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.

Spinal sensory and motor blockade by intrathecal doxylamine and triprolidine in rats.

OBJECTIVES: The aim of this experiment was mainly to examine the effects of intrathecally injected doxylamine and triprolidine, two antihistamine drugs spinal motor and sensory functions. METHODS: After intrathecally injecting the rats with five different doses, the dose-response curves of spinal sensory and motor block with doxylamine and triprolidine were constructed. In comparison with the local anaesthetic mepivacaine, the quality and duration of spinal anaesthesia with doxylamine or triprolidine were conducted. KEY FINDINGS: Doxylamine, mepivacaine and triprolidine elicited spinal motor and sensory (nociception and proprioception) blockades in a dose-dependent fashion. On the ED50 (50% effective dose) basis, the rank order of drug potency was triprolidine > mepivacaine > doxylamine (P < 0.05) at provoking spinal motor, proprioceptive and nociceptive blockades. On the equianaesthetic doses (ED25 , ED50 and ED75 ), the duration of spinal anaesthesia with doxylamine was longer (P < 0.01) than that with mepivacaine or triprolidine. Moreover, doxylamine or triprolidine displayed greater potency (ED50 ) (P < 0.05) and duration (P < 0.05) of sensory block over motor block. CONCLUSIONS: Doxylamine or triprolidine produces a dose-dependent effect of spinal motor and sensory block. Triprolidine with a better nociception-selective action over motor block has a better potency than mepivacaine or doxylamine. Doxylamine and triprolidine produce longer durations than mepivacaine.

Endogenous histamine facilitates long-term potentiation in the hippocampus during walking.

Long-term potentiation (LTP) in hippocampal CA1 depends on the behavioral state of LTP induction. We hypothesize that histaminergic activity in the septohippocampal system, which is active during walking compared with other behavioral states, is responsible for the behavioral dependence of LTP. Field basal-dendritic EPSPs of CA1 pyramidal cells were recorded in freely behaving rats, and LTP was induced by a single 200 Hz stimulation train (0.5 s duration). Basal-dendritic LTP was facilitated when induced during walking compared with awake immobility (IMM) or rapid-eye-movement sleep. The facilitation of basal-dendritic LTP during walking was abolished by lesion of tuberomammillary nucleus (TMN) neurons with orexin-saporin or by intramedial-septal infusion of the H(1) histaminergic blocker triprolidine but not the H(2) histaminergic blocker cimetidine. Conversely, histamine infusion in the medial septum enhanced the basal-dendritic LTP induced during IMM to a magnitude similar to that induced during walking. Basal-dendritic LTP induced during walking was not further enhanced by intraseptal histamine infusion. Combined with the previous result that behavior-dependent LTP is mediated by cholinergic septohippocampal neurons, we conclude that the facilitation of basal-dendritic LTP in CA1 during walking was mediated by TMN histaminergic afferents acting on H(1) receptors in the medial septum, which may then enhance cholinergic and noncholinergic inputs to the hippocampus.

The butterbur extract petasin has no effect on skin test reactivity induced by different stimuli: a randomized, double-blind crossover study using histamine, codeine, methacholine, and aeroallergen solutions.

BACKGROUND: Petasin (Ze 339) was recently introduced on the market as a potent herbal antiallergic drug for treatment of respiratory allergies such as hay fever. Few clinical studies have been performed so far addressing the clinical effectiveness of Ze 339. OBJECTIVE: To evaluate the antiallergic properties of Ze 339 using skin prick tests with different stimuli, such as codeine, histamine, methacholine, and a relevant inhalant allergen. METHODS: A randomized, double-blind, placebo-controlled study was performed in which Ze 339 was compared to acrivastine, a short-acting antihistamine, in 8 patients with respiratory allergy and in 10 nonatopic, healthy volunteers. Antiallergic activity of Ze 339 was determined by analyzing inhibitory potency in skin prick tests with codeine, histamine, methacholine, and an inhalant allergen. Wheal-and-flare reactions were assessed 90 minutes after a double dose of Ze 339, acrivastine, or placebo. An interval of at least 3 days was left between the skin tests. RESULTS: Acrivastine was identified as the only substance that significantly inhibited skin test reactivity to all solutions analyzed in all study subjects. In contrast, no significant inhibition could be demonstrated for Ze 339 with any test solution. Moreover, the results of Ze 339 did not differ significantly from placebo. CONCLUSIONS: In this study we found no antiallergic, particularly antihistaminic, effect of Ze 339 in skin tests using a variety of stimuli often used to evaluate immediate skin test reactivity. The mechanism by which Ze 339 is effective in the treatment of seasonal allergic rhinitis still needs to be elucidated.

Enhanced efficacy of triprolidine by transdermal application of the EVA matrix system in rabbits and rats.

The bioavailability of triprolidine from the ethylene vinyl acetate (EVA) matrix system containing polyoxyethylene-2-oleyl ether was studied to determine the feasibility of enhanced transdermal delivery of triprolidine in rabbits. The antihistamine effects were also confirmed to determine the percutaneous absorption of triprolidine from the EVA matrix system containing a penetration enhancer and plasticizer in rats. The triprolidine-EVA matrix (50mg/kg) was applied to the abdominal skin of rabbits. Blood samples were collected via the femoral artery for 36 h and the plasma concentrations of triprolidine were determined by HPLC. The pharmacokinetic parameters were calculated using the LAGRAN computer program. The area under the curve(AUC) was significantly higher in the enhancer group (4582+/-1456 ng/mL h) than that (2958+/-997 ng/mL h) in the control group (P<0.05), showing an approximate 155% increased bioavailability. The average Cmax in the enhancer group (241+/-46.5 ng/mL) was significantly higher than that in the control group (198+/-28.9 ng/mL), (P<0.05). The mean Tmax in the enhancer group (8.0+/-2.57 h) was higher than that in the control group (6.0+/-2.24 h, but this was not statistically significantly. The relative bioavailability of triprolidine in the transdermal application was 35.9% in the control group and 55.6% in the enhancer group compared comparing with that after oral administration. As the triprolidine-EVA matrix, which contains polyoxyethylene-2-oleyl ether as an enhancer and triethyl citrate as a plasticizer was administered to the rabbits via the transdermal routes, the relative bioavailability increased approximately 1.55 fold compared with that in the control group, showing a relatively constant, sustained blood concentration with minimal fluctuation. The antihistamine effect was determined using the Evans blue dye procedure by comparing the changes in the vascular permeability increase following the transdermal application. The vascular permeability increase was reduced significantly by the transdermal application of the EVA-triprolidine system containing triethyl citrate and polyoxyethylene-2-oleyl ether. These results show that the plasticizer and penetration enhancer increase the skin permeation of triprolidine and the triprolidine-EVA matrix system could be developed as a transdermal delivery system providing the increased constant plasma concentration and antihistamine effects.

Antihistamine effects of triprolidine from the transdermal administration of the TPX matrix in rats.

The antihistamine effects of the triprolidine were studied in rats to determine the feasibility of their enhanced transdermal delivery from the poly (4-methyl-1-pentene) (TPX) matrix system containing penetration enhancer and plasticizer. The antihistamine effects were determined by the Evans blue dye procedure by comparing the changes in vascular permeability increase following the transdermal administration. The vascular permeability increase was significantly reduced by transdermal administration of the triprolidine-TPX system containing triethyl citrate (TEC) and polyoxyethylene-2-oleyl ether (POE). Both the plasticizer and penetration enhancer played an important role in the skin permeation of triprolidine and increased the antihistamine effects. These results showed that the triprolidine-TPX matrix system containing plasticizer and penetration enhancer could be a transdermal delivery system providing the increased antihistamine effects.

Enhanced transdermal delivery of triprolidine from the ethylene-vinyl acetate matrix.

Triprolidine-containing matrix was fabricated with ethylene-vinyl acetate (EVA) copolymer to control the release of the drug. The permeation rate of triprolidine in the stripped skin was greatly larger than that in the whole skin. Thus it showed that the stratum corneum acts as a barrier of skin permeation. The effect of penetration enhancer and stripping of skin on the permeation of triprolidine through the excised mouse skin was studied. Penetrating enhancers showed increased flux probably due to the enhancing effect on the skin barrier, the stratum corneum. Among enhancers used such as glycols, fatty acids and non-ionic surfactants, polyoxyethylene-2-oleyl ether showed the best enhancement. The permeability of triprolidine was markedly increased with stripping of the mouse skin to remove the stratum corneum that acts as a barrier of skin permeation. For the controlling transdermal delivery of triprolidine, the application of EVA membrane containing permeation enhancer could be useful in the development of transdermal drug delivery system.

Controlled release of triprolidine using ethylene-vinyl acetate membrane and matrix systems.

The studies on the permeability of triprolidine through ethylene-vinyl acetate (EVA) copolymer membrane using two-chamber diffusion cell was carried out to develop the controlled delivery system. To evaluate the effect of drug concentration in reservoir, polyethylene glycol (PEG) 400 was added to saline solution as a solubilizer and a sink condition was maintained in the receptor solution. The permeation rate of drug through EVA membrane was proportional to PEG 400 volume fraction. A linear relationship existed between the permeation rate and the reciprocal of the membrane thickness. Triprolidine-containing matrix was fabricated with EVA copolymer to control the release of the drug. The plasticizers was added for preparing the pore structure of EVA membranes to increase the drug release. The effects of PEG 400, vinyl acetate (VA) contents of EVA, membrane thickness, drug concentration, temperature, and plasticizers, on drug release were studied. The release rate of drug from the EVA matrix increased with PEG 400 volume fraction, increased temperature and drug loading doses. An increased vinyl acetate comonomer content in EVA membrane increased the drug release rate and permeability coefficient. Among the plasticizers used such as alkyl citrates and phthalates, tetra ethyl citrate showed the best enhancing effects showing the enhancement factor of 1.88. The release of triprolidine from the EVA matrix follows a diffusion controlled model, where the quantity released per unit area is proportional to the square root of time. The controlled release of triprolidine could be achieved using the EVA polymer including the plasticizer.

Transdermal delivery of triprolidine using TPX polymer membrane.

Triprolidine-containing matrix was fabricated with poly(4-methyl-1-pentene) (TPX) polymer to control the release of the drug. Effect of penetration enhancer and stripping of skin on the permeation of triprolidine through the excised mouse skin was studied. Penetrating enhancers showed the increased flux probably due to the enhancing effect on the skin barrier, the stratum corneum. Among enhancers used such as glycols, fatty acids and non-ionic surfactants, polyoxyethylene-2-oleyl ether showed the best enhancement. The permeability of triprolidine was markedly increased with stripping the mouse skin to remove the stratum corneum, which acts as a barrier of skin permeation. For the controlling delivery of triprolidine, the TPX matrix containing permeation enhancer could be developed.

Enhanced bioavailability of triprolidine from the transdermal TPX matrix system in rabbits.

The pharmacokinetics and bioavailability of triprolidine, antihistamines, were studied to determine the feasibility of enhanced transdemal delivery of triprolidine from the poly(4-methyl-1-pentene) (TPX) matrix system containing polyoxyethylene-2-oleyl ether in rabbits. The triprolidine-TPX matrix (50 mg/kg) was applied to abdominal skin of rabbits. Blood samples were collected via femoral artery for 36 h and the plasma concentrations of triprolidine were determined by HPLC. Pharmacokinetic parameters was calculated using the LAGRAN computer program. The area under the curve (AUC) was significantly higher in the enhancer group (4058 +/- 1420 ng/ml h) than that (1902 +/- 857 ng/ml h) in control group (P<0.05), showing about 235% increased bioavailability. The average Cmax was increased significantly in the enhancer group (216 +/- 44.3 ng/ml) compared with control group (130 +/- 25.8 ng/ml) (P<0.05). The mean Tmax was increased in the enhancer group (8.0 +/- 2.55 h) compared with the control (6.0 +/- 2.28 h) but was not significant. The relative bioavailability was 23.1% in the control group and 49.3% in the enhancer group compared to the oral route. As the triprolidine-TPX matrix containing polyoxyethylene-2-oleyl ether as an enhancer and tiethyl citrate as a plasticizer was administered to rabbits via the transdermal routes, the relative bioavailability increased by about 2.13-fold compared to the control group, showing a relatively constant, sustained blood concentration with minimal fluctuation. The results of this study shows that triprolidine-TPX matrix could be developed as a transdermal delivery system providing consistent plasma concentration.

Zafirlukast has no beneficial effects in the treatment of chronic urticaria.

BACKGROUND: Leukotriene receptor antagonists have shown some efficacy in t he treatment of asthma. Injection of LTC4, LTD4 and LTE4 into the skin leads to a weal-and-flare reaction, suggesting an involvement of leukotrienes in the pathogenesis of urticaria. Indeed, various reports have indicated a beneficial effect for leukotriene receptor antagonists in patients with chronic urticaria. OBJECTIVE: To determine the therapeutic effect of the leukotriene receptor antagonist zafirlukast in patients with chronic urticaria. METHODS: The study was a double-blind, placebo-controlled, cross-over study lasting for 12 weeks. Fifty-two patients with chronic urticaria were investigated at a university hospital. The patients were randomized to receive 20 mg zafirlukast b.i.d. or placebo and cross-over was scheduled after 6 weeks. The efficacy of the treatment was evaluated by a daily symptom score, six physical examinations, the requirement of rescue antihistamines (acrivastine) and an overall assessment by the patient andthe investigating physician. RESULTS: Forty-six patients completed the study: zafirlukast was well tolerated without alteration of the investigated laboratory parameters. In comparison with placebo, treatment with zafirlukast resulted in no significant positive effect for any of the efficacy measures. Moreover, we were unable to identify any subgroup of patients with chronic urticaria responding with a therapeutic benefit. CONCLUSIONS: The leukotriene receptor antagonist zafirlukast does not provide a significant therapeutic benefit at a dose of 20 mg b.i.d. in patients with chronic urticaria.

The effects of single and repeated administration of ebastine on cognition and psychomotor performance in comparison to triprolidine and placebo in healthy volunteers.

OBJECTIVE: The cognitive and psychomotor effects of 10 mg, 20 mg and 30 mg ebastine, a second generation H1-receptor antagonist, were compared with sustained release triprolidine 10 mg (as a verum) and placebo in 10 healthy volunteers in a double-blind, randomised cross-over study. METHODS: Following each dose, subjects were required to perform a series of tests of cognitive function and psychomotor performance at 1 h, 2 h, 4 h and 8 h post-dose on days 1 and 5. The test battery consisted of critical flicker fusion, choice reaction time, simulated car tracking task, Sternberg memory scanning task, assessment of subjective sedation (LARS) and subjective evaluation of sleep (LSEQ). RESULTS: Ebastine at all doses investigated was not statistically significant from placebo in any of the objective tests used. However, as expected for a positive internal control, a number of objective measures were significantly disrupted by triprolidine (p < 0.05). Triprolidine produced an overall increase of the peripheral reaction time component of the simulated car tracking task (SCTT), the difference with placebo reaching statistical significance on day 1, 8 h post-dose (p < 0.05). The mean tracking accuracy scores were also significantly impaired following the administration of triprolidine after 8h on day 1 (p < 0.05). Triprolidine also produced a clear decrement on the SMST (Sternberg Memory Scanning Task), which was significantly different from placebo, at 4 h and 8 h post-dose on day 1. Subjective reports of sedation (LARS) were significantly greater at 2 h and 4 h following triprolidine administration on day 1 and ebastine (30 mg) was rated as sedative 4 h following administration on day 5. The perceived sedative activity of ebastine 30 mg was also reflected in the subjective reports on the LSEQ on day 1 (p < 0.05). CONCLUSIONS: These results allow the conclusion that ebastine, at its recommended therapeutic doses of 10-20 mg, is demonstrably free from impairment on objective aspects of psychomotor and cognitive function in a study where the psychometric assessments were shown to be sensitive to disruptive effects, as evidenced by the action of the positive control, triprolidine 10 mg.

Distribution of antihistamines into the CSF following intranasal delivery.

The preferential absorption of certain drug compounds from the nasal cavity into the cerebrospinal fluid (CSF) raises questions regarding the transport processes controlling drug disposition following intranasal delivery. The disposition characteristics of several structurally similar antihistamine compounds, hydroxyzine, chlorpheniramine, triprolidine, and chlorcyclizine, into the CSF following nasal administration were studied using the rat as an animal model. The antihistamines were administered either intranasally or intra-arterially, and serial CSF and plasma samples were collected from the cisterna magna and the femoral artery, respectively. The drug levels in CSF and plasma were assayed by HPLC. Hydroxyzine concentrations in plasma and CSF were found to be significantly greater than most of the other compounds tested. In addition, hydroxyzine also showed the most rapid systemic absorption following nasal administration. Interestingly, the hydroxyzine levels in CSF following intranasal administration were significantly higher than those following intra-arterial administration. The AUC ratios between CSF and plasma for hydroxyzine after intranasal and intra-arterial administration were 4.0 and 0.4, respectively. The AUC ratios for triprolidine, the other antihistamine with measurable CSF concentrations, were 0.5 and 0.7, respectively. The distribution of antihistamines from the nasal membrane into the CSF appears to be controlled by a combination of their molecular properties. It also appears that the intranasal delivery of drugs with optimal physicochemical characteristics can result in an improved CNS bioavailability compared to those achieved from an equivalent parenteral dose.

Effects of a single dose of loratadine on flying ability under conditions of simulated cabin pressure.

Pilots with allergic diseases, who need antihistaminic drug therapy, have to be grounded temporarily because this therapy is considered to interfere with flight safety due to its sedative effects. There is evidence that loratadine is practically void of these sedative effects, and therefore might be prescribed to pilots. A study was conducted to determine the effects of loratadine on performance and alertness. In a randomized, double-blind, within subjects design, 18 male subjects were studied, employing loratadine 10 mg, triprolidine hydrochloride 5 mg, and placebo. Objective (vigilance, complex tasks) and subjective tests, tailored to the specific tasks of aircrew, were applied under hypobaric conditions that prevail in an intact cockpit. With respect to alertness and performance, the results of this study showed no significant differences between loratadine and placebo during a period of 1 to 6 hours after drug ingestion. Triprolidine, used as a positive control, showed significant detrimental effects on both subjective and objective measures. It is anticipated that a single dose of loratadine 10 mg will not affect flying performance. This finding might also have implications for the treatment of allergic disorders of personnel involved in other highly skilled jobs.

Effects of semprex-D and diphenhydramine on learning in young adults with seasonal allergic rhinitis.

OBJECTIVES: The purpose of this study was to test the hypothesis that learning ability is impaired in patients with seasonal allergic rhinitis relative to untreated individuals and to evaluate a combination compound (acrivastine 8 mg + pseudoephedrine 60 mg) for attenuation of the learning impairment in these patients. BACKGROUND: In a previous study employing the same method it was shown that young children (10 to 12 yrs) suffering from seasonal allergic rhinitis performed significantly worse on tests of learning and using knowledge after acute treatment with a sedating antihistamine (diphenhydramine 50 mg) or placebo as compared with nontreated healthy controls. This effect was partially reversed by treatment with loratadine. METHODS: Sixty-seven young adults suffering from seasonal allergic rhinitis and 28 matched controls were trained on didactic simulation for three consecutive days. Atopic subjects were treated differentially during training according to a double-blind, randomized, parallel group design with either diphenhydramine hydrochloride 50 mg, a combination compound (acrivastine 8 mg + pseudoephedrine 60 mg, A + P), or placebo, administered qd. After training, all atopic subjects were maintained on A + P treatment for 14 days at which time all groups returned for examination. RESULTS: Mean performance at the end of training was worse for all atopic subjects combined compared with normal subjects. Subjects treated with diphenhydramine performed significantly worse than either normals (P < .001) or those treated with A + P (P < .001). At the examination, the diphenhydramine group's performance differed significantly from those of the normal (P < .001) and A + P groups (P < .001). CONCLUSION: The study supports our previous finding that allergy symptoms reduce learning ability which is further reduced learning ability which is further reduced by diphenhydramine. Atopic subjects with allergies treated with acrivastine + pseudoephedrine learned as well as normal subjects.

Antihistamine effects on actual driving performance in a standard test: a summary of Dutch experience, 1989-94.

The review summarizes the major results of eight double-blind, placebo-controlled, volunteer studies undertaken by three independent institutions for showing the effects on actual driving performance of "sedating" and "nonsedating" antihistamines (respectively, triprolidine, diphenhydramine, clemastine and terfenadine, loratadine, cetirizine, acrivastine, mizolastine, and ebastine). A common, standardized test was used that measures driving impairment from vehicular "weaving" (i.e., standard deviation of lateral position (SDLP)). Logical relationships were found between impairment and dose, time after dosing, and repeated doses over 4-5 days. The newer drugs were generally less impairing, but differences existed among their effects, and none was unimpairing at doses 1-2x the currently recommended levels. One or possibly two of the newer drugs possessed both performance-enhancing and -impairing properties, depending on dose, suggesting two mechanisms of action.