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PubMed2003

Aeroallergens, allergic rhinitis, and sedating antihistamines: risk factors for traumatic occupational injury and economic impact.

BACKGROUND: The U.S. workplace injury burden is significant. Our objective was to assess the particular impact of aeroallergen, allergic rhinitis, and antihistamine exposures and side effects on the risk of traumatic work-related injuries, and the associated economic impact. METHODS: This is an observational case-control study with 1,223 acute traumatic injury cases that are compared to 1,202 chronic back injury controls. Structured telephone interviews were conducted in 1998 and 1999 on Workers' Compensation applicants injured in 1997. Antihistamine use and pollen levels were measured 2 weeks prior to the injury date. RESULTS: Sedating antihistamine exposures elevated acute injury risk (main effect OR: 2.93). A significant increase in traumatic injury risk was observed for combined sedating antihistamine and high pollen exposures among subjects with physician and self-diagnosed allergic rhinitis (OR: 2.41). Direct medical costs associated with this increased risk were estimated at $143 million in 2001. CONCLUSIONS: Workers with physician-diagnosed allergic rhinitis have as high a reliance on sedating antihistamines as do self-diagnosed and self-medicating nasal allergy sufferers. High pollen exposures along with sedating antihistamine use may confer significant additional injury risks among allergic rhinitis sufferers. Medical management "best practices" of diagnosed allergic rhinitis should include avoidance of sedating antihistamines to minimize acute, traumatic injury risks.

Adult↗
PubMed1989

Characterization of seven antihistamines, their N-oxides and related metabolites by fast atom bombardment mass spectrometry and fast atom bombardment tandem mass spectrometry.

We have examined the synthetic N-oxides of five ethylenediamine-type antihistamines using fast atom bombardment (FAB) mass spectrometry and FAB tandem mass spectrometry (MS/MS). Fragmentation of the protonated molecule in the normal and collisionally activated spectra appeared to be characteristic for this class of antihistamine N-oxide. Spectra were also acquired from an ethanolamine and a propylamine antihistamine N-oxide for comparison. These results were very similar to those obtained from biologically produced antihistamine N-oxides, as well as isomeric metabolites, which were readily distinguished from the N-oxides by characteristic fragmentation. In addition, a prominent ion 16 daltons lower in mass, which has been attributed to loss of elemental oxygen from the protonated N-oxide in chemical ionization mass spectral studies, was shown to be a matrix-dependent product of the solution-phase reduction of the antihistamine N-oxide to the parent antihistamine during FAB ionization. These results demonstrate that with a non-reducing matrix such as glycerol, FAB mass spectrometry and FAB MS/MS are excellent methods for the characterization of the non-conjugated antihistamine metabolites such as the N-oxides.

Ethanolamines↗
PubMed1984

Evaluation of the CNS properties of SCH 29851, a potential non-sedating antihistamine.

SCH 29851 [8-chloro[6,11-dihydro-11-(1-carboethoxy-4-piperidylidene)- 5-H-benzo [5,6]cyclohepta[1,2-b]-pyridine] was discovered as part of a search for a new antihistamine without effects on the central nervous system (CHS). Antihistaminic potency and duration of action of SCH 29851 and other antihistamines were assessed by inhibition of histamine-induced lethality in guinea pigs and histamine-induced paw edema in mice. Evaluation of possible CNS effects included gross observation of mice, rats, dogs and monkeys, prevention of electroshock-induced convulsions, acetic acid-induced writhing and physostigmine-induced lethality in mice and biochemical measures related to sedative liability such as displacement of in vivo 3H-mepyramine binding in mouse brain and in vitro 3H-WB 4101 binding in guinea pig cortex. Comparisons were made to several antihistamines considered to be sedative to varying degrees, including diphenhydramine, promethazine, chlorpheniramine and azatadine and to the newer antihistamines terfenadine and astemizole which are reported to be non-sedating in man at doses that antagonize the effects of histamine peripherally. SCH 29851 had antihistamine activity in the tests used with a potency at least comparable to most standards and was devoid of activity in all the functional and biochemical models used as indices of CNS activity. It is expected that SCH 29851 should be an effective, long acting, antihistamine in man without sedative effects at therapeutic doses.

Animals↗
PubMed2003

Comparison of intranasal corticosteroids and antihistamines in allergic rhinitis: a review of randomized, controlled trials.

For several years there has been discussion of whether first-line pharmacological treatment of allergic rhinitis should be antihistamines or intranasal corticosteroids. No well documented, clinically relevant differences seem to exist for individual nonsedating antihistamines in the treatment of allergic rhinitis. Likewise, the current body of literature does not seem to favor any specific intranasal corticosteroid. When comparing efficacy of antihistamines and intranasal corticosteroids in allergic rhinitis, present data favor intranasal corticosteroids. Interestingly, data do not support antihistamines as superior in treating conjunctivitis associated with allergic rhinitis. Safety data from comparative studies in allergic rhinitis do not indicate differences between antihistamines and intranasal corticosteroids. Combining antihistamines and intranasal corticosteroids in the treatment of allergic rhinitis does not provide additional beneficial effects to intranasal corticosteroids alone. Considering present data, intranasal corticosteroids seem to offer superior relief in allergic rhinitis, when compared with antihistamines.

Administration, Inhalation↗
PubMed2002

Second-generation antihistamines in asthma therapy: is there a protective effect?

Second-generation histamine H(1) receptor antagonists are recognized as being highly effective treatments for allergic-based disease and are among the most frequently prescribed drugs in the world. The newer antihistamines represent a heterogeneous group of compounds with markedly different chemical structures, a spectrum of antihistaminic properties, adverse effects, half-life, tissue distribution, metabolism and varying degrees of anti-inflammatory effects. Histamine is an important mast cell- and basophil-derived mediator that has been implicated in the pathogenesis of asthma, resulting in smooth muscle contraction, mucus hypersecretion, and increased vascular permeability leading to mucosal edema. Antihistamines should never be used as monotherapy for asthma but there is evidence that these drugs give a measure of protection in histamine-induced bronchoconstriction. Furthermore, several studies have demonstrated that the use of second-generation antihistamines, as adjunct therapy, may benefit those patients whose allergic asthma co-exists with allergic rhinitis. Indeed, many patients present with both allergic rhinitis and asthma. The link between the upper and lower respiratory airways is now well established and there is increasing evidence that allergic rhinitis is a risk factor for the development of asthma. More recently, a number of novel antihistamines have been developed which are either metabolites of active drugs or enantiomers and there is emerging evidence that at least one of these drugs, desloratadine, may give significant symptomatic benefit in some types of asthma. It is of interest to note that cetirizine provides a primary pharmacological intervention strategy to prevent the development of asthma in specifically-sensitized high risk groups of infants. Moreover, the documented anti-inflammatory activities of antihistamines may provide a novel mechanism of action for the therapeutic control of virus-induced asthma exacerbations by inhibiting the expression of intercellular adhesion molecule-1 (ICAM-1) by airway epithelial cells. Finally, several well-conducted studies suggest that combination therapy with antihistamines and antileukotrienes may be as effective as corticosteroid use in patients with allergic asthma and seasonal allergic rhinitis.

Asthma↗
PubMed2002

Histamine release in mesenteric traction syndrome during abdominal aortic aneurysm surgery: prophylaxis with H1 and H2 antihistamines.

OBJECTIVE AND DESIGN: Mesenteric traction syndrome is described as sudden tachycardia, hypotension and flush. Among other etiological factors eventeration or mesenteric traction of the small intestine may cause histamine release from mesenteric mast cells. We hypothesized that mesenteric traction syndrome may be positively influenced by prophylactic antihistamine administration. METHODS: Male patients (n = 17, ASA groups III-IV, 48-78 years old) were investigated in a randomised double blind study during elective abdominal aortic aneurysm (AAA) repair. Eight patients had pre-anaesthetic prophylaxis with dimetindene (H1-receptor antagonist) plus cimetidine (H2-receptor antagonist), 9 patients received placebo. Anaesthesia and invasive haemodynamic monitoring were standardised in all patients. Haemodynamic parameters, plasma histamine concentrations and clinical symptoms were determined 1 min after skin incision, as well as 5 and 20 min after mesenteric traction. Statistical analyses were performed using the Student's t-test, Chi2-test for incidences and Mann-Whitney-U-test for continuous data. RESULTS: The incidence of histamine release was 55.5% (5/9) in the placebo group vs. 37.5% (3/8) in the antihistamine group (p > 0.05, Chi2-test). Plasma histamine levels (mean +/- SD) were higher in the placebo group than in the antihistamine group at 5 and 20 min after mesenteric traction but the difference did not reach statistical significance. Arrhythmias were significantly more frequent in the placebo group (6 times) than in the antihistamine group (none) (p = 0.005 Chi2-test). Systolic blood pressure was not statistically different between groups (e.g. 5 min after mesenteric traction, mean +/- SD; placebo 111 +/- 20 mm Hg vs. antihistamines 119 +/- 35 mm Hg). However, in the placebo group the haemodynamics only stabilised 5 min after mesenteric traction when anaesthetic gas concentration was repeatedly reduced and vasopressor/volume administration was increased (placebo-group = 20 times/antihistamine-group = 8 times, p = 0.001, t-test). CONCLUSION: Prophylactic administration of antihistamines reduced the incidence of histamine release as well as the incidence of arrhythmias and the amount of stabilising measures during mesenteric traction. Prophylaxis with H1 and H2 antihistamines may be of perioperative benefit and should therefore be considered in AAA-surgery.

Aortic Aneurysm, Abdominal↗
PubMedDate not supplied

Risk of selected serious cardiac events among new users of antihistamines.

This retrospective cohort study examined the risk of selected serious cardiac events in new users of either astemizole or sedating antihistamines identified from the COMPASS Ohio Medicaid population of approximately 1 million active lives per year (1986-1992). (COMPASS is an automated claims database.) There were 15,585 patients in the astemizole group and 30,105 in the sedating antihistamines group. Reports of ventricular arrhythmia or sudden death occurring within 30 days of the first antihistamine claim were identified from Medicaid claims. Medical records were obtained and reviewed by a clinician for validity of diagnoses. Records for patients without a full 30 days of follow-up were sought in the National Death Index. Death certificates were obtained for all patients who died within 30 days of the first antihistamine claim. Of 53 cases identified, 6 were in the astemizole group and 47 in the sedating antihistamines group. The relative risk for all selected cardiac events among astemizole users compared with sedating antihistamine users was 0.25 (95% confidence interval: 0.11 to 0.58), and this estimate did not change substantially when adjusted for age; sex; race; recent history of cardiovascular disease, arrhythmias, asthma/pulmonary disease, or malignant neoplasms; or concomitant prescription of other drugs. This study provided no evidence that astemizole users are at increased risk for cardiac events in the first month of use when compared with users of sedating antihistamines.

Adolescent↗
PubMed1993

Effects of antihistamines on joint stiffness and bone healing after periarticular fracture.

In an effort to blunt the inflammatory response following injury, we studied the effects of antihistamines on joint stiffness and bone healing after periarticular fracture. The hind limbs of 37 New Zealand white rabbits were instrumented with intramedullary Steinmann pins to allow immobilization after creating a distal tibia fracture. After periarticular ankle fracture, the rabbits were divided into groups to receive chlorpheniramine, low-dose terfenadine, high-dose terfenadine, or no antihistamine. Antihistamine was administered for the first 5 days after fracture. At 3 weeks after fracture, the rabbits treated with antihistamines showed a significant reduction in joint stiffness compared to control animals. To determine if antihistamine also retarded bone healing, an additional 12 New Zealand white rabbits underwent bilateral drilling of the midshaft of the femur with a 2.5 mm Steinmann pin. Six animals received oral terfenadine, and six served as controls. After 5 weeks of cage activity, the animals treated with the antihistamine showed a significant decrease in energy to failure of the femurs on torsional testing. Qualitative microscopic examination revealed less mature callus at the site of the femoral cortical defect in those animals treated with the terfenadine. Antihistamine may have heretofore unconsidered benefits in preventing post-traumatic joint stiffness but may slow healing of associated bony injuries.

Animals↗
PubMed1990

Performance effects of antihistamines.

In 1988 an estimated 30 million Americans spent more than $500 million for single-entity antihistamines. Classic first-generation antihistamines, which are available without prescription, can cross the blood-brain barrier and have been reported to produce various central nervous system effects. Sedation, the most common adverse effect of these agents, occurs in 10% to 25% of antihistamine users. Drowsiness has been attributed to the blockade of central histaminergic receptors; antagonism of other brain receptors, such as serotonergic, cholinergic, and central alpha-adrenergic receptors, has also been proposed. The newer second-generation H1-receptor antagonists are typically large, lipophobic molecules with a charged side chain and are extensively bound to albumin. Consequently, these agents have difficulty entering the brain, and they appear no more likely to induce sedation than does placebo. The effects of antihistamines on psychomotor reflexes and driving, antihistamine-induced drowsiness, and interaction of antihistamines with alcohol and tranquilizers have been studied with numerous methodologies. The centrally acting first-generation agents commonly cause greater performance decrements as compared with the newer, nonsedating, second-generation antihistamines.

Automobile Driving↗
PubMed2002

Comparison of five new antihistamines (H1-receptor antagonists) in patients with allergic rhinitis using nasal provocation studies and skin tests.

BACKGROUND: It was the aim of the authors to compare all of the latest second-generation antihistamines and to see if there were significant differences in their efficacy. It is important for ENT specialists to know if these differences exist, as it is for general practitioners trying to choose between these drugs. METHODS: In 12 confirmed grass pollen allergic patients the authors performed nasal smears to asses eosinophilia, histamine/grass pollen skin tests, and grass pollen nasal provocation tests. All tests were performed before and after administration of one of five different antihistamines (cetirizine, loratadine, ebastine, fexofenadine, mizolastine) or placebo. The order of administration of antihistamines and placebo was randomised, and patients were not aware of which drug they were given. A decrease in nasal eosinophilia (nasal smear), or nasal or skin reactivity (provocation tests) was looked for. RESULTS: A significant decrease in nasal eosinophilia was observed for all antihistamines but not for placebo. For the grass pollen nasal provocation tests, the decrease was significant for nasal blockage and sneezing; for rhinorrhea there was an insignificant decrease that was true for all antihistamines. A significant reduction in histamine/grass pollen skin test reactivity was also observed for all antihistamines, during an 8 h observation period. A significant difference in efficacy between the different antihistamines could not be found with any of the tests performed. CONCLUSIONS: For the newer nonsedating H1-antagonists there appears to be no clinically relevant differences in activities--at least not in our study. Preference of the patient may be the most important factor in making a choice between these drugs.

Allergens↗
PubMed1999

Risk of ventricular arrhythmias associated with nonsedating antihistamine drugs.

AIMS: To quantify and compare the incidence of ventricular arrhythniias associated with the use of five nonsedating antihistamines: acrivastine, astemizole, cetirizine, loratadine and terfenadine. The effects of age, sex, dose, duration of treatment, and the interaction with P450 inhibitor drugs were also examined. METHODS: We carried out a cohort study with a nested case-control analysis using the UK-based General Practice Research database (GPRD). The study cohort included persons aged less than 80 years old who received their first prescription for any of the five study drugs between January 1, 1992 and September 30, 1996. We estimated relative risks and 95% confidence intervals of idiopathic ventricular arrhythmias with current use of antihistamines as compared with non use. RESULTS: The study cohort included 197425 persons who received 513012 prescriptions. Over the study period 18 valid cases of idiopathic ventricular arrhythmias were detected. Nine occurred during the current use of any antihistamine, resulting in a crude incidence of 1.9 per 10000 person-years (95%CI: 1.0-3.6) and a relative risk of 4.2 (95%CI: 1.5-11.8) as compared with non use. Astemizole presented the highest relative risk (RR= 19.0; 95%CI: 4.8-76.0) of all study drugs, while terfenadine (RR=2.1; 95%CI:0.5-8.5) was in the range of other nonsedating antihistamines. Older age was associated with a greater risk of ventricular arrhythmias (RR=7.4; 95%CI: 2.6-21.4) and seemed to increase the effect of antihistamines (RR=6.4; 95%CI: 1.7-24.8). The proportions of high dose terfenadine and the concomitant use with P450 inhibitors among current users of terfenadine were 2.7% and 3.4%, respectively over the study period with no single case of ventricular arrhythmias occurring in the presence of these two risk factors. CONCLUSIONS: The use of nonsedating antihistamines increases the risk of ventricular arrhythmias by a factor of four in the general population. Yet, the absolute effect is quite low requiring 57000 prescriptions, or 5300 person-years of use for one case to occur. The risk associated with terfenadine was no different from that with other nonsedating antihistamines.

Adolescent↗
PubMed1999

Antihistamines: models to assess sedative properties, assessment of sedation, safety and other side-effects.

Behavioural changes are produced by any drug that enters the central nervous system. These psychoactive effects include changes in alertness, concentration, attention, memory, cognition, psychomotor accuracy, skilled performance and affect. Changes in psychological performance may affect the safety of both the individuals taking the drug and of those people coming into contact with them. The aims of psychopharmacological performance tests are to describe the nature, extent and severity of these changes and identify drugs without deleterious effects upon performance. Use of traditional antihistamines has until recently been associated with a number of undesirable side-effects, the most troublesome of which is sedation. There are two aspects to sedation. Firstly, an objectively determined one based on the results of psychometric tests from controlled trials and secondly, the subjects response to the administration of a drug. Although the second generation of antihistamines have a much more favourable therapeutic index, use of these agents has also been reported to cause varying degrees of sedation. As antihistamines are largely used by ambulant patients, a complete evaluation of sedation should be performed through standardized objective tests, shown to be sensitive to the central effects of antihistamines as well as reliable ratings of subjective experiences. An extensive review of the literature has identified a number of tests which appear to be sensitive to the central effects of antihistamines. These include tests of psychomotor performance, sensori-motor co-ordination speed, information processing, sensory skills as well as physiological measures and subjective rating scales. Using this battery of cognitive and psychomotor tests, it is evident that only a very limited number of antihistamines can claim to be virtually free of both objective and subjective sedative effects, although the second generation of antihistamines are generally less impairing than the original ones; when prescribed at their recommended doses.

Cognition↗
PubMed1999

Arrhythmogenic mechanisms of non-sedating antihistamines.

Antihistamines (H1-receptor antagonists) are amongst the most frequently prescribed drugs worldwide for the treatment of allergic conditions. Recently, there have been reports that certain non-sedating antihistamines, mainly terfenadine and astemizole, might be associated with the risk of rare but severe arrhythmias, namely torsades de pointes, particularly in overdosage, concomitant ingestion of imidazole or macrolide antibiotics and in patients with underlying cardiac or liver diseases. It has now been shown that the molecular target in human ventricle for the potassium channel blockade of antihistamine is HERG gene located in chromosome 7 that expresses the delayed rectifier IKr and appears to be involved in the congenital long QT syndrome. Mechanistic studies showed that blockade of IKr channels by these drugs leads to prolongation of the monophasic action potential (QT interval on surface electrocardiogram) which may then induce the development of early after-depolarization and dispersion of repolarisation leading to torsades de pointes through re-entry mechanism. There are still many questions that need to be answered such as the roles of other potassium channels (IKs, Ito, and Iped) and the relative expression of various potassium channels in different individuals which may be important in the pathogenesis of torsades de pointes with non-sedating antihistamines. There is also a lack of information on the cardiac actions of newer non-sedating antihistamines. It is hoped that with a better understanding of the arrhythmogenic mechanism of non-sedating antihistamines, one will be able to identify those at risk patients and prevent any cardiac toxicity associated with antihistamines and ultimately death.

Arrhythmias, Cardiac↗
PubMed2005

[Oral second generation antihistamines in allergic rhinitis].

BACKGROUND: Histamine is a key mediator of the allergic immediate reaction. Antihistamines belong to the most frequently used treatment modalities in allergic rhinitis. METHODS: The National Libraray of Medicine was searched for current data of the effects of histamine and antihistamines in allergic rhinitis. RESULTS: Histamine acts on 4 different histamine receptors. Activation of H1-receptors on nasal trigeminal nerve fibers transmits nasal itch and sneezing. Nasal hypersecretion is mainly mediated by an trigeminal-parasympathetic reflex. Activation of H1-receptors results in contraction of nasal endothelial cells with consecutive plasma extravasation and edema formation. Histamine also activates H2-receptors on smooth muscle cells surrounding nasal capacitance vessels. They transmit muscle relaxation, increased blood content and an enlarged volume of nasal mucosa. Via peripheral H3-receptors, histamine modulates neurogenic inflammation and via H4-receptors functions of immune cells. Oral second generation antihistamines inhibit histamine dependent activation of nasal H1-receptors. They mainly reduce nasal itch, sneezing, and hypersecretion. In addition, allergy related activity impairment is reduced resulting in improved physical and mental performance. Second generation antihistamines reduce proinflammatory effects mediated by H1-receptors, however, drug concentrations necessary for mast cell stabilization as observed in vitro are not reached in vivo. Oral second generation antihistamines are readily absorbed and reduce allergy symptoms for approximately 24 hours, allowing convenient once daily medication. Modern antihistamines are generally safe; tachyphylaxis, tolerance or rebound has not been observed. CONCLUSION: Due to their minimal adverse effects and efficient symptom reduction oral second generation antihistamines are particularly useful for the treatment of less severe intermittent forms of nasal allergy.

Administration, Oral↗
PubMed2003

Sedation and performance impairment of diphenhydramine and second-generation antihistamines: a meta-analysis.

BACKGROUND: Antihistamines are among the most frequently used medications in the United States. Despite dramatically higher cost, second-generation antihistamines are replacing diphenhydramine because of the perception that they are not constrained by its sedating effects. OBJECTIVE: We sought to examine, through meta-analytic procedures, the collective evidence regarding the sedating and performance-impairing effects of diphenhydramine relative to placebo and second-generation antihistamines. METHODS: A search that began with the MEDLINE database was limited to those studies that included patients with atopic disease and control subjects, were blinded and randomized clinical trials, objectively examined alertness and psychomotor performance, reported means and variances, and were written in English. Information was systematically abstracted from the resulting 18 articles, and effect size was calculated. RESULTS: Diphenhydramine impaired performance relative to placebo control and second-generation antihistamines, including acrivastine, astemizole, cetirizine, fexofenadine, loratadine, and terfenadine. However, results were quite varied, the average sedating effect of diphenhydramine was modest, and in some instances results of tests of performance in the diphenhydramine group showed less sedation than in the control or second-generation antihistamine groups. A significant (P <.05) average effect size indicated a mild sedating effect caused by second-generation antihistamines in comparison with placebo. CONCLUSION: The absence of a consistent finding of diphenhydramine-induced sedation is surprising given that most studies have been designed to increase the probability of this outcome, including administering a 50-mg dose. On the basis of this meta-analysis of performance-impairment trials, a clear and consistent distinction between sedating and nonsedating antihistamines does not exist.

Diphenhydramine↗
PubMed2003

Interactions of olopatadine and selected antihistamines with model and natural membranes.

OBJECTIVE: Olopatadine, an effective topical ocular human conjunctival mast cell stabilizer/antihistaminic antiallergic drug, was evaluated and compared to selected classical antihistamines for their interaction with model and natural membranes to ascertain potential functional consequences of such interactions. METHODS: The model membranes examined consisted of the argon-buffer interface and monomolecular films of 1-stearoyl-2-oleoyl-sn-glycero-3-phosphocholine (SOPC) at the argon-buffer interface. Interactions with the model membranes were detected as changes in surface tension, i.e., surface pressure. Functional consequences of these interactions were assessed with natural membranes by 6-carboxyfluorescein leakage, hemoglobin release, lactate dehydrogenase release, and histamine release from appropriate cell types. RESULTS: Measurements at the argon-buffer interface revealed intrinsic surface activity for all agents that ranged from highly surface-active to weakly surface-active in the order of: desloratadine > clemastine > azelastine congruent with ketotifen > diphenhydramine> pyrilamine > emedastine > epinastine > or = olopatadine. This order of amphipathic behavior was confirmed for most of the compounds by estimates of their dissociation constants (K(d,L)) determined from interactions with SOPC monolayers adjusted to a surface pressure approximating that of natural membranes. Epinastine was the only antihistamine that showed a disproportionately greater increase in surface activity toward SOPC in monolayer when compared to other antihistamines. Dissociation constants could not be established for olopatadine because of its low affinity for both the argon-buffer interface and the SOPC monolayer. Functional consequences of these interactions were assessed with natural membranes by 6-carboxyfluorescein leakage (erythrocyte ghosts), hemoglobin release (erythrocytes), lactate dehydrogenase release (conjunctival mast cells, corneal epithelial cells), and histamine release (conjunctival mast cells). Aside from olopatadine and emedastine, all antihistamines promoted a concentration-dependent leakage of hemoglobin from intact erythrocytes. The concentration of drug required to cause half-maximal hemoglobin release (H(50)) from erythrocytes correlated linearly (r = 0.98) with the SOPC dissociation constants (K( d,L)) estimated for the different antihistaminic agents interacting with SOPC monolayers. A similarly high correlation (r = 0.85) emerged from a plot with a slope approaching unity that related drug concentrations required for half-maximal hemoglobin leakage from erythrocytes to threshold doses of drug that caused histamine release from human conjunctival mast cells. Olopatadine was the only agent that did not promote membrane perturbation as monitored by either hemoglobin release from intact erythrocytes, LDH release from human conjunctival mast cells, or 6-carboxyfluorescein release from erythrocyte ghosts. Assessment of the lytic potential of marketed concentrations of ketotifen (0.025%), azelastine (0.05%), and epinastine (0.05%) revealed significant membrane perturbation of human conjunctival mast cells and, importantly, human corneal epithelial cells as indexed by LDH release. This was in contrast to marketed concentrations of olopatadine (0.1%) which maintained normal mast cell and corneal epithelial cell membrane function. CONCLUSIONS: Combined, these results support the notion that the disruption of natural cell membranes by surface-active antihistamines occurs not through a receptor-mediated process, but is the consequence of a direct interaction of these agents with the cell membrane. This is corroborated by surface pressure-concentration isotherms for adsorption of five different antihistaminic agents to SOPC monolayers where 50% lysis occurred at a surface pressure of 42.9 +/- 1.1 mN/m. Olopatadine appears to be unique among the agents tested by demonstrating low intrinsic surface activity, thus limiting its interaction with natural membranes. At concentrations of about half-maximal compound solubility (, 5.0 mM or a 0.19% drug solution), olopatadine generated SOPC monolayer surface pressures (i.e., 39.82 +/- 0.10 mN/m) that were below those that promoted membrane perturbation and onset of hemoglobin leakage. Olopatadine's restricted interaction with membrane phospholipids limits the degree of membrane perturbation and release of intracellular constituents, including histamine, LDH, and hemoglobin, which is believed to contribute to olopatadine's topical ocular comfort and patient acceptance.

Animals↗
PubMed2001

Variant effect of first- and second-generation antihistamines as clues to their mechanism of action on the sneeze reflex in the common cold.

Treatment with first-generation antihistamines reduces sneezing, rhinorrhea, nasal mucus weight, and, in some instances, cough in subjects with experimental or natural colds; however, treatment with second-generation antihistamines has not been effective for these complaints in trials in subjects with natural colds. This article reports the negative results of a clinical trial with loratadine, a second-generation antihistamine, in adults in the rhinovirus challenge model. This finding in the highly controlled setting of the challenge model confirms the earlier negative studies with second-generation antihistamines in natural colds. First-generation antihistamines block both histaminic and muscarinic receptors as well as passing the blood-brain barrier. Second-generation antihistamines mainly block histaminic receptors and do not pass the blood-brain barrier. The effectiveness of first-generation antihistamines in blocking sneezing in colds may be due primarily to neuropharmacological manipulation of histaminic and muscarinic receptors in the medulla.

Adult↗
PubMed1998

Oral antihistamines reduce the side effects from rapid vancomycin infusion.

UNLABELLED: Rapid infusion of vancomycin causes histamine-mediated side effects, hypotension, and rash, known as "red man syndrome." In this prospective, randomized, double-blind, placebo-controlled study, we examined the ability of oral antihistamines to attenuate three clinical end points: rash, hypotension, and vancomycin discontinuation, and we compared these findings with those of a similar study using IV antihistamines. Patients (ASA physical status I-III) who required vancomycin prophylaxis for elective arthroplasty received either oral antihistamines (diphenhydramine < or = 1 mg/kg and cimetidine < or = 4 mg/kg, n = 20) or placebo (n = 10) 1 h before rapid vancomycin infusion (1 g over 10 min). The vancomycin infusion was discontinued if the mean arterial blood pressure decreased by > or = 20% or if itching was intolerable for the patient. Clinically significant hypotension developed in no treated patients, compared with five (50%) patients in the placebo group (P = 0.001). Rapid infusion was stopped for one treated patient (5%) and for five (50%) patients in the placebo group (P = 0.004). Incidence (P = 0.011) and severity of rash (P = 0.015) were also reduced in treated patients. Peak histamine levels were increased but were similar for patients in both groups (mean +/- SD, 1.9+/-2.5 vs 1.6+/-2.4 ng/mL; P = 0.75). Oral antihistamines were as effective as IV antihistamines. In conclusion, oral H1 and H2 antihistamine pretreatment is a practical, safe, and inexpensive option to attenuate histamine-mediated side effects associated with rapid vancomycin infusion. IMPLICATIONS: Clinicians often must administer vancomycin faster than the 1-h recommended time, which can cause "red man syndrome" (rash, itching, hypotension). Our randomized, double-blind, placebo-controlled study showed that oral H1 and H2 antihistamine pretreatment significantly reduced the histamine-related side effects of rapid vancomycin infusion.

Administration, Oral↗