Simultaneous determination of paracetamol, dextromethorphan, chlorpheniramine, pseudoephedrine and major impurities of paracetamol and pseudoephedrine by using capillary electrophoresis

Abstract A capillary electrophoresis method was developed for the first time and optimized for the determination of paracetamol, pseudoephedrine, dextromethorphan, chlorpheniramine, 4-aminophenol and ephedrine in tablet formulation. Optimum electrophoretic conditions were achieved by using a background electrolyte of 75 mmol L-1 sodium borate buffer at pH 8.0, a capillary temperature of 30°C, a separation voltage of 30 kV and a pressure injection of the sample at 50 mbar for 10 s. Calibration graphs showed a good linearity with a coefficient of determination (R2) of at least 0.999 for all compounds. Intraday and interday precision (expressed as relative standard deviation (RSD) %) were lower than 1.39% for capillary electrophoresis method. The developed method was demonstrated to be simple and rapid for the determination of paracetamol, pseudoephedrine, dextromethorphan, chlorpheniramine, 4-aminophenol and ephedrine in tablet formulation providing recoveries in the range between 99.62 and 100.57% for all analytes.

Mecamylamine attenuates ephedrine-induced hyperactivity in rats.

Ephedrine is a central nervous system stimulant that has a pharmacological profile similar to amphetamines. Ephedrine induces hyperactivity after acute administration to rats and locomotor sensitization develops to ephedrine with repeated administration. Recent research suggests that nicotinic receptors (nAChRs) play a role in the development of locomotor sensitization to d-amphetamine and the goal of the present study was to determine if nAChRs similarly mediate the effects of ephedrine after acute and repeated drug injection. On 12 consecutive days, rats were pretreated with the nAChR antagonist mecamylamine (0.3-3.0 mg/kg) or saline followed by (-)-ephedrine (10-30 mg/kg) or saline injection and locomotor activity was measured. Ephedrine produced a dose-dependent increase in locomotor activity, and sensitization to ephedrine developed with repeated injection. Mecamylamine pretreatment attenuated the hyperactivity and sensitization produced by repeated, but not acute, ephedrine (10 mg/kg) injection. The inhibitory effect of mecamylamine was overcome at the higher ephedrine dose (30 mg/kg). The present results indicate that nAChRs play a mediating role in the development of locomotor sensitization to ephedrine.

Discriminative stimulus effects of (-)-ephedrine in rats: analysis with catecholamine transporter and receptor ligands.

A drug discrimination procedure was used to examine the neuropharmacology of (-)-ephedrine (5 mg/kg), a sympathomimetic amine found in a variety of dietary supplements. (-)-Ephedrine has caused concern because of its use as a precursor in the manufacture of street drugs (e.g. methamphetamine) and its potential for abuse and toxicity. In the present study, the catecholamine reuptake inhibitors mazindol and nomifensine, the norepinephrine (NE) reuptake inhibitor desipramine, and the dopamine D(2)-like (e.g. D(2), D(3) and D(4)) agonist quinpirole substituted for (-)-ephedrine (>/=80% (-)-ephedrine-lever responding). The NE reuptake inhibitor nisoxetine, the D(1)-like (e.g. D(1) and D(5)) agonists (+/-)-SKF 38393 and SKF 82958, and the mixed D(1)-/D(2)-like agonist apomorphine occasioned intermediate levels of responding (50-79% (-)-ephedrine-lever responding). The (-)-ephedrine cue was antagonized by the D(1)-like antagonist SCH 23390 and the alpha(1)-adrenoceptor antagonist prazosin as well as the D(2)-like antagonists (-)-eticlopride and haloperidol, although only at doses that disrupted responding in some rats. The discriminative stimulus effects of a small dose of (-)-ephedrine (1.25 mg/kg) were enhanced by the alpha(2)-adrenoceptor antagonist idazoxan and to a lesser extent by the beta-adrenoceptor antagonist (-)-propranolol. However, the alpha(2)-adrenoceptor agonist clonidine (0.04 mg/kg) did not attenuate the (-)-ephedrine stimulus. These results suggest that D(1)-, D(2)-like, and alpha(1)-adrenergic receptors mediate the discriminative stimulus effects of (-)-ephedrine. Substitution of desipramine for (-)-ephedrine and not for some other stimulants suggests that NE transmission is a prominent feature of the (-)-ephedrine discriminative stimulus, and that NE underlies therapeutic and abuse-related effects of (-)-ephedrine that diverge from those of other stimulants.

Evaluation of the sedative properties of the ethanolic root extract of Cissampelos mucronata.

The ethanolic root extract of Cissampelos mucronata was investigated for sedative activity. Phytochemical analysis indicated the presence of alkaloids: sterols/triterpenes, tannins, carbohydrates, glycosides, and flavonoids. Acute lethality test gave an LD50 of 282.84 mg/kg. The study of the effect of the extract on the behavioural pattern of mice showed changes indicative of central nervous system depression. The results further revealed that the extract progressively reduced ephedrine-induced spontaneous motor activity in rats, and prolonged pentobarbitone-sleeping time in mice. Pre-treatment of mice with the extract also protected 40% of the animals against pentylenetetrazole-induced convulsions. The mechanism of action is not precisely known but may probably be attributed to central nervous system depressant action.

Stimulatory effect of D-ephedrine on beta3-adrenoceptors in adipose tissue of rats.

The effect of ephedrine on beta3-adrenoceptos (beta3-AR) was studied in the isolated adipose tissue of Wistar rat. Incubation with D-ephedrine (0.1-10 microM) induced a concentration-dependent decrease of uptake of [14C]-deoxy-D-glucose into white adipose tissues (WAT). The inhibitory effect of D-ephedrine was potentiated by BRL 37344, the agonist of beta3-AR and concentration-dependently inhibited by SR 59230A, the selective antagonist of beta3-AR. The action of D-ephedrine on beta3-AR was further blocked by the antibodies for beta3-AR, but not the immunoglobulin. in a concentration-dependent manner. Moreover, D-ephedrine increased glycerol release from the isolated brown adipose tissues (BAT) and this action was also abolished by SR 59230A at concentration sufficient to block beta3-AR. Thus, these results suggest that D-ephedrine has the ability to activate beta3-AR both in WAT and BAT of Wistar rats in vitro.

Ephedrine and amphetamine induced pecking in chickens: possible indirect D-1/D-2 dopaminergic mechanism.

The involvement of dopaminergic mechanism in pecking behaviour has been suggested. In the present work, the involvement of D-1/D-2 dopamine receptors in pecking induced by ephedrine and amphetamine in chickens has been studied. Both ephedrine and amphetamine induced pecking in a dose-dependent manner. Pretreatment of animals with D-1 antagonist SCH 23390, D-2 antagonist sulpiride or reserpine decreased the pecking response induced by both drugs. Phenoxybenzamine or propranolol (alpha- or beta-adrenergic blockers, respectively) and the antimuscarinic drug atropine did not decrease the response of these drugs. The results may indicate that the pecking induced by these drugs in chickens are mediated indirectly through D-1/D-2 dopaminergic mechanisms.

[Characteristics of antagonism between ceruletide and various central-acting drugs: investigation by means of ambulatory activity in mice].

Behavioral characteristics of ceruletide, a cholecystokinin-like decapeptide, were investigated by means of ambulatory activity in mice. Ceruletide at 100 and 300 micrograms/kg, i.p. slightly but significantly decreased the mouse's activity for 20 min. Therefore, 100 micrograms/kg of ceruletide was used in the experiment of combined administration with the central-acting drugs. Ceruletide reduced the increased activity which was produced by methamphetamine (2 mg/kg, s.c.), ephedrine (80 mg/kg, i.p.), methylphenidate (4 mg/kg, s.c.), cocaine (20 mg/kg, s.c.), mazindol (2.5 mg/kg, s.c.), apomorphine (0.5 mg/kg, s.c.), bromocriptine (8 mg/kg, i.p.), scopolamine (0.5 mg/kg, s.c.), caffeine (10 mg/kg, s.c.) and morphine (20 mg/kg, s.c.) with different potencies and durations. The mice that had experienced ceruletide at 3 micrograms/kg for 5 times at intervals of 3-4 days demonstrated a significant increase in the sensitivity to methamphetamine, although the same treatment with 10-300 micrograms/kg of ceruletide was without effect. On the other hand, when 3-300 micrograms/kg of ceruletide was combined with 2 mg/kg of methamphetamine, the development of reverse tolerance to the ambulation-increasing effect of methamphetamine was inhibited dependently on the doses of ceruletide. However, the reverse tolerance to methamphetamine once established was scarcely modified by ceruletide when it was administered afterwards.

Anorectic effect of ephedrine.

1. Different doses of ephedrine (3.1-50 mg kg-1) were given intraperitoneally to rats and found to decrease food intake dose-dependently. 2. The anorectic effect of ephedrine was decreased by animal pretreatment with pimozide, but phenoxybenzamine, propranolol and methergoline did not decrease the response. 3. The results show that the anorexia produced by ephedrine may be due to indirect dopaminergic mechanism of the drug.

Dopaminergic agonist properties of ephedrine--theoretical implications.

Reports of ephedrine-induced psychoses resembling amphetamine psychosis prompted studies of this classic sympathomimetic agent in systems that indicate central dopaminergic actions. Ephedrine induced dose-related stereotyped behavior in rats. This behavior was antagonized by haloperidol, but not by alpha- or beta-adrenergic blockers. Pretreatment with AMPT, but not reserpine, attenuated the stereotypy induced by ephedrine under one of two sets of conditions. Consistent prolactin suppression in humans was not seen. These findings are discussed in the context of clinical and pharmacologic data regarding other dopamine agonist drugs (the central nervous system stimulants, apomorphine, ET 495). These data suggest the possibility that synergistic noradrenergic and dopaminergic facilitation may be important in the induction of the stimulant psychoses.

Influence of thymoxamine on changes in pupil diameter and accommodation produced by homatropine and ephedrine.

Local instillation of thymoxamine eye drops (0-1%) completely reversed the mydriasis produced by ephedrine (5%) but not that produced by ephedrine (5%) together with homatropine (0-5%). Small but significant changes in accomodation were found with ephedrine and with thymoxamine, as well as the larger expected changes with homatropine.

Turning behaviour as an index of the action of amphetamines and ephedrines on central dopamine-containing neurones.

1. Rats lesioned unilaterally in the substantia nigra show no obvious abnormalities after recovery from the operation but rotate towards the lesioned side after administration of drugs of the amphetamine and ephedrine groups.2. (+)-Amphetamine and (-)-amphetamine are equally potent in producing turning behaviour but (+)-methylamphetamine is considerably more effective.3. (-)-Ephedrine (with a beta-OH group on the ethylamine side chain) induces turning but only in doses approximately 20 times greater than (+)-methylamphetamine.4. (+)-Norpseudoephedrine was the most effective of the ephedrine isomers tested followed by (-)-ephedrine and (+)-pseudoephedrine.5. Turning produced by (-)-ephedrine and (+)-methylamphetamine is not reduced by FLA63 (50 mg/kg) 4 h previously, but is almost completely inhibited by alpha-methyl-p-tyrosine (150 mg/kg) 12 h previously.6. Reserpine pretreatment potentiates turning produced by (-)-ephedrine.7. Chlorpromazine (5 mg/kg) completely blocks turning induced by (+)-methylamphetamine although it concurrently increases exploratory activity. The level of exploratory activity after the (+)-methylamphetamine-chlorpromazine combination is more than 3 times that attained after saline alone.