Efficacy of Triprolidine in the Treatment of Temporary Sleep Disturbance.

Triprolidine, a first-generation antihistamine for allergic rhinitis, has a shorter half-life and fewer persistent effects relative to other antihistamines and may be useful in the treatment of temporary sleep disturbance. Patients aged ≥18 years old were randomized 1:1:1 to receive either triprolidine 2.5 mg (n = 65), triprolidine 5 mg (n = 66), or placebo (n = 67) on 3 consecutive nights. Sleep disturbance index was monitored via wrist actimeter. Subjective measures were assessed via diary card. Triprolidine 2.5 mg had a significantly lower sleep disturbance index versus placebo on night 1 (P = .02); however, when adjusted for outliers, sleep disturbance index did not significantly differ between either dose of triprolidine versus placebo on night 1. Adjusted sleep disturbance index was significantly lower with triprolidine 2.5 and 5 mg versus placebo on night 3 (P = .0017 and P = .011, respectively) and for the mean of all 3 nights (P = .01 and P = .015, respectively). Sleep latency was significantly improved for triprolidine 2.5 mg versus placebo on nights 2 and 3 and for the mean of all 3 nights and for triprolidine 5 mg versus placebo for the mean of all 3 nights. Subjective measures showed those on both doses of triprolidine felt more refreshed on awakening versus placebo for the mean of all 3 nights, with no increase in daytime sleepiness. The frequency of adverse events was similar across groups. The optimum dose of triprolidine for treatment of temporary sleep disturbance was 2.5 mg. There were improvements in both objective and subjective measures of sleep quality versus placebo, with no safety concerns raised.

Bioavailability of Triprolidine as a Single Agent or in Combination With Pseudoephedrine: A Randomized, Open-Label Crossover Study in Healthy Volunteers.

Antihistamines have been in clinical use for more than 70 years to treat allergic and nonallergic symptoms including relief from cold and flu symptoms. Despite their widespread use, pharmacokinetic (PK) data are sparse for older, first-generation antihistamines. This phase 1 single-center open-label, randomized, single-dose, 3-way crossover trial evaluated the PK profiles of 2 doses of film-coated triprolidine caplets (2.5 and 5 mg) compared with a reference combination tablet (triprolidine 2.5 mg + pseudoephedrine 60 mg) in 24 healthy adults. Blood samples were collected predose and at specified intervals across a 24-hour period after administration, and triprolidine was quantified using liquid chromatography-tandem mass spectrometry. Maximum plasma concentration of triprolidine for the 2.5 mg and dose-normalized 5 mg single-agent tablets were comparable (8.4 versus 7.1 ng/mL, respectively) and higher for the combination tablet (9.5 ng/mL). PK parameters, including time to maximum plasma concentration (∼1.5 hours) and elimination half-life (∼4 hours), were comparable between the 3 treatment arms. The safety profile of this sedating antihistamine was as expected; however, adverse effects were reported in a markedly higher proportion of women than men. There were no significant sex differences in any of the measured PK parameters.

Cocaine-like neurochemical effects of antihistaminic medications.

The pattern of activation of dopamine (DA) neurotransmission in the nucleus accumbens (NAc) of rats produced by H(1) histamine antagonists which have behavioral effects like those of psychostimulant drugs was examined. Diphenhydramine and (+)-chlorpheniramine were compared with triprolidine, a potent and selective H(1) antagonist and (-)-chlorpheniramine which is less active than its enantiomer at H(1) receptors. Affinities of the drugs to DA, serotonin, and norepinephrine transporters at H(1) receptors and potencies for DA uptake inhibition in striatal synaptosomes were determined to assess mechanisms by which the compounds increased DA levels. Intravenous diphenhydramine (1.0-3.0 mg/kg) (+)- and (-)-chlorpheniramine (1.0-5.6 mg/kg) but not triprolidine (1.0-3.0 mg/kg) elicited a cocaine-like pattern of stimulation of DA transmission with larger effects in the NAc shell than core. The absence of stereospecific effects with chlorpheniramine enantiomers along with the lack of an effect with triprolidine suggest that the effects on DA transmission were not related to H(1) receptor antagonism. Although in vivo potencies were not directly related to DA transporter affinities, it is hypothesized that actions at that site modulated by other actions, possibly those at the serotonin transporter, are primarily responsible for the neurochemical actions of the drugs on DA neurotransmission and might underlie the occasional misuse of these medications.

The acute effects of acrivastine (BW825C), a new antihistamine, compared with triprolidine on measures of central nervous system performance and subjective effects.

The new H1-antagonist acrivastine (BW825C) in doses of 4, 8, and 16 mg was compared with triprolidine HCl (2.5 and 5 mg) in a double-blind crossover study in 12 subjects. Adaptive tracking performance 1.5 hours after dosing was impaired by triprolidine, 2.5 and 5 mg; the impairment was still detectable 3.5 hours after 5 mg. Acrivastine did not impair adaptive tracking after any of the doses. Triprolidine increased reaction times after 1.5 hours (2.5 and 5 mg) and 3 hours (5 mg), but acrivastine did not have any effect on reaction time at any dose. Both doses of triprolidine caused subjective central nervous system effects after 1.5 hours, and triprolidine, 5 mg, still had some detectable effects on subjective rating scales after 3 hours. No subjective effects were noted after acrivastine. We conclude that acrivastine at doses causing more peripheral H1-antagonism than triprolidine has considerably reduced central nervous system activity.

Randomized single-blind trial in general practice comparing the efficacy and palatability of two cough linctus preparations, 'Pholcolix' and 'Actifed' Compound, in children with acute cough.

Two hundred and seventeen patients between 6 and 12 years of age suffering from acute cough took part in a randomized, single-blind study comparing 'Pholcolix' and 'Actifed' Compound. No significant difference in efficacy was demonstrated but analysis of palatability components (taste, smell, aftertaste and feeling in the mouth) showed numerical superiority for 'Pholcolix' for all parameters, with a high degree of significance for overall taste. 'Pholcolix' caused significantly fewer side-effects, with 'Actifed' Compound causing markedly more drowsiness after daytime dosage.

Comparison of the effects of astemizole/pseudoephedrine and triprolidine/pseudoephedrine on CNS activity and psychomotor function.

The sedative properties of astemizole-D and triprolidine-D were compared in a double-blind, placebo-controlled, repeated-measures design study comprising three experimental treatments, each with a duration of 2 days (n = 12). Sedation was assessed by continuous electroencephalographic measurement (C-EEG), intermittent performance testing and subjective measures. C-EEG monitoring revealed that triprolidine-D produced significantly more daytime sedation and drowsiness than either astemizole-D or placebo (p < 0.05). Intermittent performance testing did not reveal consistent psychomotor deficits. There were no differences from placebo; the only significant findings showed that astemizole-D improved tracking accuracy at T + 65 h (p < 0.05) compared to baseline. Also, when scores were summed across all time points, astemizole-D improved scores significantly in contrast to triprolidine-D for the total scores (p < 0.05). It is concluded that, in contrast to triprolidine-D, astemizole-D does not produce daytime drowsiness or sedation.

Cardiotoxicity of new antihistamines and cisapride.

Although the new second-generation nonsedative antihistamines terfenadine and astemizole were launched as highly selective and specific H(1)-receptor antagonists, they were later found to cause prolongation of the QT-interval and severe cardiac arrhythmias. The prolongation of the QT-interval is caused by the blockade of one or more of the cardiac potassium channels, among which the delayed rectifier I(Kr), encoded by the HERG-gene, appears to be the most significant. The potency of the prokinetic drug cisapride to block I(Kr) appears to be similar to that of terfenadine (IC(50) about 50 nmol/l). These drugs cause problems when overdosed, used in combination with inhibitors of their CYP3A4-mediated metabolism, or when given to individuals with altered drug kinetics (the aged) or patients with existing cardiac disease (congenitally long QT). Moreover, interactions with other QT-interval prolonging drugs require special attention. Active hydrophilic metabolites of the second-generation antihistaminic compounds (ebastine-carebastine, loratadine-desloratadine, terfenadine-fexofenadine, astemizole-norastemizole) are new compounds with probably reduced risk for drug interactions and cardiac toxicity.

Inhibition of histamine or allergen-induced wheals by a single dose of acrivastine, fexofenadine or cetirizine.

Certirizine, a potent H1-blocking agent, is often recommended as an emergency drug in anaphylactic reactions because of its well documented fast onset of action. In this randomized, cross-over study we compared the onset of action after a single dose of two recently introduced antihistamines, acrivastine and fexofenadine, with that of cetirizine. The inhibition of the wheal-and-flare reaction produced by skin prick test with histamine in 20 healthy volunteers and with a relevant pollen allergen in 20 atopic patients, respectively, were measured before and at regular intervals up to 60 min after the ingestion of acrivastine (8 mg and 16 mg), fexofenadine (120 mg) and cetirizine (10 mg and 20 mg). Wheal-and-flare reaction were significantly inhibited 20 min after the intake of 16 mg acrivastine in atopic patients and 30 min after intake of 8 mg acrivastine in healthy volunteers, whereas cetirizine produced a significant inhibition of the wheal-and-flare reaction within 40-60 min. No significant inhibition could be observed within 60 min after fexofenadine intake. Therefore, in clinical settings when a fast onset of the H1-blocking action is mandatory (e.g., after insect stings or for short-term prophylaxis) we recommend acrivastine.

Acrivastine in allergic rhinitis: a review of clinical experience.

Acrivastine is an antihistamine with reduced sedating potential. This comprehensive review of clinical experience with acrivastine in allergic rhinitis considers all currently available data both published and, as yet, unpublished. Unequivocal evidence of the efficacy of 8 mg acrivastine three times daily for the control of symptoms of seasonal allergic rhinitis has been provided by 11 placebo-controlled studies involving almost 1000 patients. Additional trials have generated further supportive data as well as evidence for the use of acrivastine in the treatment of perennial allergic rhinitis. In common with most antihistamines, acrivastine alone has limited effect on the symptom of blocked nose. In a further series of 11 studies, mainly conducted in the USA, the combination of 8 mg acrivastine plus 60 mg pseudoephedrine was found to control not only the histamine-mediated symptoms of allergic rhinitis but also blocked nose. There were few adverse events associated with the use of acrivastine and the small increase in incidence of drowsiness over that found with placebo was similar to that observed for terfenadine. The marked absence of other signs of significant depression of the central nervous system (or anticholinergic activity) suggests that acrivastine will be an important addition for the antihistaminic control of symptoms of allergic rhinitis.

Acrivastine in seasonal allergic rhinitis: two randomized crossover studies to evaluate efficacy and safety.

In two randomized crossover studies, the antihistamine, acrivastine, was evaluated for the treatment of seasonal allergic rhinitis. One study on 31 patients found both 4 and 8 mg acrivastine given three times daily to be significantly better than placebo for alleviating hay fever. There were no significant differences in symptom scores between the two doses, although more patients (63%) favoured 8 mg acrivastine over the 4 mg dose (46%) or placebo (35%). The other study found the higher dosage regimen to be similar in efficacy to 1 mg clemastine given three times daily. Both dosages were significantly better than placebo for reducing symptom scores in all 18 evaluable patients. The incidence of adverse experiences was low in both studies; there being no dose-related effects of acrivastine. In the second study, drowsiness, probably or possibly treatment related, occurred on seven occasions during clemastine treatment and once with acrivastine. These studies indicate that 8 mg acrivastine given three times daily is both well tolerated and of equal efficacy to clemastine for the treatment of seasonal allergic rhinitis.

French multicentre double-blind study to evaluate the efficacy and safety of acrivastine as compared with terfenadine in seasonal allergic rhinitis.

In this double-blind, multicentre study the antihistamine acrivastine was compared with terfenadine for the treatment of seasonal allergic rhinitis. The study was divided into three periods which together lasted 56 days. Patients (n = 83) were randomly assigned treatment with either 8 mg acrivastine three times daily or 60 mg terfenadine twice daily. Both agents were equally efficacious in reducing the severity of sneezing, itchy nose, blocked nose, running nose, itchy eyes, watery eyes and itchy throat as recorded daily by patients, and as rated by both the patients and their physicians at the end of each treatment period. Acrivastine and terfenadine were equally well tolerated with no serious side-effects. Both effectively controlled the symptoms of seasonal allergic rhinitis in otherwise healthy individuals.

A cross-over comparison of acrivastine, pseudoephedrine and their combination in seasonal allergic rhinitis.

In a four period, double-blind cross-over study, forty patients with moderate to severe symptoms of seasonal allergic rhinitis received in randomised order 8 mg acrivastine, 60 mg pseudoephedrine, 8 mg acrivastine plus 60 mg pseudoephedrine and placebo. Each treatment was given three times daily for six days with a one day washout period between treatments. Acrivastine alone significantly reduced all the symptom severity scores when compared to placebo or pseudoephedrine alone (p less than 0.01). These severity scores were assigned daily by patients for itchy nose/throat, sneezing, running nose, blocked nose, watery eyes, itchy eyes and overall symptoms. The combination of acrivastine and pseudoephedrine was significantly better than either placebo or pseudoephedrine alone in controlling all symptom scores (p less than 0.01) and it was also superior to acrivastine alone (p less than 0.05) in controlling all symptoms except itchy eyes. The results confirm the expected additive rather than synergistic effect of acrivastine and pseudoephedrine in combination. The control of symptoms assessed at the end of each treatment period was considered either excellent or good by 79% of patients and 84% of investigators for acrivastine plus pseudoephedrine and, for acrivastine alone, by 69% of patients and 67% of investigators. Both acrivastine alone and acrivastine and pseudoephedrine in combination were well tolerated. There was no significant difference in the number of adverse experiences reported in either of these two groups compared to the number of adverse experiences reported in the placebo group.

Cardiorespiratory assessment of decongestant-antihistamine effects on altitude, +Gz, and fatigue tolerances.

Decongestants and antihistamines are known to produce effects capable of adversely modifying physiological function and psychomotor task performance. Because of relevance to safe pilot performance, the effects of single doses of two decongestant-antihistamine preparations (Compound A and Compound B), or a placebo on cardiorespiratory responses to two equally spaced +2 Gz tests during separate 2-h exposures at 388 m (1,274 ft MSL) ground level (GL) and 3,810 m (12,500 ft) chamber altitude were assessed. Post-altitude fatigue was assessed by cardiorespiratory responses to submaximal bicycle ergometry. Compound A and Compound B appeared to exert no significant detrimental effects on short-duration post-altitude ergometric fatigue-ability. With two exceptions, all combinations of medication, altitude, and +Gz were well tolerated. Two subjects were clearly incapacitated during the first +2 Gz test under Compound A at 3,810 m (12,500 ft) altitude. It is felt that the +Gz-intolerance resulted mainly from an adverse interactive effect of Compound A and altitude on vasomotor and/or chronotropic mechanisms.

Sedation with "non-sedating" antihistamines: four prescription-event monitoring studies in general practice.

OBJECTIVES: To investigate the frequency with which sedation was reported in post-marketing surveillance studies of four second generation antihistamines: loratadine, cetirizine, fexofenadine, and acrivastine. DESIGN: Prescription-event monitoring studies. SETTING: Prescriptions were obtained for each cohort in the immediate post-marketing period. SUBJECTS: Event data were obtained for a total of 43 363 patients. MAIN OUTCOME MEASURES: Reporting of sedation or drowsiness. RESULTS: The odds ratios (adjusted for age and sex) for the incidence of sedation were 0.63 (95% confidence interval 0.36 to 1.11; P=0.1) for fexofenadine; 2.79 (1.69 to 4.58; P<0.0001) for acrivastine, and 3.53 (2.07 to 5.42; P<0.0001) for cetirizine compared with loratadine. No increased risk of accident or injury was evident with any of the four drugs. CONCLUSIONS: Although the risk of sedation was low with all four drugs, fexofenadine and loratadine may be more appropriate for people working in safety critical jobs.

Treatment of the common cold.

BACKGROUND: Common colds are usually treated by the patients themselves with over-the-counter (OTC) cold medications. Many cough and cold remedies are available and sold freely without prescription. The authors conducted a study to compare the efficacy, adverse effects, the quality of life (QOL) and the patient's opinion and appreciation on the drugs (POD) between Dayquil/Nyquil and Actifed DM plus paracetamol syrup. METHOD: In this prospective, investigator-blinded clinical trial, 120 patients, aged between 15 and 60 years old, with common colds within 72 hours, who accepted the trial and gave informed written consent, were randomized into two treatment groups. One patient was excluded due to evidence of bacterial infection. Fifty-nine patients were treated with Dayquil/Nyquil (D/N group), while the other 60 patients had Actifed DM plus paracetamol (ADM/P group) for three days. On day 1 the patient's demographic data (sex, age, body weight, blood pressure, co-existing diseases/conditions, drug use, and allergy to any drugs), the most prominent symptoms and its duration were recorded. All patients were screened for bacterial infection by physical examination, complete blood count and sinus radiographs. The symptoms (nasal obstruction, rhinorrhea, sneezing, cough, sore throat, fever and headache) and signs (injected nasal mucosa, nasal discharge and pharyngeal discharge) were scored, based on 4-point scale (0 to 3), on days 1 and 4. Changing of the symptoms and QOL were recorded on the diary card. The patient's opinion and appreciation on the drugs (POD) was assessed on day 4. The effectiveness (the ability to lessen the symptoms and signs), QOL and POD between two treatments were compared. RESULTS: The demographic data between the two groups were similar. The four most common prominent symptoms of common colds in our series were cough (47.9%), sore throat (26.17%), rhinorrhea (8.4%) and headache (8.4%). However, both treatments were equally effective in lessening the symptoms (P = 0.426) and signs (P = 0.716) of common cold from days 1 to 4. The adverse effects were significantly higher in ADM/P group than in D/N group (p = 0.006). In contrast, QOL in terms of alertness, freshness and sound sleep improved from day 1 to day 3 in both treatments, but the overall day-3 score was significantly higher in the D/N group than the ADM/P group (1.85 +/- 1.83; 1.25 +/- 1.94: p = 0.024). POD in terms of convenience, flavour of drug, effectiveness of the drug and a need to repeat the drug assessed on day 4, was also significantly higher in the D/N group than the ADM/P group (10.68 +/- 2.56; 8.92 +/- 2.27: p < 0.001). CONCLUSION: Dayquil/Nyquil are as effective as Actifed DM plus paracetamol in controlling the symptoms and signs of the common cold, but have fewer adverse effects. The quality of life assessed during the use of the drugs was significantly higher in the Dayquil/Nyquil group, and according to the patients, they prefered Dayquil/Nyquil more than Actifed DM plus paracetamol.