Efficacy of acrivastine plus pseudoephedrine for symptomatic relief of seasonal allergic rhinitis due to mountain cedar.

BACKGROUND: Acrivastine is a second-generation H1-antagonist chemically related to triprolidine, but more polar and with less central nervous system penetration than triprolidine. OBJECTIVE: The efficacy of the antihistamine-decongestant combination product (Semprex-D capsules) containing acrivastine 8 mg plus pseudoephedrine HCl 60 mg was evaluated for the treatment of seasonal allergic rhinitis symptoms. METHODS: A total of 676 patients sensitive to mountain cedar pollen was enrolled into a 6-center, randomized, double-blind, placebo-controlled, parallel, 4-group study designed to compare acrivastine + pseudoephedrine, acrivastine, pseudoephedrine, and placebo. Patients with demonstrable diary symptom scores at baseline took study medication (4 doses/day) and recorded symptom scores twice daily for 2 weeks. The effectiveness of the acrivastine + pseudoephedrine combination was examined relative to the individual components and placebo in terms of changes in diary symptom scores. RESULTS: Over the 2-week period, the combination of acrivastine plus pseudoephedrine was significantly more effective than (1) acrivastine, pseudoephedrine, and placebo (P < .001) for relief of all symptoms; (2) pseudoephedrine (P < .001) for relieving allergy symptoms, ie, running nose, sneezing, itchy nose/throat and tearing; and (3) acrivastine (P < .001) for reducing nasal congestion. Relative to placebo, small increases in adverse experience rates were observed with acrivastine + pseudoephedrine for dry mouth, insomnia, somnolence, and headache. CONCLUSION: These findings in a large clinical trial demonstrate (1) the efficacy of acrivastine and (2) that each component of the combination of acrivastine 8 mg plus pseudoephedrine HCl 60 mg contributes to the overall efficacy, thereby supporting the conclusion that the combination is rational, safe, and effective for the treatment of allergic rhinitis.

Pharmacokinetics of oral and transdermal triprolidine.

In this open, nonrandomized, three-way crossover study, six healthy male volunteers received single doses of triprolidine (TPL) hydrochloride syrup orally (2.5 mg) and wore transdermal TPL patches (5 mg and 10 mg doses) to compare the pharmacokinetic profiles and dose tolerance of the two formulations. A washout period of at least 1 week was scheduled between the three dosing periods. Blood samples were collected at defined times, and plasma concentrations were determined using a radioimmunoassay. Maximum plasma drug concentration (Cmax) decreased from 5.6 +/- 2.9 ng/mL (mean +/- SD) with oral dosing to 2.0 +/- 1.0 ng/mL and 4.2 +/- 2.0 ng/mL following 5 mg and 10 mg transdermal doses, respectively. Time to reach peak concentration (tmax) increased from 2.0 +/- 1.2 hours with oral dosing to 12.0 +/- 5.9 and 14.3 +/- 9.9 hours following 5 mg and 10 mg transdermal doses, respectively. The differences between AUC0-alpha values with the oral syrup and the 5 mg and 10 mg transdermal doses were not significant when normalized to 2.09 mg (TPL base). The bioavailabilities of the 5 mg and 10 mg transdermal doses relative to the oral 2.09 mg doses were 0.89 +/- 0.32 and 1.04 +/- 0.33, respectively. Mild erythema and pruritus were the most common adverse effects secondary to TPL transdermal application. Drowsiness observed following oral TPL, was not evident following either transdermal dose. The results of this study, therefore, indicate that TPL can be absorbed transdermally, providing consistent plasma concentrations.

Pharmacokinetics of acrivastine after oral and colonic administration.

Six healthy male volunteers participated in this randomized, crossover open-label pharmacokinetic study consisting of two dosing segments separated by a washout period of at least 5 days. During each dosing segment, each volunteer received 12 mg of acrivastine, an investigational histamine H1-receptor antagonist, in a syrup form either orally or by colonic administration in random order. After oral and colonic administration, respectively, the following mean +/- SD pharmacokinetic parameters were obtained: Cmax 179 +/- 11 and 13.8 +/- 5.2 ng/ml; tmax, 0.85 +/- 0.13 and 3.60 +/- 0.56 hr; AUC0-12 hr, 576 +/- 57 and 104 +/- 46 hr.ng/ml. Differences between the oral and colonic administration for all three parameters were statistically significant (P less than 0.001). The mean +/- SD relative bioavailability of acrivastine from colonic compared to oral dosing was 0.18 +/- 0.09. It may be concluded, therefore, that appreciable absorption of acrivastine from the colon does not take place. These results suggest that comparison of pharmacokinetic profiles of some drugs after oral and colonic administration may be a useful technique for predicting bioavailability from a sustained release oral formulation.

Pulmonary alterations in rats due to acute phosgene inhalation.

This study evaluated the relationship between low-level phosgene (COCl2) exposure and pulmonary change or damage. Male Sprague-Dawley rats were exposed to phosgene for 4 hr at concentrations of 0.125 to 1.0 ppm (30, 60, 120, and 240 ppm X min). We examined the dose-related changes in body weight, lung wet and dry weights, lavage fluid protein concentrations (LFP), total cell count, and cell differential in rats exposed to phosgene under carefully controlled conditions. These parameters were measured at the conclusion of single acute exposures and for 3 days postexposure. Significant changes in lung weights (wet and dry) were observed following exposure to 120 and 240 ppm X min phosgene and the LFP was significantly altered at 60 ppm X min. The changes in lung wet and dry weights pooled over all times and phosgene concentrations each correlated significantly with the change in LFP induced by phosgene. The total number of cells in the lavage fluid of phosgene-exposed rats was increased, and the most sensitive cellular indicator of phosgene inhalation was the increase in the percentage of polymorphonuclear leukocytes (PMNs). These results confirm that LFP concentration and cellular differentials can be used as an index of lung damage due to phosgene. A dose-response relationship for the measured parameters was observed. Over the dosage range studied, the return of all measured parameters to near control levels within 3 days following exposure showed that the pulmonary damage was reversible or rapidly reparable. Although the acute effects were shown to be reversible, studies on chronic, low-level phosgene exposures are necessary to determine safe levels for industrial employees.

Changes in lung ATP concentration in the rat after low-level phosgene exposure.

Inhibition of mitochondrial respiratory activity and decreased lung adenosine triphosphate (ATP) concentration occur following exposure to 240 ppm.min phosgene. To determine the relationship between energy stores and the onset of phosgene-induced pulmonary edema, we measured the ATP concentration in rapidly frozen rat lung tissue before and during pulmonary edema. Male Sprague-Dawley rats were exposed to phosgene for four hours at concentrations of 0.05 to 1.0 ppm (12, 30, 60, 120, and 240 ppm.min). Lung wet and dry weight and ATP concentration were measured immediately after exposure and for three days postexposure. The accumulation of lavage fluid protein (LFP) was also measured as an index of damage or edema due to phosgene. Lung dry weight was significantly elevated one day postexposure to 0.5 ppm phosgene, while the LFP was elevated by 0.2 ppm phosgene. Time course studies at these doses of phosgene showed that decreased ATP levels preceded the onset of edema or increase in lung weight. The ATP values expressed on a per-lung basis showed that ATP levels were significantly lowered immediately following phosgene exposure, suggesting that the ATP changes were not the result of edema. This study is the first demonstration of a biochemical change that occurs following exposure to phosgene at a level significantly below the threshold limit value for this gas.

A comparison of the acute hemodynamic effects of prostacyclin and hydralazine in primary pulmonary hypertension.

In patients with primary pulmonary hypertension the administration of a vasodilating drug is often used to test pulmonary vasoreactivity. Hydralazine has been employed as a test drug, but because of its long duration of action there is a risk of sustained systemic arterial hypotension in patients with a fixed pulmonary vascular resistance. In this study we compared the acute hemodynamic effects of intravenous prostacyclin, a potent, short-acting vasodilator, with the effects of oral or intravenous hydralazine. Both prostacyclin and hydralazine increased cardiac output and decreased systemic pressure without changing pulmonary arterial pressure in seven patients with primary pulmonary hypertension. The average decrease in total pulmonary resistance with prostacyclin (-46% +/- 5%) was more than that with hydralazine (-32% +/- 6%). The respective decreases in total systemic resistance were -50% +/- 4% vs -43% +/- 6%. The percent changes in individual responses to the two agents were correlated (p less than 0.05) for pulmonary arterial pressure, systemic arterial pressure, total pulmonary resistance, and total systemic resistance. We concluded that the pulmonary hemodynamic effects of prostacyclin resembled those of hydralazine. Prostacyclin may predict the acute pulmonary hemodynamic effects of hydralazine in primary pulmonary hypertension and because of its prompt, brief action may provide greater patient safety.

Response of pulmonary energy metabolism to phosgene.

Rats were exposed to phosgene at a concentration of 1.0 ppm for 4 hours in a Rochester-type chamber. At intervals thereafter over a 4 day period, lungs were obtained for histological and biochemical assessments. Edema was estimated by histological examination and by measurement of lung wet and dry weights. In parallel studies, pulmonary mitochondrial respiratory activity was measured using Clark oxygen electrodes. The significant reduction in respiratory control index (State 3 respiration/State 4 respiration) found immediately following phosgene exposure coincided with the highest level of % lung water. There was a concomitant decrease of ATP concentration that persisted on the third day after exposure. Na-K-ATPase activity was reduced 1 day after exposure, thus a lowered ATP level preceded a reduction in Na-K-ATPase or sodium pump activity. The reduction in ATP level and Na-K-ATPase activity may play a major role in damage to lung tissue following exposure to phosgene.

Prophylactic and antidotal effects of hexamethylenetetramine against phosgene poisoning in rabbits.

New Zealand white rabbits were exposed to phosgene doses, expressed as Ct factors, of 125-3120 ppm X min. Hexamethylenetetramine (HMT), 0.3 gm/kg as a 40% aqueous solution, was injected via an ear vein into separate groups of animals at 5-10 min pre-exposure or at 15 min post-exposure to the gas. Non-exposed and exposed, non-HMT-treated animals served as controls. As assessed by survival times, gross morphology of the lungs, percent lung water measurements, serum LDH values, and respiratory gas parameters, pre-exposure administration of HMT at Ct factors as high as 3120 ppm X min provided significant prophylaxis against the effects of phosgene. Post-exposure administration of HMT, however, provided no antidotal effect even when administered as soon as 15 min after exposure to 125 ppm X min phosgene.

Response of the pulmonary surfactant system to phosgene.

Rats were exposed to 240 ppm X min phosgene (1.0 ppm for 4 hrs) in a Rochester-type chamber. At intervals thereafter over a 4 day period, lungs were removed for determination of wet weight; total, microsomal and surfactant protein concentrations; surfactant phospholipid concentrations; and 1-acyl-2-lyso-phosphatidylcholine: palmitoyl-CoA acyl transferase activity. Immediately upon termination of the phosgene exposure, microsomal protein and acyl transferase activity were reduced below, and lung wet weight was elevated above, control levels. From Day 1 through Day 3 after the exposure, all measured parameters, except for the phosphatidylinositol constituent of the surfactant fraction, were increased above the control values. In general, maximum levels were observed on Day 2; however, the acyl transferase activity and surfactant concentration continued to increase on Day 3. The results suggest components of the pulmonary surfactant system may be involved in maintenance of pulmonary fluid balance and the presence of excess water in the lungs as a result of phosgene exposure may represent a signal for increased synthesis of anti-edematogenic materials in order to promote removal of the inappropriate fluid.

Relation of arachidonate metabolites to abnormal control of the pulmonary circulation in a child.

To evaluate the role of arachidonate metabolites in regulating pulmonary vascular tone, we performed multiple studies on a 17-month-old girl with idiopathic pulmonary hypertension, systemic arterial hypoxemia (due to ventilation-perfusion mismatching), and an elevated thromboxane A2 (TXA2) to prostacyclin (PGI2) ratio due to increased TXA2 (measured as their stable metabolites, TXB2 and 6-keto-PGF1 alpha, respectively). Intravenous infusions of PGI2 reduced mean pulmonary arterial pressure (from 80 to 47 mmHg), increased cardiac output (from 3.43 to 3.97 L/min), increased systemic arterial oxygen saturation (from 60 to 72 percent), and decreased the TXB2 to 6-keto-PGF1 alpha ratio (from 5.9 to 0.2); mean systemic arterial pressure was unchanged. Pharmacologically decreasing the TXB2 to 6-keto-PGF1 alpha ratio with administration of nifedipine or diltiazem also reduced pulmonary hypertension and increased systemic arterial oxygen saturation in this patient. Nifedipine and diltiazem decreased the ratio by decreasing TXB2. Prostacyclin decreased the ratio by increasing 6-keto-PGF1 alpha. These studies support the hypothesis that the balance between TXA2 and PGI2 is an important influence on pulmonary vascular tone.

Comparison of pseudoephedrine and triprolidine, alone and in combination in preventing nasal congestion in subjects with allergic rhinitis using nasal histamine challenge.

The abilities of triprolidine 2.5 mg and pseudoephedrine 60 mg, alone and in combination, to protect against an increase in nasal airway resistance (NAR) after histamine challenge were determined in eighteen individuals with grass pollen allergy. The study was conducted outside the pollen season using a double-blind, placebo controlled crossover design. The prior administration of pseudoephedrine 60 mg and triprolidine 2.5 mg alone or in combination was superior to placebo in reducing the increase in NAR after challenge with 1.0% histamine. However, such NAR measurements did not differentiate between pseudoephedrine 60 mg and triprolidine 2.5 mg administered alone or in combination. Challenge with 0.1% histamine failed to discriminate between any of the test medications.

The role of acyl transferase in the biosynthesis of pulmonary microsomal phosphatidylglycerol.

Dog lung microsome contain an enzymatic system capable of catalyzing the transfer of radiolabel from [14C]-acyl CoA, palmitoyl or oleoyl, to 1-acyl-2-lysophosphatidylglycerol thereby forming phosphatidylglycerol. This synthetic activity is consistent with a 1-acyl-2-lyso-phosphatidylglycerol:acyl-CoA acyl transferase. Kinetic analysis suggests the enzyme is preferentially, but not exclusively, orientated to the production of 1-acyl-2-oleoyl-phosphatidylglycerol. When enzymatic activity was examined with palmitoyl-CoA as the donor substrate and either 2-lysophosphatidylglycerol or 2-lysophosphatidylcholine as the acceptor substrates, the preferred product seemed to be phosphatidylglycerol. When the activity was examined with both acceptor substrates present, phosphatidylglycerol formation decreased while phosphatidylcholine formation increased. This observation may represent an effective control mechanism for the differential synthesis of pulmonary phospholipids, according to metabolic or physiological requirements.

1-Acyl-2-lysophosphatidylcholine: phosphatidylglycerol-2-acyltransacylase in lung microsomes and type II pneumocyte-derived cultures.

The formation of [3H]phosphatidylcholine from 1-acyl-2-lysophosphatidylcholine and 1-acyl-2-[9,10-3H]palmitoylphosphatidylglycerol, presumably by 1-acyl-2-lysophosphatidylcholine : phosphatidylglycerol-2-acyltransacylase (phosphatidylglycerol transacylase), was detected in lung microsomes and Set 4 type II pneumocyte-derived cultured cells but not in A549 adenocarcinoma-derived type II cell analogs. There was greater phosphatidylglycerol transacylase activity in Set 4 cells at confluence than at the mid-log stage. Since the phosphatidylglycerol transacylase activity was always markedly less than that observed for 1-acyl-2-lysophosphatidylcholine : acyl-CoA acyltransferase, the former does not appear to represent a major pathway for synthesis of pulmonary dipalmitoylphosphatidylcholine.

Surface-active material in human amniotic fluid.

Surface-active fractions similar to the biochemical constituents of the pulmonary surfactant system can be isolated from human amniotic fluid and lung tissue from week 10 of gestation through term. Amniotic fluid yielded 10 mg. per 100 ml. surface-active material at 10 to 28 weeks' gestation and 330 mg. per 100 ml. at term. Fetal lung at 10 weeks of gestation gave 1,233 mg. per 100 ml. and 1,670 mg. per 100 ml. at 4 days after birth. The constituent PC of these surface-active fractions from amniotic fluid and lung contained in excess of 60 per cent palmitoyl residues. PC associated with the surface-active fraction accounted for no more than 15 per cent of the total amniotic fluid concentration of this compound. Minimum surface tensions obtained with these preparations from amniotic fluid ranged from 2.5 dynes per centimeter at 33 weeks to 8.3 dynes per centimeter at 40 weeks. At 14 to 28 weeks, the surface-active fraction from lung gave a minimum surface tension of 18.1 dynes per centimeter and 7.0 dynes per centimeter by 4 days after birth. These findings are consistent with the observation that an increase in the activity or concentration of the fetal lung surfactant system takes place in the last 4 weeks of gestation. Some constituents of this system, or their derivatives which have possibly been altered as a result of biochemical changes, are found in amniotic fluid. We infer that the majority of PC in amniotic fluid is not directly associated with the biochemical constituents of the fetal lung surfactant system.

Effect of phosgene on rat lungs after single high-level exposure.

Rats were exposed under static conditions to phosgene at concentrations within the LCt50 range and above. Lungs were removed at various postexposure intervals. Degrees of pulmonary edema were estimated by increases in percentage of water in the lungs of exposed groups as opposed to control animals. Lungs were fractionated into four major subcellular organelle fractions: nuclear debris, mitochondrial-lysosomal, microsomal, and soluble (cytoplasmic). Activities of p-nitrophenyl phosphatase, cytochrome C oxidase, ATP'ase, and LDH within these fractions were decreased after phosgene exposure. There was a concomitant increase in serum LDH levels. One possible mechanism that may play a role in phosgene damage can be associated with either inhibition or loss of enzyme activities from the lung.

Culture characteristics of cells derived from type II pneumocyte enriched fractions from rabbit and rat.

Type II cell enriched fractions were isolated from rabbit and rat lungs using density gradient centrifugation. Cultures established from these fractions contained predominantly cells similar in most morphological respects to type II pneumocytes. These were in continuous replicating culture for 1 year and still exhibited contact inhibition. Membrane-bound structures reminiscent of, but no longer strictly identical to, type II cell lamellar cytosomes were seen in cells from these long-term cultures although their numbers were reduced in comparison to lamellar bodies in freshly isolated cells. Mitochondrial numbers and sizes, determined morphometrically, were reduced after culture in comparison to freshly isolated type II cells and those in situ. Phosphatidylcholine was synthesized by these cells and released into the extracellular medium. Application of laser activated electronic sizing data, confirmed by direct micrometry, demonstrated a significant increase in cell size as a function of culture. This sizing data, after prior confirmation by electron microscopy, was used as an aid in identifying type II cells and macrophages in dispersion, especially with those cells derived from rabbit lungs.