Histamine is an intracellular messenger mediating platelet aggregation.

Inhibition of human platelet aggregation by N,N-diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine-HCl (DPPE), a novel antagonist of histamine binding, suggested that histamine might serve a critical role in cell function. Phorbol-12-myristate-13-acetate (PMA) or collagen was found to increase platelet histamine content in parallel with promotion of aggregation. Inhibitors of histidine decarboxylase (HDC) suppressed both aggregation and the elevation of histamine content, whereas DPPE inhibited aggregation only. In saponin-permeabilized platelets, added histamine reversed the inhibition by DPPE or HDC inhibitors on aggregation induced by PMA or collagen. The results indicate a role for histamine as an intracellular messenger, which in platelets promotes aggregation.

Results of a clinical trial in humans with refractory cancer of the intracellular histamine antagonist, N,N-diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine-HCl, in combination with various single antineoplastic agents.

PURPOSE: We assessed N,N-diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine-HCl (DPPE) potentiation of chemotherapy in vitro and performed a pharmacokinetic study and phase I/II trial of DPPE, combined with various single agents, in patients with advanced refractory cancer. PATIENTS AND METHODS: In vitro chemopotentiation by DPPE was assessed in drug-sensitive and -resistant (multidrug resistant-positive [MDR+]) human tumor cells using a colony survival assay. The effect of DPPE and verapamil on the intracellular concentration of daunorubicin in MDR+ cells was compared. For the clinical study, subjects with progressive malignancy received a weekly infusion of a maximally tolerated dose of DPPE (240 mg/m2) over 80 or 440 minutes, in conjunction with a single chemotherapy drug to which, in most cases, the patient's tumor was previously resistant. Concentrations of DPPE in blood and urine were determined by high-performance liquid chromatography (HPLC). RESULTS: In vitro, micromolar concentrations of DPPE potentiated (fivefold to 10-fold) chemotherapy cytotoxicity to both drug-sensitive and -resistant cells, but did not inhibit the p-glycoprotein pump; in vivo, serum levels of DPPE were 3 to 5 mumol/L at the end of 80 minutes and 1 to 2 mumol/L after 440 minutes of infusion. Of 48 patients monitored for a minimum of four DPPE/chemotherapy treatment cycles, 16 (33%) progressed, 12 (25%) stabilized, 12 (25%) improved, and eight (17%) responded (one complete and seven partial remissions). Four of 11 subjects who did not respond to the 80-minute infusion regimen improved with the 440-minute infusion; one had a partial remission of melanoma. In more than 600 patient-treatments, bone marrow toxicity was negligible (mean absolute neutrophil count [ANC] > 2.0 x 10(9)/L). Acute CNS symptoms associated with DPPE infusions were of relatively short duration (1 to 4 hours); delayed toxicity attributable to DPPE consisted of mild nausea and/or fatigue (1 to 2 days). CONCLUSION: Although preliminary, the results suggest that more structured trials should be performed to determine whether DPPE may increase the therapeutic index of certain chemotherapy drugs.

Pharmacokinetic and pharmacodynamic studies of the H1-receptor antagonist hydroxyzine in the elderly.

The pharmacokinetics and pharmacodynamics of the antipruritic H1-receptor antagonist hydroxyzine hydrochloride were studied in nine healthy, fasting subjects (mean age 69.5 +/- 3.7 years) who ingested a single dose of hydroxyzine syrup, 0.7 mg/kg (mean dose 49.0 +/- 6.7 mg). Blood samples were collected hourly for 6 hours, every 2 hours from 6 to 12 hours, at 24 hours, and then every 24 hours for 144 hours. At these times an intradermal injection of 0.01 ml of a 0.1 mg/ml histamine phosphate solution was performed, and wheal and flare areas were computed. The serum elimination t1/2 of hydroxyzine was 29.3 +/- 10.1 hours; the volume of distribution was 22.5 +/- 6.3 L/kg; the clearance rate was 9.6 +/- 3.2 ml/min/kg, and the AUC was 1383.1 +/- 1039.0 ng.hr/ml. The mean serum elimination t1/2 of cetirizine, the active metabolite of hydroxyzine generated in vivo, was 24.8 +/- 7.7 hours, not significantly different from that of the parent compound (p = 0.05). After a single dose of hydroxyzine the mean wheal and flare areas were significantly suppressed from 1 to 144 hours, compared with the mean predose wheal and flare sizes (p less than 0.01). Maximum wheal suppression, compared with all other wheals measured during the study, occurred from 4 to 10 hours, inclusive, and maximum flare suppression occurred from 2 to 72 hours, inclusive (p less than 0.01). Hydroxyzine has a long t1/2 and a large volume of distribution in the elderly. The suppressive effect on the wheal and flare after a single dose of hydroxyzine is also extremely prolonged, suggesting the possibility of enhanced H1-receptor activity in old age.

Efficacy of dyphylline (dihydroxypropyltheophylline) in exercise-induced bronchospasm.

The efficacy of dyphlline in prevention of exercise-induced bronchospasm (EIB) was studied in seven subjects. A single 15 mg/kg dose of dyphylline 40 minutes prior to exercise prevented EIB as documented by a significantly smaller mean greatest percent decrease in forced expiratory volume in one second when compared to placebo. Mean serum dyphylline concentrations 40 minutes after a dose of 15 mg/kg were probably in the lower portion of the therapeutic range.

Pharmacokinetic optimisation of histamine H1-receptor antagonist therapy.

Second-generation, relatively nonsedating histamine H1-receptor antagonists (H1-RA) are extensively used worldwide for the symptomatic treatment of allergic rhinoconjunctivitis and chronic urticaria. Information about the pharmacokinetics and pharmacodynamics of these medications, while still incomplete, is now sufficient to permit optimisation of therapy. Published pharmacokinetic and pharmacodynamic information on these H1-RA is summarised here, and areas where more data are required are delineated. Serum concentrations of most second-generation H1-RA are relatively low, and are usually measured by radioimmunoassay. After oral administration, peak concentrations are observed within 2 or 3 h. Bioavailability has not been well studied, due to the lack of intravenous formulations. Most H1-RA are metabolised in the hepatic cytochrome P450 system: terfenadine, astemizole, loratadine, azelastine, and ebastine have 1 or more active metabolites which are present in serum in higher concentrations than the respective parent compound, and therefore can be measured by high performance liquid chromatography. Cetirizine, an active metabolite of the first generation H1-receptor antagonist hydroxyzine, is not further metabolised to any great extent in vivo, and is eliminated via renal excretion. Levocabastine is also eliminated primarily by excretion. Serum elimination half-life values differ greatly from 1 H1-RA to another, and are 24 h or less for terfenadine, astemizole, loratadine, cetirizine, azelastine and ebastine, and the active metabolites of terfenadine, loratadine and ebastine. The active metabolite of azelastine (demethylazelastine) has a serum elimination half-life value of about 2 days, while that of astemizole (demethyl-astemizole) has a value of 9.5 days. From the few published studies in which the apparent volumes of distribution of the second-generation H1-RA have been calculated, it appears that tissue distribution is extensive. In children, the half-lives of H1-RA are generally shorter than are found in adults; there is no published information on the pharmacokinetics of astemizole, loratadine, azelastine, or ebastine in children. In some elderly adults, terfenadine, loratadine and cetirizine may have longer half-lives than in young healthy adults. There is little published data on the pharmacokinetics of the second-generation H1-RA in patients with impaired hepatic function. The half-life of cetirizine is prolonged in those with impaired renal function. There is a paucity of information on the pharmacokinetics of H1-RA in neonates, in pregnancy or during lactation.(ABSTRACT TRUNCATED AT 400 WORDS)

Clinical pharmacology of new histamine H1 receptor antagonists.

The recently introduced H1 receptor antagonists ebastine, fexofenadine and mizolastine, and the relatively new H1 antagonists acrivastine, astemizole, azelastine, cetirizine, levocabastine and loratadine, are diverse in terms of chemical structure and clinical pharmacology, although they have similar efficacy in the treatment of patients with allergic disorders. Acrivastine is characterised by a short terminal elimination half-life (t1/2 beta) [1.7 hours] and an 8-hour duration of action. Astemizole and its metabolites, in contrast, have relatively long terminal t1/2 beta values; astemizole has a duration of action of at least 24 hours and is characterised by a long-lasting residual action after a short course of treatment. Azelastine, which has a half-life of approximately 22 hours, is primarily administered intranasally although an oral dosage formulation is used in some countries. Cetirizine is eliminated largely unchanged in the urine, has a terminal t1/2 beta of approximately 7 hours and a duration of action of at least 24 hours. Ebastine is extensively and rapidly metabolised to its active metabolite; carebastine, has a half-life of approximately 15 hours and duration of action of at least 24 hours. Fexofenadine, eliminated largely unchanged in the faeces and urine, has a terminal t1/2 beta of approximately 14 hours and duration of action of 24 hours, making it suitable for once or twice daily administration. Levocabastine has a terminal t1/2 beta of 35 to 40 hours regardless of the route of administration, but is only available as a topical application administered intranasally or ophthalmically in patients with allergic rhinoconjunctivitis. Loratadine is rapidly metabolised to an active metabolite descarboethoxyloratadine and has a 24-hour duration of action. Mizolastine has a terminal t1/2 beta of approximately 13 hours and duration of action of at least 24 hours. Most orally administered new H1 receptor antagonists are well absorbed and appear to be extensively distributed into body tissues; many are highly protein-bound. Most of the new H1 antagonists do not accumulate in tissues during repeated administration and have a residual action of less than 3 days after a short course has been completed. Tachyphylaxis, or loss of peripheral H1 receptor blocking activity during regular daily use, has not been found for any new H1 antagonist. Understanding the pharmacokinetics and pharmacodynamics of these new H1 antagonists provides the objective basis for selection of an appropriate dose and dosage interval and the rationale for modification in the dosage regimen that may be needed in special populations, including elderly patients, and those with hepatic dysfunction or renal dysfunction. The studies cited in this review provide the scientific foundation for using the new H1 antagonists with optimal effectiveness and safety.

Optimum pharmacological management of chronic rhinitis.

Pharmacological treatment of chronic rhinitis has greatly improved with the introduction of the relatively non-sedating H1-receptor antagonists such as terfenadine, astemizole, loratadine, and cetirizine, and the safe, highly efficacious topical glucocorticosteroids such as beclomethasone dipropionate, flunisolide, budesonide, fluocortin butyl, and triamcinolone acetonide. In patients whose chief complaint is rhinorrhoea, topical ipratropium bromide may be of value. Patients whose major symptom is nasal congestion will benefit from intermittent use of topically or orally administered decongestants. In patients with allergic rhinitis, sodium cromoglycate (cromolyn sodium) or nedocromil sodium applied topically intranasally have a moderate beneficial effect and are associated with a low incidence of adverse effects. Non-pharmacological treatment of chronic rhinitis cannot be ignored. Patients must avoid inhalation of cigarette smoke and other irritants. Patients with chronic allergic rhinitis should avoid antigens to which they have known sensitivity: in addition, selected patients with allergic rhinitis may benefit from immunotherapy with the offending antigen(s).

Development of chronic airway hyperresponsiveness in ragweed-sensitized dogs.

We studied dogs neonatally sensitized to ragweed and their littermate controls at 4, 6, 8, 10, 12, and 15 mo of age. Acute allergic airway response to inhalation of ragweed in the sensitized dogs was marked (greater than 12-fold increase from base line) and reproducible at all times. Nonallergic airway responsiveness, measured as the concentration of acetylcholine required to increase airway resistance by 5 cmH2O.l-1.s (PC5), increased in sensitized and decreased in nonsensitized dogs from 4 to 15 mo of age (P less than 0.01). Before antigen, at 12 and 15 mo, sensitized dogs were significantly (P less than 0.05) more responsive to acetylcholine than controls. Six hours after antigen, sensitized dogs were 11-fold more responsive (P less than 0.005) than controls at those times. More eosinophils and mast cells and fewer macrophages (P less than 0.05) were present in bronchoalveolar lavage (BAL) from 12- and 15-mo-old sensitized dogs than their controls. BAL fluid histamine was higher (P less than 0.05) in sensitized than control dogs. Regression analysis revealed r = -0.75 (P = 0.003) between BAL mast cells and PC5 in sensitized dogs and R2 = 0.89 for PC5 and BAL mast cells, macrophages, and eosinophils. Neonatally sensitized dogs represent an excellent animal model in which to study the pathophysiology of asthma.

Pharmacokinetics of theophylline in infancy.

Theophylline clearance rates and half-life values were measured in 15 infants aged three to 23 months, after infusion of aminophylline by the intravenous route for at least 24 hours. The mean clearance rate was 1.07 +/- 0.55 ml/min-kg, which is comparable with values obtained by others in older children. There was some correlation of clearance rates with age. The mean half-life was 4.4 +/- 2.2 hours. There was a tenfold variability in half-life, suggesting that individualization of theophylline dose is especially important in infants if undertreatment and toxicity are to be avoided.

Bioavailability of a sustained-release dyphylline formulation.

The bioavailability of dyphylline from sustained-release tablets, studied in seven normal subjects given a single dose of the drug, was 67.8 per cent of that from conventional tablets. In three subjects given 40 mg/kg dyphylline as sustained-release tablets every 8 hours for four days, serum dyphylline concentrations were maintained above 7.88 microng/ml once steady state was achieved. No adverse effects were noted, though in one subject peak serum dyphylline concentrations reached 30 microng/ml after multiple doses.

Diphenhydramine: pharmacokinetics and pharmacodynamics in elderly adults, young adults, and children.

The pharmacokinetics and pharmacodynamics of the H1-receptor antagonist diphenhydramine were studied in 21 fasting subjects divided into three age groups: elderly, (mean age 69.4 +/- 4.3 years), young adults, (mean age 31.5 +/- 10.4 years), and children, (mean age 8.9 +/- 1.7 years). All subjects ingested a single dose of diphenhydramine syrup 1.25 mg/kg, in mean doses of 86.0 +/- 7.3 mg, 87.9 +/- 12.4 mg, and 39.5 +/- 8.4 mg, respectively. Blood samples were collected hourly for 6 hours, every 2 hours until 12 hours, at 24 hours, and, in the adults, up to 72 hours after diphenhydramine administration. At these times, histamine skin tests were performed and wheal and flare areas were computed. The mean serum elimination half-life values for diphenhydramine differed significantly in elderly adults, young adults, and children, with values of 13.5 +/- 4.2 hours, 9.2 +/- 2.5 hours, and 5.4 +/- 1.8 hours being found respectively in each age group. Clearance rates for diphenhydramine also differed significantly with age, being 11.7 +/- 3.1 mL/min/kg in elderly adults, 23.3 +/- 9.4 mL/min/kg in young adults and 49.2 +/- 22.8 mL/min/kg in children. Diphenhydramine produced a maximum wheal suppression of 39.6 +/- 22.5% and a maximum flare suppression of 46.5 +/- 32.1% at 5 and 6 hours respectively in the elderly; a maximum wheal suppression of 45.5 +/- 25.0% and a maximum flare suppression of 53.4 +/- 16.9% at 6 and 4 hours respectively in young adults; and a maximum wheal suppression of 68.4 +/- 10.2% and a maximum flare suppression of 87.2 +/- 4.2% at 2 hours in children.

The pharmacokinetics and pharmacodynamics of hydroxyzine in patients with primary biliary cirrhosis.

Hydroxyzine, a potent H1-receptor antagonist often used for relief of pruritus in patients with hepatic dysfunction, was studied in eight patients, mean age 53.4 +/- SD 11.2 years, with primary biliary cirrhosis. The patients ingested a single dose of hydroxyzine, 0.7 mg/kg (mean dose 43.9 +/- 6.6 mg). Before the dose, then hourly for 6 hours, every 2 hours from 6-12 hours, at 24 hours, and every 24 hours for 6 days, serum hydroxyzine and cetirizine were measured and an intradermal injection of 0.01 mL of a 0.1 mg/mL solution of histamine phosphate was performed. Wheals and flares were traced at 10 minutes and the areas were calculated. Mean peak hydroxyzine levels of 116.5 +/- 60.6 ng/mL occurred at 2.3 +/- 0.7 hours and mean peak cetirizine levels of 500.4 +/- 302.0 ng/mL occurred at 4.8 +/- 2.8 hours. The mean serum elimination half-life of hydroxyzine was 36.6 +/- 13.1 hours, and the mean serum elimination half-life of cetirizine was 25.0 +/- 8.2 hours. The mean hydroxyzine clearance rate was 8.65 +/- 7.46 mL/min/kg, and the mean volume of distribution was 22.7 +/- 13.3 L/kg. The mean wheal area was suppressed (P less than 0.01) from 1 to 120 hours, with maximal suppression from 2 to 48 hours. The mean flare area was suppressed from 1 to 144 hours, with maximal suppression from 3 to 24 hours (P less than 0.01). All patients became sleepy from 0.5 to 6 hours. Blurred vision, dizziness and dry mouth each occurred in two patients. Hydroxyzine elimination is impaired in patients with primary biliary cirrhosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Cetirizine pharmacokinetics and pharmacodynamics in primary biliary cirrhosis.

The new H1-receptor antagonist, cetirizine, is eliminated primarily unchanged by renal excretion and is thus potentially useful for relief of pruritus in patients with hepatic dysfunction, in whom many H1-receptor antagonists are contraindicated. The authors studied the elimination of cetirizine in six patients with primary biliary cirrhosis. In contrast to data obtained in healthy adults with normal hepatic function reported in the medical literature, they found that the mean serum elimination half-life value of cetirizine, 13.8 +/- 1.8 hours, was longer, and the mean clearance rate, 0.44 +/- 0.10 mL/min/kg, was lower (P < .05). The mean peak serum cetirizine concentration, 498 +/- 118 ng/mL, was higher, the mean area under the curve, 6438 +/- 1621 ng/mL/hr, was larger, and the mean fraction of the dose excreted as unchanged cetirizine in the urine, .32 +/- .14, was lower (P < .05). The duration of action of cetirizine was prolonged, as evidenced by significant suppression of the histamine-induced wheal and flare for 48 and 72 hours, respectively, after a single dose. Cetirizine elimination was impaired in patients with hepatic dysfunction.

Pharmacokinetics of theophylline in neonates.

Theophylline is a safe, effective drug for the treatment of apnea of prematurity. The pharmacokinetics of theophylline have been studied extensively in preterm neonates. There is some inter-infant variability, but generally, compared to children and adults, prolonged half-life values and low clearance rates have been found: the apparent volume of distribution is larger and protein binding of the drug is decreased. A unique pattern of metabolism involving methylation to caffeine has been identified. Theophylline maintenance dose requirements are much lower in neonates than in children. When therapy is begun, a useful guide is to give a loading dose of 5 mg/kg anhydrous theophylline followed by maintenance doses of 2 mg/kg every 12 hr. In many infants, this will suffice to prevent apnea without producing signs of toxicity. After commencement of therapy, doses must be individualized for each infant on the basis of serum theophylline concentration monitoring and monitoring for apnea. Evidence of theophylline toxicity in neonates may be subtle, and only scanty data are available regarding possible long-term effects of chronic theophylline treatment of neonates.

Urinary excretion of dyphylline in humans.

The pharmacokinetics and urinary excretion of a single dyphylline dose were studied in five normal volunteers. The mean dyphylline half-life was 1.8 +/- 0.2 hr; the mean total body clearance rate and mean renal clearance rate were 333 +/- 62 and 276 +/- 52 ml/min, respectively; and the mean volume of distribution was 0.8 +/- 0.2 liter/kg. In the urine, 83 +/- 5% of the dose was excreted as unchanged drug, and theophylline was not detected. Dyphylline doses of 19--27 mg/kg, resulting in peak serum dyphylline concentrations of 19.3--23.5 micrograms/ml, were tolerated well by four subjects. One subject had a severe headache following a 28-mg/kg dose, associated with a peak serum dyphylline concentration of 36.4 micrograms/ml. This study confirms speculation that dyphylline is not metabolized to theophylline in vivo.

GLC determination of procainamide in biological fluids.

A GLC method for the determination of procainamide in biological fluids is presented. By using a dipropyl analog of procainamide as an internal standard, both compounds can be chromatographed directly, yielding linear calibration curves and a sensitivity that allows quantitative determination of concentrations as low as 0.1 mug/ml. The extraction procedure was carefully modified to avoid hydrolysis of N-acetylprocainamide, a major metabolite of procainamide. The usefulness of the procedure is demonstrated by following the disappearance of procainamide from the plasma and urine of human subjects treated with the drug.

Theophylline protein binding in humans.

Theophylline protein binding was 58-82% in serum from six normal adults and 42 asthmatic patients, 1-25 years old, who were given 5 mg of theophylline/kg. The binding range was greatest in young patients, but the proportion of protein-bound drug did not correlate with age. Theophylline protein binding was higher than previously reported. The effect of binding should be considered in patients who do not have optimal bronchodilation from theophylline despite total serum theophylline concentrations of 10-20 microgram/ml.

Dissolution and bioavailability studies of whole and halved sustained-release theophylline tablets.

In dissolution studies of whole and halved 100-mg sustained-release theophylline tablets, drug release from halved tablets was significantly higher. These differences were not reflected in the bioavailability studies. The area under the curve (AUC) mean absorption time and fraction-of-dose recovered in urine at 24 hr were not significantly different following the ingestion of whole or halved 100-mg tablets. The elimination rate constant, half-life, volume of distribution, plasma, and renal clearance values were consistent with values reported previously. Discrepancies were found in the 24-hr metabolite distribution as compared to literature values and may be accounted for by the age and health of the subjects and the frequency of dosing.

Dissolution studies of some sustained-release theophylline dosage forms.

Dissolution studies were carried out with the USP rotating-basket apparatus in both simulated gastric and intestinal fluids. Four different brands of sustained-release theophylline products of different strengths (nine formulations) were studied. The percentage of the dose released in 1 h in gastric fluid ranged from (mean +/- SD) 6.6 +/- 0.9 to 50.1 +/- 3.8%. By 6 h, the percentage of the dose released ranged from 10.8 +/- 1.8 to 86.5 +/- 5.2%. Similar formulations of different strengths released significantly different fractions of their dose at respective sampling times. In intestinal fluid, some formulations released 100% of their dose within 3-4 h, behaving more like enteric-coated preparations. One dosage form appeared to release drug by an apparent zero-order rate. From one brand of theophylline (two strengths), only 48.1 +/- 5.6 and 29.9 +/- 4.1% of label strength, respectively, dissolved in 25 h in intestinal fluid. Some of these in vitro results were rank-correlated to previously reported bioavailability and pharmacokinetic studies.

Urinary excretion of chlorpheniramine and its metabolites in children.

The pharmacokinetics and urinary excretion of chlorpheniramine were studied in 11 patients, aged 6-16 years, with allergic rhinitis. In these children, chlorpheniramine had a mean elimination half-life of 13.1 +/- 6.6 h, a mean clearance rate of 7.23 +/- 3.16 mL/min/kg, and a mean apparent volume of distribution of 7.0 +/- 2.8 L/kg. Over 48 h, the recovery in urine was as follows: chlorpheniramine, 11.3 +/- 6.7%; demethylchlorpheniramine , 23.3 +/- 11.1%; and didemethylchlorpheniramine , 9.6 +/- 9.4%. Urine flow rate and urine pH were uncontrolled and ranged from 2.2 to 113.3 mL/h and 5.1-7.9, respectively, over the 48-h period. In some children urine flow rate and pH were constant, while in others there was great variability. When drug and metabolite excretion rates versus both urine flow rates and pH values were analyzed by multiple linear regression, the results were significantly better (p less than or equal to 0.05) than when each factor was analyzed independently. The excretion rate of chlorpheniramine and its two demethylated metabolites decreased as urine pH increased and urine flow rate decreased. This information must be considered in future pharmacokinetic studies of this drug.