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PubMed1989

[Behavior of chlorpheniramine in vivo after administration of d- and l-chlorpheniramine maleate].

A high performance liquid chromatographic (HPLC) method was developed for the determination of chlorpheniramine (I) in the plasma. By this method, 1 ng of I could be measured. Plasma levels of I were determined by the HPLC method after oral administration of d-chlorpheniramine maleate (II) or l-chlorpheniramine maleate (III) to healthy subjects and dogs. Plasma levels of I brought about by oral administration of II were evidently higher than those by III both in humans and dogs. On the other hand, there was no difference in plasma levels of I when II or III was injected intravenously into dogs. Therefore, it was considered that the discrepancy in plasma levels of I after oral administration of II and III to dogs was neither due to a difference in elimination rate nor a distribution volume but rather in first-pass effect in absorption process. The result observed in the human study could be also explained in the same way as that in dogs.

Administration, Oral↗
PubMed1996

[Quantitative analysis of chlorpheniramine maleate in cough and cold drugs by ion-pair high-performance liquid chromatography for the simultaneous determination of chlorpheniramine and maleate].

A simple, rapid and convenient chromatographic method, which permits the simultaneous determination of chlorpheniramine (CP) and maleate (MA), recently developed by the authors was applied to the analysis of chlorpheniramine maleate (CPM) in cough and cold drugs. In this method, a Capcell Pak C8 column and an isocratic mobile phase containing 15% methanol, 50 mM KH2PO4 and 5mM tetra-n-butylammonium phosphate as an ion-pair reagent were used. By using the mobile phase adjusted to pH 3.0 with orthophosphoric acid, fumaric acid, MA, CP, acetaminophen (paracetamol), caffeine, and m- and p-hydroxybenzoic acid as candidates for an internal standard were eluted separately within 17 min. Detection was carried out with UV detector at 215 nm. Under the same conditions, five other antihistamines analogous to CPM were also separated. The calibration graphs for CP and MA showed good linearity in the range of 0.5-10 nmol (0.195-3.9 micrograms) per 20 microliters injection, respectively. The proposed method was successfully applied to the simultaneous determination of CP and MA, i.e., CPM analysis, in commercial cough and cold drugs which pharmaceutical forms were tablet, granule and syrups.

Antitussive Agents↗
PubMed1979

Chlorpheniramine. I. Rapid quantitative analysis of chlorpheniramine in plasma, saliva and urine by high-performance liquid chromatography.

A method was developed for the rapid quantitative analysis of chlorpheniramine in plasma, saliva and urine using high-performance liquid chromatography. A diethyl ether or hexane extract of the alkalinized biological samples was extracted with dilute acid which was chromatographed on a reversed-phase column using mixtures of acetonitrile and ammonium phosphate buffer as the mobile phase. Ultraviolet absorption at 254 nm was monitored for the detection and brompheniramine was employed as the internal standard for the quantitation. The effects of buffer, pH, and acetonitrile concentration in the mobile phase on the chromatographic separation were investigated. A mobile phase 20% acetonitrile in 0.0075 M phosphate buffer at a flow-rate of 2 ml/min was used for the assays of plasma and saliva samples. A similar mobile phase was used for urine samples. The drug and internal standard were eluted at retention volumes of less than 17 ml. The method can also be used to quantify two metabolites, didesmethyl- and desmethylchlorpheniramine, in the urine. The method can accurately measure chlorpheniramine levels down to 2 ng/ml in plasma or saliva using 1 ml of sample, and should be adequate for biopharmaceutical and pharmacokinetic studies. Various precautions for using the assay are discussed.

Chlorpheniramine↗
PubMed2002

Differential cognitive effects of ebastine and (+)-chlorpheniramine in healthy subjects: correlation between cognitive impairment and plasma drug concentration.

AIMS: It has been widely recognized that classical antihistamines induce sedation as an adverse effect, while second-generation antihistamines have few if any sedative effects. In order to evaluate the sedative properties of ebastine, a second-generation antihistamine, its effect on cognitive performance in healthy subjects was compared with placebo and (+)-chlorpheniramine. METHODS: Twelve healthy male subjects were instructed to perform six types of attention-demanding cognitive tasks, and objective measurements of reaction times and accuracy was made before and after drug administration. Their sleepiness levels were also monitored. Test drugs were ebastine 10 mg, placebo and two doses of (+)-chlorpheniramine 2 mg and 6 mg, as positive controls. Plasma drug concentrations at the end of the study were analysed. RESULTS: After treatments with (+)-chlorpheniramine, the reaction times of the tasks were significantly prolonged (e.g. ratios of after/before dosing: placebo (0.998 +/- 0.113) vs (+)-chlorpheniramine 2 mg (1.103 +/- 0.083; P<0.05) or (+)-chlorpheniramine 6 mg (1.170 +/- 0.139; P<0.001) in a 7 ms visual discrimination time task) and the accuracy was significantly decreased (e.g. ratios: placebo (1.038 +/- 0.158) vs (+)-chlorpheniramine 2 mg (0.792 +/- 0.202; P<0.01) or (+)-chlorpheniramine 6 mg (0.837 +/- 0.222; P<0.05) in a 7 ms task). On the other hand, performance was not affected by ebastine or placebo treatment (e.g. ebastine 10 mg (reaction time ratio; 1.014 +/- 0.067 and accuracy ratio; 0.990 +/- 0.146) in a 7 ms task). Subjective sleepiness was also not affected by ebastine but (+)-chlorpheniramine significantly increased sedation. With respect to the relationship between plasma drug concentrations and task performance, the latter deteriorated with an increase in plasma (+)-chlorpheniramine concentration (e.g. r=0.439 (P=0.007) in a 5 ms and r = 0.352 (P=0.039) in a 7 ms task), but it did not correlate with the plasma concentration of carebastine, an active metabolite of ebastine. CONCLUSIONS: Ebastine 10 mg did not cause any cognitive impairment or subjective sleepiness. On the other hand, (+)-chlorpheniramine impaired cognitive function and induced sleepiness even at 2 mg, the recommended dose in over-the-counter medication. In addition, impaired CNS performance was significantly correlated with plasma (+)-chlorpheniramine concentration.

Administration, Oral↗
PubMed1986

NTP Toxicology and Carcinogenesis Studies of Chlorpheniramine Maleate (CAS No. 113-92-8) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

Toxicology and carcinogenesis studies of chlorpheniramine maleate (99% pure), a widely used antihistaminic drug in human and veterinary medicine, were conducted by administering this chemical in deionized water by gavage to groups of 50 male and 50 female F344/N rats and B6C3F1 mice, 5 days per week for 103 weeks. The doses used were: male rats-- 0, 15, or 30 mg/kg; female rats-- 0, 30, or 60 mg/kg; male mice-- 0, 25, or 50 mg/kg; female mice-- 0, 100, or 200 mg/kg. The selection of these doses was based largely on data from 14-day or 16-day studies and 13-week studies in which reduced body weight gain and reduced survival occurred at higher doses. Doses used in the 2-week studies ranged from 40 to 640 mg/kg in rats and 25 to 800 mg/kg in mice; in the 13-week studies, doses ranged from 3.75 to 60 mg/kg in rats and 12.5 to 200 mg/kg in mice. The recommended human adult daily oral dose of chlorpheniramine maleate is up to 0.32 mg/kg. Doses originally selected for male mice in the 2-year study were 0, 100, or 200 mg/kg; however, because of poor survival, that study was stopped and a new study was started at doses of 0, 25, or 50 mg/kg. At the termination of the study (week 104), survival of high dose female rats (6/50) and high dose male mice (15/50) was lower than that of the vehicle controls (29/50 and 39/50, respectively). Survival of all other dosed groups was comparable to that of respective vehicle control groups. Mean body weights of dosed rats were about 10%-15% (male) or about 10%-25% (female) lower than those of vehicle controls; mean body weights of female mice were generally 20%-35% lower than those of vehicle controls. No compound-related gross or microscopic pathologic effects were observed in either species in the 16-day or 13-week studies. Hyperactivity and hyperexcitability associated with dosing were frequently noted in the 13-week and 2-year studies. There were no significant positive trends or increases in the incidences of neoplasms in either male or female rats dosed with chlorpheniramine maleate for 103 weeks. Marginal increases in the incidences of adrenal gland capsule adenomas in male mice (vehicle control, 2/50; low dose, 7/49; high dose, 4/49) were not considered to be compound related, since there was not a corresponding increase in the incidence of adrenal gland capsule hyperplasia (46/50; 33/49; 22/49). A positive trend was seen for subcutaneous tissue tumors in male mice (4/50; 5/49; 8/50); this marginal effect was not considered to be compound related. The incidences of thyroid gland follicular cell cysts (2/48; 10/49; 13/47), thyroid gland follicular cell hyperplasia (3/48; 29/49; 36/47), and thyroid gland follicular cell adenomas (0/48; 4/49; 2/47) were greater in dosed female mice than in vehicle controls. This finding is toxicologically important,since thyroid gland neoplasms are uncommon in mice and are often preceded by hyperplasia of the follicular epithelium. The major route of excretion of chlorpheniramine or its metabolites is in the urine. In male F344 rats orally administered 14C-chlorpheniramine maleate at doses of 2 or 20 mg/kg, there was essentially no difference in the percentage of urinary or fecal excretion of radioactivity between these dose levels. Chlorpheniramine maleate was not mutagenic to Salmonella strains TA98, TA100, TA1535, or T1537 in the presence or absence of S9 metabolic activation systems prepared from the liver of Aroclor 1254-treated male Sprague-Dawley rats or male Syrian hamsters. Chlorpheniramine maleate did not induce forward mutations at the TK locus of L5178Y mouse lymphoma cells with or without metabolic activation. In Chinese hamster ovary cells in culture, chlorpheniramine maleate induced a weak but reproducible increase in sister-chromatid exchanges in the absence of exogenous metabolic activation. Chromosomal aberrations were induced at the highest dose tested but only in the presence of S9 from Aroclor 1254-induced Sprague-Dawley male rat liver. An audit of the experimental data was conducted for these 2-year carcinogenesis studies on chlorpher these 2-year carcinogenesis studies on chlorpheniramine maleate. No data discrepancies were found that influenced the final interpretations. Under the conditions of these 2-year gavage studies, there was no evidence of carcinogenicity for F344/N rats or B6C3F1 mice of either sex administered chlorpheniramine maleate in deionized water, 5 days per week for 2 years. Due to high mortality in high dose female rats and high dose male mice, the sensitivity of these groups to detect a carcinogenic response was reduced. Chlorpheniramine maleate had a proliferative effect in the thyroid gland of female mice, as shown by the increased incidences of follicular cell cysts and hyperplasia in both low dose and high dose groups. Synonyms: 2-p-chloro-a-(2-dimethylaminoethyl) benzyl]pyridine maleate; 2-Pyridinepropanamine; gamma-[4-chlorophenyl]-N,N-dimethyl-[z]-2-butenedioate Trade Names: Allerclor; Allergisan; Antagonate; Chlormene; Chlorprophenpyridamine maleate; Chlor-Trimeton; Chlor-Tripolon; Chloropiril; C-Meton; Histadur; Histaspan; Lorphen; M.P. Chlorcaps T.D.; Piriton; Pyridamal-100; Teldrin

Journal Article↗
PubMed2002

The roles of CYP2D6 and stereoselectivity in the clinical pharmacokinetics of chlorpheniramine.

AIMS: To examine the stereoselective disposition of chlorpheniramine and to evaluate the role of CYP2D6 in chlorpheniramine pharmacokinetics in humans. METHODS: Eight healthy volunteers (six extensive metabolizers with respect to CYP2D6 and two poor metabolizers) received a single 8 mg oral dose of rac-chlorpheniramine either given alone or following administration of quinidine 50 mg every 6 h for 2 days prior to the study day and every 6 h thereafter until the end of the study. Plasma concentrations of (S)-(+)- and (R)-(-)-enantiomers of chlorpheniramine were determined using liquid chromatography/mass spectrometry. RESULTS: In extensive metabolizers, mean Cmax was greater (12.55+/-1.51 ng ml-1vs 5.38+/-0.44 ng ml-1) and CLoral was lower (0.49+/-0.08 l h-1 kg-1vs 1.07+/-0.15 l h-1 kg-1) for (S)-(+)- than for (R)-(-)-chlorpheniramine (P<0.005). For (S)-(+)-chlorpheniramine, administration of quinidine, an inhibitor of CYP2D6, resulted in an increase in Cmax to 13.94+/-1.51 (P<0.01), a reduction in CLoral to 0.22+/-0.03 l h-1 kg-1 (P<0.01), and a prolongation of elimination half-life from 18.0+/-2.0 h to 29.3+/-2.0 h (P<0.001). Administration of quinidine decreased CLoral for (R)-(-)-chlorpheniramine to 0.60+/-0.10 l h-1 kg-1 (P<0.005). In CYP2D6 poor metabolizers, systemic exposure was greater after chlorpheniramine alone than in extensive metabolizers, and administration of quinidine resulted in a slight increase in CLoral. CONCLUSIONS: Stereoselective elimination of chlorpheniramine occurs in humans, with the most pharmacologically active (S)-(+)-enantiomer cleared more slowly than the (R)-(-)-enantiomer. CYP2D6 plays a role in the metabolism of chlorpheniramine in humans.

Adult↗
PubMed1997

Stereoselective N-demethylation of chlorpheniramine by rat-liver microsomes and the involvement of cytochrome P450 isozymes.

Previous studies have suggested that degradation of the two stereoisomers of chlorpheniramine in the liver might be catalysed by different types of cytochrome P450. Stereoselective N-demethylation of chlorpheniramine and the involvement of cytochrome P450 (CYP) isozymes have, therefore, been investigated in the liver microsomes of eight-week-old male rats. Incubation of racemic chlorpheniramine with liver microsomes from the male rat resulted in the formation of both enantiomers of monodesmethylchlorpheniramine (DMChp). Further metabolism of DMChp to didesmethylchlorpheniramine (DDMChp) did not, however, occur. The S/R enantiomeric ratio for intrinsic clearance (Vmax/Km) was approximately 2.0, suggesting that the N-demethylation was stereoselective for S-(+)-chlorpheniramine. On the other hand, although the Vmax/Km value for the formation of S-(+)- and R-(-)-DMChp increased with phenobarbitone-inducible rat-liver microsomes, there was no difference between the rates of N-demethylation of the enantiomers. In contrast, 3-methylcholanthrene reduced the intrinsic clearance of S-(+)-chlorpheniramine by N-demethylation and increased its value for R-(-)-chlorpheniramine, showing no stereoselectivity for the N-demethylation of chlorpheniramine. The difference between the intrinsic clearance of the two enantiomers by N-demethylation was because of differences in affinity for the catalysing enzyme. This is indicative of stereoselective involvement of the main enzyme concerned in the N-demethylation of the enantiomers, considered to be CYP 2C11. Anti-CYP 2C11 also partially inhibited the N-demethylation of racemic chlorpheniramine in rat-liver microsomes exposed to phenobarbitone and 3-methylcholanthrene. That CYP 2B1 was involved in the N-demethylation of both enantiomers was also supported by results from an experiment using phenobarbitone-inducible rat-liver microsomes. CYP1A1 did not, however, catalyse the N-demethylation of either enantiomer. These results indicate that N-demethylation of the S-(+)-enantiomer of chlorpheniramine occurs preferentially in the microsomes, demonstrating the stereoselective contribution of CYP2C11. Immunoinhibition studies suggest, moreover, that the N-demethylation of both chlorpheniramine enantiomers is catalysed by CYP2B1, but not by CYP1A1.

Animals↗
PubMed1992

Potentiation of 5-hydroxytryptamine-induced contraction in rat aorta by chlorpheniramine, citalopram and fluoxetine.

This study examined the effects of chlorpheniramine, citalopram and fluoxetine on 5-hydroxytryptamine (5-HT)-induced contraction and 5-HT uptake in rat thoracic aortic rings in vitro. Chlorpheniramine and citalopram markedly potentiated 5-HT-induced contraction. Potentiation by fluoxetine was less pronounced. Chlorpheniramine (0.01-1 microM) and citalopram (0.1-1 microM) induced concentration-dependent parallel shifts to the left of the 5-HT concentration-response curves. The potentiation by chlorpheniramine was selective as chlorpheniramine (1 microM) did not potentiate phenylephrine-induced contraction. The potentiation did not depend upon the presence of endothelium, and was not related to H1 receptor antagonism as diphenhydramine and pyrilamine (1 microM) did not similarly enhance 5-HT-induced contractions. Whereas cocaine (1-10 microM) similarly potentiated 5-HT-induced contraction, imipramine (1-10 microM) inhibited, rather than enhanced, contraction elicited by 5-HT. In the presence of 10 microM cocaine, maximally effective concentrations of chlorpheniramine (1 microM) or citalopram (100 nM) did not induce any additional potentiation of 5-HT-induced contraction. Cooling (4 degrees C) markedly inhibited uptake of [3H]5-HT in rings with and without endothelium. Although less marked, imipramine (10 microM), cocaine (1 microM), chlorpheniramine (1 microM) and citalopram (100 nM) inhibited [3H]5-HT uptake in endothelium-intact and endothelium-denuded rings. Fluoxetine also inhibited [3H]5-HT uptake, but the inhibition was only statistically significant in endothelium-intact rings. The monoamine oxidase (MAO) inhibitor, pargyline (10-100 microM), did not significantly affect 5-HT-induced contraction. The results demonstrate that chlorpheniramine, citalopram and to a lesser extent, fluoxetine potentiate 5-HT-induced contraction in rat aorta in which neuronal 5-HT uptake is negligible. The data are consistent with inhibition of non-neuronal 5-HT uptake as at least one mechanism responsible for potentiation of 5-HT-induced contraction in rat aorta by chlorpheniramine, citalopram and fluoxetine.

Animals↗
PubMed1977

Bronchodilating activity of an H1 blocker, chlorpheniramine.

The purpose of this study was to test the hypothesis that chlorpheniramine (CP), and H1 blocker, can cause bronchodilatation if administered intravenously (iv) and in higher doses than those currently prescribed. In 10 subjects with allergic asthma, forced expiratory flows (FEF) were recorded on different days, at comparable baseline values, before and up to 5 hr after administration of 8 mg per os (po) chlorpheniramine, 10 mg iv CP (repeated twice), 5.5 mg/kg iv aminophylline, and 30 mg po butabarbital as well as during a day without drug. Chlorpheniramine administered intravenously produced reproducible increases (+ delta) in FEF, starting at 15 min, peaking at 120 min, and still persisting at 5 hr; the peak + delta averaged 15% for FEV1 and 27% to 53% for flows at low lung volume. FEF showed a comparable + delta after aminophylline, a smaller + delta after orally administered chlorpheniramine and no significant + delta during butabarbital or control sessions. The ratio change over time/variability was higher for FEV1, FEF50%, and FEF25%-75% than for the remaining parameters. In six subjects a double-blind study (chlorpheniramine vs. saline solution) confirmed the effectiveness of the doses administered in the open study. In three subjects, 10 mg iv chlorpheniramine was given at four different baseline values; the highest + delta occurred when the basal FEV1 was approximately 50% of the predicted value and the basal FEF at low lung volume 30% to 40% of the predicted value. In two subjects, log dose-response curves to 2.5, 5.0, and 10.0 mg iv chlorpheniramine were obtained by using FEV1, FEF50%, and FEF25%-75%. Thus chlorpheniramine in high iv doses can dilate the bronchi, the + delta FEF depending on the dose, the percent of the predicted basal FEF value, and "individual" responsiveness. Withing the dose range used, bronchodilatation to chlorpheniramine and aminophylline administered intravenously was best detected by FEV1, FEF50%, and FEF25%-75%.

Aminophylline↗
PubMedDate not supplied

Enhanced efficacy of chloroquine-chlorpheniramine combination in acute uncomplicated falciparum malaria in children.

Chlorpheniramine, a histamine H1 receptor antagonist, reverse chloroquine resistance in Plasmodium falciparum in vitro. However, the clinical significance of this remains unclear. We have evaluated the efficacy of chloroquine and a chloroquine-chlorpheniramine combination in 112 consecutive children with acute symptomatic uncomplicated falciparum malaria. There was no significant difference in the parasite and fever clearance times in the 2 treatment groups. However, the proportion of patients in whom parasitaemia increased 24 h after commencement of treatment was significantly higher in the chloroquine group than in the chloroquine-chlorpheniramine group (28.5% vs. 8.3%, chi 2 = 6.61, P < 0.01). There was also a higher proportion of children with RII and RIII responses to treatment in the chloroquine than in the chloroquine-chlorpheniramine group but the difference was not statistically significant. The cure rate on day 14 was higher in the chloroquine-chlorpheniramine group than in the chloroquine group. Chloroquine and its combination with chlorpheniramine were well tolerated, the only prominent adverse effect being pruritus, with equal incidence in both groups. Chlorpheniramine reversed chloroquine resistance in vitro in a similar manner to verapamil in isolates of P. falciparum obtained from the patients. Failure of a response in vivo to chloroquine correlated with resistance in vitro in patients treated with this drug. In contrast, all but one patient with isolates which were chloroquine resistant in vitro were successfully treated with chloroquine-chlorpheniramine combination. These data suggest the enhanced efficacy of chloroquine-chlorpheniramine combination in treating acute uncomplicated P. falciparum infection in children from an endemic area of Nigeria.

Acute Disease↗
PubMed1990

Is blockade of conditioned flavor aversions by chlorpheniramine the result of state dependency?

Conditioned flavor aversions induced by pairing flavored fluids with ionizing irradiation, lithium chloride, estrogen, or centrifugal rotation have been blocked by prior administration of chlorpheniramine. The blockade may be due to state dependency. This possibility was evaluated in the present experiment, which assigned female Long-Evans rats to a factorial combination of chlorpheniramine (20 mg/kg) vs saline during training, centrifugal rotation (150 rpm for 15 min) vs none as an UCS, and chlorpheniramine vs saline in testing. Rats conditioned with saline and rotation showed strong aversions when tested with either same or chlorpheniramine. Rats conditioned with chlorpheniramine and rotation showed no change during conditioning; when tested with saline they showed no aversion, and when tested with chlorpheniramine they showed no change from conditioning. Rats conditioned with either chlorpheniramine or saline and no rotation showed high fluid intake when tested with saline and reduced fluid intake when tested with chlorpheniramine. The results were interpreted as offering little support for state dependency.

Animals↗
PubMed2006

Chlorpheniramine, selective serotonin-reuptake inhibitors (SSRIs) and over-the-counter (OTC) treatment.

Some old antihistamines were selective serotonin-reuptake inhibitors (SSRIs) and the SSRI effect was discovered by Nobel Laureate Professor Arvid Carlsson as early as 1969. Chlorpheniramine was the most active of the tested drugs, and it compares favourably with amitriptyline and imipramine with respect to actions on both serotonergic and noradrenergic neurons. Chlorpheniramine can be called a SSRI, since the blocking of 5HT is stronger than the effect on noradrenaline neurons; however it might also be called a selective serotonin and noradrenaline reuptake inhibitor (SSNRI) and be compared with new drugs, such as venlafaxine. Carlsson suggested the potential value of clinical studies of the antidepressant properties of this and related antihistamine drugs. But, in the event, no such trials were ever performed at the time. However, later clinical observations of the benefits of dex-chlorpheniramine treatment in panic disorder have been published. Clinical experience suggests that patients using chlorpheniramine, and having also a concomitant depression or panic disorder, may experience a return of symptoms when their old drug is changed to a new antihistamine lacking SSRI effects. Yet this phenomenon is not known to many doctors, and even less known to the large number of patients buying chlorpheniramine under various trade names over-the-counter (OTC) at a low price for self-treatment of hay fewer or as a cold remedy. Chlorpheniramine was introduced in USA under the name Chlor-Trimeton as long ago as July 1950, and is still on the market. Therefore, this SSRI is now over 50 years old. If chlorpheniramine had been tested in depression in the nineteen seventies, it is probable that a safe, inexpensive SSRI drug could have been used some 15 years earlier than fluoxetine - which became available in 1987. Chlorpheniramine might have been the first safe, non-cardiotoxic and well-tolerated antidepressant. Billions of dollars in the development and marketing costs would have been saved, and the suffering of millions of patients alleviated.

Chlorpheniramine↗
PubMed2001

Neuroimaging of histamine H1-receptor occupancy in human brain by positron emission tomography (PET): a comparative study of ebastine, a second-generation antihistamine, and (+)-chlorpheniramine, a classical antihistamine.

AIMS: Sedation induced by antihistamines is widely recognized to be caused by their penetration through the blood-brain-barrier and the consequent occupation of brain histamine H1-receptors. We previously studied the mechanism of sedation caused by antihistamines using positron emission tomography (PET). Recently, we revealed the nonsedative characteristic of ebastine, a second-generation antihistamine, with cognitive performance tests. In the present study, H1-receptor occupation by ebastine was examined in the human brain using PET. METHODS: Ebastine 10 mg and (+)-chlorpheniramine 2 or 6 mg were orally given to healthy male volunteers. PET scans with [11C]-doxepin, a potent H1-receptor antagonist, were conducted near tmax of respective drugs. Other volunteers in the control group also received PET scans. The binding potential of doxepin (BP = Bmax/Kd) for available brain H1-receptors was imaged on a voxel-by-voxel basis through graphical analysis. By setting regions of interest, the H1-receptor occupancy of drugs was calculated in several H1-receptor rich regions. RESULTS: Brain distribution of radioactivity after ebastine treatment was similar to that without any drugs. However, after the oral administration of 2 mg (+)-chlorpheniramine, the level was lower than after ebastine and nondrug treatments. Graphical analysis followed by statistical parametric mapping (SPM96) revealed that H1-receptor rich regions such as cortices, cingulate gyrus and thalamus were regions where the BPs after ebastine were significantly higher than after (+)-chlorpheniramine (2 mg). H1-receptor occupancies in cortex were approximately 10% by ebastine and > or = 50% by either dose of (+)-chlorpheniramine (95% confidence interval for difference in the mean receptor occupancies: 27%, 54% for 2 mg and 35%, 62% for 6 mg vs ebastine, respectively). Receptor occupancies increased with increasing plasma concentration of (+)-chlorpheniramine, but not with concentration of carebastine, an active metabolite of ebastine. CONCLUSIONS: Ebastine (10 mg orally) causes brain histamine H1-receptor occupation of approximately 10%, consistent with its lower incidence of sedative effect, whereas (+)-chlorpheniramine occupied about 50% of brain H1-receptors even at a low but sedative dose of 2 mg; occupancy of (+)-chlorpheniramine was correlated with plasma (+)-chlorpheniramine concentration.

Adult↗
PubMed2006

[Simultaneous determination of ephedrine and chlorpheniramine in human plasma by a highly sensitive liquid chromatography-tandem mass spectrometric method].

AIM: To develop and validate a liquid chromatography-tandem mass spectrometric (LC/MS/MS) method for the simultaneous quantification of ephedrine and chlorpheniramine in human plasma after oral administration of a compound preparation. METHODS: The analytes and the internal standard, diphenhydramine, were isolated from plasma by protein precipitation with methanol, then chromatographied on a Zorbax SB-C18 column (150 mm x 4.6 mm ID) using a mobile phase consisted of methanol-water-formic acid (80: 20: 0.5, v/v), at a flow rate of 0.5 mL x min(-1). A tandem mass spectrometer equipped with electrospray ionization source was used as detector and was operated in the positive ion mode. Selected reaction monitoring (SRM) using the precursor to produce ion combinations of m/z 166-->115, m/z 275-->230 and m/z 256-->167 were used to quantify ephedrine, chlorpheniramine and the internal standard, respectively. Results The linear concentration ranges of the calibration curves for ephedrine and chlorpheniramine were 0.50 - 200 microg x L(-1) and 0.050 - 20.0 microg x L(-1), respectively. The lower limits of quantification were 0. 50 microg x L(-1) for ephedrine and 0.050 microg x L(-1) for chlorpheniramine, individually. The intra- and inter-day relative standard deviation (RSD) across three validation runs over the entire concentration range was less than 9.3% for both ephedrine and chlorpheniramine. The inter-day accuracy (RE) was within +/- 3.4% for the analytes. Each sample was chromatographied within 3.3 min. The method was successfully used in pharmacokinetics study of ephedrine and chlorpheniramine in human plasma after oral administration of a compound preparation containing 5 mg ephedrine hydrochloride, 1 mg chlorpheniramine maleate, 50 mg phenytoin, 12.5 mg theophylline, 12.5 mg theobromine and 7.5 mg caffeine. No interaction among the six components was observed on their pharmacokinetic parameters. CONCLUSION: The method was proved to be highly sensitive, selective, and suitable for pharmacokinetics investigations of different compound preparations containing low dosage of both ephedrine and chlorpheniramine.

Administration, Oral↗
PubMed1987

Chronic chlorpheniramine therapy: subsensitivity, drug metabolism, and compliance.

To investigate whether patients develop true subsensitivity to antihistamines during chronic therapy, we studied 14 adult subjects who received chlorpheniramine for 3-day and 3-week trials of therapy. Titrated skin tests to histamine and compound 48/80, chlorpheniramine blood levels (by HPLC), compliance, and side effects were monitored and compared during the two courses of therapy and their respective 72-hour washout periods. We found a significant correlation between chlorpheniramine blood levels and skin test suppression during both the 3-day and 3-week therapies. The 3-day chlorpheniramine therapy was more clinically effective (measured by skin test suppression corrected for serum chlorpheniramine concentration) than the 3-week therapy (P less than .01). Chlorpheniramine serum half-lives and 2-hour chlorpheniramine blood levels were not significantly different after the 3-day and 3-week trials. Compliance was significantly worse (P less than .01) during 3-week therapy. Medication side effects (particularly drowsiness) were frequently reported during both courses of therapy. We conclude that subsensitivity to chlorpheniramine does develop in adult patients receiving 3 weeks of therapy. This subsensitivity is not explained by changes in drug metabolism. In addition to subsensitivity, poor compliance may contribute to sub-therapeutic results during chronic antihistamine therapy. Side effects from antihistamines may also require individualization of therapy for certain patients.

Adult↗
PubMed1980

Evaluation of sustained-action chlorpheniramine-pseudoephedrine dosage form in humans.

This investigation compared the bioavailability of chlorpheniramine and pseudoephedrine from a sustained-action capsule and a combination of two reference standard tablets in 24 normal human subjects. The capsule contained 8 mg of chlorpheniramine maleate and 120 mg of pseudoephedrine hydrochloride, and the tablets each contained half of the amount of the chlorpheniramine or pseudoephedrine in the capsule. Because the capsule was a combination product, a new study design had to be developed to accommodate steady-state conditions for both drugs. Each subject received the capsule (every 12 hr) and the combination of the reference tablets (every 6 hr) for 8 days according to a two-way crossover design. Serial blood and urine samples were taken during the entire study. Plasma and urine samples were assayed for chlorpheniramine and pseudoephedrine by sensitive and specific high-pressure liquid chromatographic or GLC methods. There were no significant differences in the plasma concentration profiles of chlorpheniramine and pseudoephedrine at all times, except when the capsule developed peaks or the tablets developed nadirs. The highest mean peak plasma concentrations for the capsule and the tablets were 38.7 and 32.9 ng of chlorpheniramine/,ml and 525 and 515 ng of pseudoephedrine/ml, respectively. The mean biological half-lives of chlorpheniramine and pseudoephedrine were 21.6 and 8.0 hr, respectively. The AUC and unchanged drug excreted in urine, after a single dose and at steady state, showed that the sustained-action capsule (given every 12 hr) and the reference standard tablets (given every 6 hr) were bioequivalent.

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