impressive expression of the normal defense mechanisms of the respiratory system. Productive cough associated with catarrh is an important protective system for the lung because it favors the upward movement of secretions and foreign bodies to the larynx and mouth. Cough may also appear without bronchial secretions, as dry cough, which may be persistent when inflammatory disease is chronic or when, in the early stages of respiratory disease, bronchial secretions are not yet fluid. Sometimes bronchitis-induced cough does not significantly affect quality of life, whilst in other cases cough may become so intense as to impair daily activities severely, resulting in permanent disability. This type of cough is one of the most frequent reasons for seeking medical advice. The use of cough suppressants may be appropriate for reaching a precise diagnosis and when dry cough is persistent. Cloperastine has been investigated in various types of cough and, unlike codeine, has been shown to possess dual activity. It also acts as a mild bronchorelaxant and has antihistaminic activity, without acting on the central nervous system or the respiratory center. Here we review the preclinical and clinical evidence of the efficacy and tolerability of cloperastine.Keywords: cough, cloperastine, inflammation, bronchitis

Acute dystonic reactions are usually observed after exposure to drugs with antidopaminergic actions. We report on one patient with acute dystonia associated with ingestion of a cloperastine containing syrup, who suffered from schizophrenia but had been neuroleptic-free for 6 months. Cloperastine has antihistaminic properties. We suggest that antihistaminic agents may induce acute dystonia by altering the balance between dopamine and acetylcholine in the striatum.

A comparison of the enantiorecognition ability of linear, neutral polysaccharides was performed on a series of basic drug racemates in acidic running buffer (pH 3.0). Dextrin 20, Dextran 70 and Pullulan were chosen as chiral selectors for their different characteristics. Dextrin 20, high-dextrose equivalent maltodextrin, showed good enantioresolution for a limited number of racemic drugs. In contrast, Dextran 70, a low-equivalent dextrose polysaccharide, exhibited poorer enantioresolution but had wider applicability allowing nine basic racemates to be resolved; in particular, at high concentrations enantioseparation of amphetamine and congeners was achieved in relatively short time. The results obtained appear to support different mechanisms of enantiorecognition for the polysaccharides studied.

Capillary electrophoresis has been used for the enantiomeric resolution of several basic compounds of pharmaceutical interest employing a background electrolyte containing pepsin as chiral selector. The separations have been performed in a polyacrylamide-coated capillary to suppress or minimize the electroosmotic flow as well as the adsorption on the wall. The chiral selector filled only part of the capillary, moving in the opposite direction of analytes and keeping the detector cell free of the strong absorbing protein. The effect of pepsin concentration, pH, and concentration of the background electrolyte on resolution of enantiomers was studied. Enantiomeric resolution was achieved for trimipramine, propranolol, promethazine, verapamil, cloperastine, oxprenolol, and pindolol. © 1997 John Wiley & Sons, Inc. J Micro Sep9: 9–14, 1997