Guaifenesin

Study objective: The mechanism of action of potential mucoactive agents could relate to effects on the mucociliary apparatus or to direct effects on the secretions. The purpose of this study was to determine the in vitro effects of several agents on the properties of mucus simulants and sputum collected from 30 adults with stable chronic bronchitis.

Design: Sputum or simulants were analyzed untreated and after the addition of the test agent at 1:5 volume to volume ratio for a contact period of 60 s. The concentrations of the agents were as follows: guaifenesin, 20 mg/mL; iodinated glycerol, 3 mg/mL; surfactant (Exosurf; Glaxo Wellcome; Research Triangle Park, NC) containing 13.5 mg of phospholipid per milliliter; albuterol, 5 mg/mL; and amphibian Ringer's solution (ARS) as a control. Dynamic viscoelasticity and surface mechanical impedance were measured in a magnetic microrheometer. Cohesiveness was measured using a filancemeter. The wettability of a hydrophilic surface was measured using an image processing system. The mucociliary transportability of sputum was timed on the frog palate, and cough transportability (CTR) was measured in a cough machine.

Results: When compared to sputum that had no test agent or ARS added, all agents reduced sputum elasticity G', with surfactant, albuterol, and guaifenesin significant at p [is less than] 0.001. As well, guaifenesin (p = 0.006), albuterol (p = 0.003), and surfactant (p = 0.02) decreased surface mechanical impedance (frictional adhesiveness) compared to untreated sputum. However, there were no significant changes in wettability, hydration, cohesiveness, or CTR with any agent, and there were no significant changes in the properties of sputum or simulants treated with test agents when compared to those treated with ARS. Guaifenesin irreversibly disrupted mucociliary transport when applied directly to the frog palate.

Conclusions: These agents appear to have a minimal direct action on sputum in vitro, suggesting that at the concentrations studied, these agents do not have a significant beneficial effect on either the mucociliary transportability or CTR of chronic bronchitis sputum. However, there could be an effect of some of these agents after oral administration, especially if there is a secondary effect of the agent on an effector cell. (CHEST 1999; 116:195-200)

Key words: chronic bronchitis; mucolytics; sputum; surfactant

Abbreviations: ARS = amphibian Ringer's solution; CTR = cough transportability; G' = storage modulus (elasticity); G'' = loss modulus (viscosity); G* = mechanical impedance "rigidity"; IPG = iodinated glycerol; MCTR = in vitro mucociliary transportability on the frog palate; NS = not significant

A variety of pharmaceutical agents are thought to influence the clearance of abnormal respiratory secretions. Therefore, understanding the action of agents that influence sputum clearance is important. It has been suggested that evaluating the mechanism whereby mucoactive agents affect the biophysical properties, mucociliary clearability, and cough clearability of sputum or sputum simulants in vitro may permit the development of medications with potentially greater efficacy; it may also help determine which patients might benefit most from specific pharmacotherapy. These evaluations might also better predict the appropriate medication dose, onset, and duration of action in vivo.[1,2]

The mechanisms of action of mucoactive agents are often unclear, and they could relate to the effects on the secretory and mucociliary apparatus or to direct effects on the secretions.[2,4] The purpose of this study was to determine the in vitro effects of several agents on the properties of sputum collected from 30 adults with stable chronic bronchitis. We deliberately did not evaluate classic, direct-acting mucolytic agents such as thiol derivatives (N-acetyl-L-cysteine) or dornase alfa (Pulmozyme; Genentech; San Francisco, CA), because we wished to determine if nonmucolytic but putatively mucoactive agents would have a direct effect on sputum or mucus simulants. We hypothesized that we might detect the direct effects of these agents on the expectorated bronchitis sputum, especially as these relate to mucociliary and cough clearability.

MATERIALS AND METHODS

We studied the following medications, all at the calculated maximum dose available to the secretions in the proximal airways.

1. Guaifenesin is a secretagogue that is readily available in many over-the-counter cough and cold medications. The concentration of guaifenesin used was 20 mg/mL, corresponding to the maximum airway concentration after oral dosing.[5] This agent is thought to enter the airway secretions unmetabolized and to have a direct effect either on the mucus or the epithelium.[2,5]

2. Iodinated glycerol (IPG) has been reported to be a mucolytic in vitro, but was shown to have no effect on mucus properties or pulmonary function in vivo.[6] The concentration of IPG used was 3 mg/mL, corresponding to the maximum calculated airway concentration after IV dosing.[7]

3. The surfactant used (Exosurf; Glaxo Wellcome; Research Triangle Park, NC) has been demonstrated to alter the active surface properties of respiratory mucus and to enhance mucociliary clearance.[8] The concentration of phospholipid (DPPC) in the surfactant was 13.5 mg/mL, corresponding to the reconstituted concentration for aerosol administration in the neonate.

4. Albuterol nebulizer solution is a [[Beta].sub.2]-agonist that has been shown to enhance ciliary beat frequency and power, and possibly to promote mucociliary clearance.[9] Albuterol is also thought to induce mucin secretion in the large airway.[10] The concentration of albuterol used was 5 mg/mL, corresponding to the concentration of albuterol in the nebulizer solution.

5. In order to preserve mucociliary clearance on the mucus-depleted frog palate, all medications were prepared in amphibian Ringer's solution (ARS) with an osmolarity of 9,06.5 mOsm/L containing the following: NaCl, 98.3 mmol/L; KCl, 2.7 mmol/L; and Ca[Cl.sub.2], 1.5 mmol/L. This solution served as a control.

Mucus Simulant Studies

Mucus simulants were prepared by crosslinking locust bean gum (9,% and 4% weight/volume), dissolved in ARS using 0.02 mol/L sodium tetraborate ([Na.sub.2][B.sub.4][O.sub.7]). To stabilize the mucus simulant and to raise the solids composition to levels seen in chronic bronchitis sputum, sucrose at 4% weight/volume was added to the solution before crosslinking. Three 2-mL aliquots of these two simulants with well-characterized physical and transport characteristics were placed in a 5-mL, wide-mouthed container and layered with 0.5 mL of the test solution for a contact period of 60 s at 37 [degrees] C. The supernatant was removed by careful pipetting, and the mucus simulant was then tested for viscoelasticity, cohesiveness, hydration, surface mechanical impedance, wettability, mucociliary clearability, and cough clearability. Each experiment was repeated with three test samples for a total of 30 analyses. The testing was performed at an ambient temperature (24 [+ or -] 2 [degrees] C).

Studies of Expectorated Sputum

Expectorated sputum was collected from 30 subjects [is greater than] 16 years old with chronic bronchitis as defined by the American Thoracic Society criteria.[11] The patients participating in this study were in stable condition and had required no adjustment in their medications in the previous 6 months. None of the patients were taking oral corticosteroids, mucoactive medications, oral or inhaled anticholinergic medications, theophylline, or [Beta] -agonist medications. Two patients were taking nasal corticosteroids. None of the patients were taking inhaled corticosteroids or oral antihistamines. Other medications used included antihypertensive medication in five patients, cholesterol-reducing agents in seven patients, and insulin in one patient. Patients with tuberculosis, HIV infection, or active hemoptysis were excluded.

Sputum was collected by direct expectoration into a sterile cup over a 30-min period during the course of pulmonary function testing. The patients were asked to swallow all saliva before expectorating, and dental cotton was placed between their lips and gum as previously described by Puchelle and colleagues.[12] The sputum was then visually separated from any remaining saliva before being divided into five aliquots of 200 [micro] L each. This was accomplished using a Teflon-tipped, positive-displacement pipette that allows accurate collection of a specific volume of mucus without altering sputum properties.[3,4] The aliquots were placed in airtight containers fitted with an O-ring and stored at -70 [degrees] C until analyzed. Because mucin and DNA polymers may be susceptible to degradation with freezing and thawing, it is the viscoelastic properties of sputum that would be most sensitive to this handling. However, freezing and thawing in this manner have been demonstrated to have minimal effects on sputum viscosity or elasticity.[13,14] The sputum was analyzed untreated and after the addition of the test agent at 1:5 volume to volume ratio for a contact period of 60 s at 37 [degrees] C. The testing was performed at an ambient temperature (24 [+ or -] 2 [degrees] C).

The Physical Properties of Secretions

Viscoelasticity (Rheology): In the magnetic microrheometer, a dissecting microscope was used to position a small steel ball, 100 [micro] m in diameter, in a 4- [micro] L sample of mucus; this was then placed in the field of an electromagnet, where it was oscillated at driving frequencies of 1 and 100 rad/s. The image of the ball was magnified and projected onto photocells, where the magnitude of displacement of the ball and its phase lag with respect to the driving force are used to calculate the dynamic loss modulus (viscosity) (G") and the storage modulus (elasticity) (G') of the specimen. Mechanical impedance "rigidity" (G*) is the vectorial sum of viscosity and elasticity, and the loss tangent "recoil" (tangent 8) is the ratio of G" to G'. Both are calculated from the viscoelastic data.[4]

Cohesiveness: Cohesiveness (spinnability) is the thread-forming ability of mucus under the influence of large-amplitude elastic deformation. This was measured in millimeters using the filancemeter. The measurement was performed with a 25-[micro]L mucus sample at a distraction velocity of 10 mm/s. An electric signal conducted through the mucus sample was interrupted at the point where the stretched mucus thread was broken. This distance represents the mucus cohesiveness.[15]

Sputum Hydration (Percent Solids'): The sputum samples were weighed in a microbalance and then dried by lyophilization overnight. The dried sample was weighed again to calculate the percent solids composition.

The Transport Properties of Secretions

In Vitro Cough Transportability: A simulated cough machine was used to measure the airflow-dependent clearability of sputum. A model Plexiglas trachea, rectangular in cross-section (1.2 x 2 cm) was connected to a 6.4-L tank containing air pressurized to 12 psi, giving a flow rate of about 11 L/s. A solenoid valve controlled the air release through a flow-constrictive element that mimicked the airflow pattern of a natural cough. A sinusoidal constriction (length, 7.7 cm; height, 8 mm) was used to decrease the airway diameter while minimizing the turbulence of the system. A sample (volume, 40 [micro]L; depth, 0.5 mm) was placed in a thin line across the base of the Plexiglas trachea. The bulk transport of the sample was measured in millimeters after a single cough maneuver. Three successive measurements were made, and the results were averaged.[16]

In Vitro Mucociliary Transportability: Using hypothermia as anesthesia, a mature northern leopard frog was rapidly decapitated, the jaw was disarticulated, and the palate was removed by cutting through from the junction of the posterior pharynx and esophagus out to the skin of the back. The excised palate was placed on a piece of gauze saturated with ARS. The palate was placed in a dish loosely covered with plastic wrap and allowed to rest in a refrigerator at 4 [degrees] C for 12 to 18 h to deplete the mucus.

The following morning, the palate was placed in a box with a fitted-glass top. Humidity was maintained at 95 to 100%, and the temperature was kept at 22 to 24 [degrees] C. The palate was focused under a microscope so that a 12.7-mm micrometer scale ran between the optic bulges to the opening of the esophagus. The movement of a 4-[micro]L sputum specimen was timed as the trailing edge moved across a 7.62-mm segment. Three measurements of mucus transport rate were taken to minimize variability, and the average transport rate was normalized to the transport rate for collected endogenous frog mucus.[17]

The Surface Properties of Secretions

Sputum Surface Mechanical Impedance by the Rolling Ball Technique: The rolling ball technique is used in industry to measure the adhesiveness of glue strips. The magnetic microrheometer and computer measurement software were modified so that we could make rolling ball adhesion measurements on small mucus specimens. The steel microprobe was placed on the surface of the mucus layer without using a paraffin oil cover. The magnetic force needed to roll the sphere across the surface of the sample was used to calculate the surface G* at 1 rad/s. This is a measurement of frictional adhesion.[18]

Sputum Wettability (Contact Angle [Theta]): A 20-[micro]L drop of test material was gently placed onto the surface of a glass microscope slide cleaned with chromic sulfuric acid and rinsed with deionized water. It was then stored in absolute ethanol to maintain dehydration before use. A stabilization time of 1 min was allowed before capturing the image of the drop in the video processing system.[19,20]

Data Analysis

Statistical analysis of the data was performed using a statistics package (StatView 5; SAS Institute; Cary, NC). The relationships between the physical and transport properties of mucus or sputum and how these relate to in vitro pharmacologic treatment were examined using the equality of variance F test.

RESULTS

Simulant Studies

Adding IPG to mucus simulants reduced bulk G* at both 1 and 100 rad/s to a greater extent than adding ARS, and this was mainly due to a reduction in elasticity. There was also a significant increase in the percent solids composition of simulant mucus with both IPG and guaifenesin (p [is less than] 0.01).

The in vitro mucociliary transportability on the frog palate (MCTR) of mucus simulants was severely decreased after guaifenesin to less than one third of the untreated or control-treated values. It was subsequently shown that guaifenesin irreversibly disrupted MCTR when applied directly to the frog palate.

Studies of Expectorated Sputum

As shown in Table 1, all agents reduced G', compared to untreated secretions, with surfactant, albuterol, and guaifenesin significant at p [is less than] 0.001. This result was associated with a decrease in viscosity and, for guaifenesin and IPG, a decrease in hydration (increased percent solids). However, these changes were not significant (NS) when compared to ARS treatment. Surfactant, albuterol, and guaifenesin all decreased G* when compared to untreated sputum (p [is less than] 0.001), but again these changes were NS when compared to the ARS treatment. There were no significant changes in wettability, cohesiveness, or cough transportability (CTR) with any agent when compared to ARS treatment in vitro.

[TABULAR DATA 1 NOT REPRODUCIBLE IN ASCII]

DISCUSSION

Mucus clearance depends on the physical properties of the mucus gel, ciliary function, and interactions between mucus and epithelium. An obstruction of the airway by mucus can result from mucus hypersecretion, epithelial damage, ciliary dysfunction, or abnormal mucus biophysical properties. In recent years, techniques have been developed for measuring bulk theologic (viscoelastic), surface (or interfacial), and transport properties of mucus or sputum. There is evidence that both the rheologic and surface properties of mucus can affect mucociliary clearance; with increasing epithelial damage and inflammation, these properties become progressively abnormal.[2-4]

Mucus is a viscoelastic gel consisting primarily of water and high-molecular-weight, crosslinked glycoproteins that form a tangled network. Respiratory mucus is usually cleared by cilia. Sputum, which is mucus mixed with inflammatory cells, cellular debris, and often bacteria, is generally cleared by coughing. The theology of mucus is its capacity to undergo flow and deformation.[4] A true solid responds to a stress with a finite elastic deformation that is totally recovered after the stress is removed. A liquid responds to a stress with viscous deformation, flowing continuously for the time that the stress is applied. After the removal of the stress, the flow ceases and there is no recovery of the strain. A viscoelastic gel such as mucus initially stores energy; with continued stress, it will begin to flow like a liquid. The viscoelastic behavior of mucus was thought to be one of the major determinants of mucociliary clearance. Studies using mucus simulant gels (made from crosslinked vegetable gums) suggest that MCTR on the frog palate is impeded by increasing mucus G*, but increases with greater mucus recoil.[21] However, the relationship between the properties of actual airway secretions and MCTR is unclear. Giordano and colleagues[22] studied the tracheal mucus velocity of dogs and found a negative correlation between the tracheal clearance rate and the elasticity of mucus secreted in a tracheal pouch. Recent studies using human airway secretions have shown little relationship between MCTR and rheology,[23] and almost no relationship with in vitro CTR in the cough machine.[24]

There is increasing recognition that the surface interaction of secretions with the epithelium is most critical in regulating mucus transport, especially by coughing.[8,16,18,20] This is consistent with the fluid dynamics of low mechanical impedance, non-Newtonian liquids (like mucous gels), where airflow-dependent transport is most influenced by interfacial interactions and is far less dependent on stress-strain (viscoelastic) characteristics.

Surfactant phospholipids may increase mucociliary transport and ciliary beat frequency. Allegra et al[25] evaluated mucociliary transport on the frog palate after either saline solution or surfactant obtained from pig lung was sprayed on the excised palate. Saline solution induced a constant decrease in transport rate (p [is less than] 0.01), while the surfactant caused an increase of approximately 16% (p = NS). The difference between the two treatments was highly significant (p [is less than] 0.001). This could be due to the surfactant increasing the efficiency of energy transfer from the beating cilia to the mucus layer by reducing mucociliary frictional energy loss. In vitro experiments have shown that the addition of surfactants to cystic fibrosis sputum reduces tenacity and increases clearability.[26] The high adhesion tension and abnormal surface properties of sputum suggest that an aerosolized surfactant could be an effective mucokinetic therapy for patients with inflammatory airway disease. We tested this hypothesis in a multicenter, placebo-controlled trial of aerosolized surfactant in 66 patients with stable chronic bronchitis who were randomized to receive surfactant and 21 patients who were randomized to receive saline solution treatment. The patient demographics among groups were similar at the baseline. In patients who received 607.5 mg of surfactant for 2 weeks, prebronchodilator [FEV.sub.1] increased from 1.22 [+ or -] 0.08 L at baseline to 1.33 [+ or -] 0.09 L at day 21 (p [is less than] 0.05); postbronchodilator [FEV.sub.1] improved 10.4% by clays 14 and 21 (p [is less than] 0.05); and the ratio of residual volume to total lung capacity, a measure of thoracic gas trapping, decreased 6.22% by day 21 (p [is less than] 0.05). In the surfactant group, there was a dose-dependent increase in sputum MCTR.[8]

The effect of the agents tested in this study did not appear to be mediated by direct action on sputum or sputum simulants alone, and, as anticipated, none had specific mucolytic properties. At the concentrations studied, these agents do not seem to have a physiologically significant direct beneficial effect on either the mucociliary or cough clearability of chronic bronchitis sputum.

Mucolytics are assumed to act directly on secretions. Although we showed an in vitro reduction of elasticity with some of these agents, there was no change in viscosity in contradistinction to data reported earlier by Braga and colleagues,[27] who found a reduction in viscosity but not elasticity, albeit with S-carboxymethylcysteine, an agent not tested in these studies. Other researchers[28] have reported no change in viscoelasticity or clinical function with the use of mucolytic therapy. Based on in vitro studies, Puchelle et al[29] suggested that when using mucoactive agents, for optimal sputum clearance, the specific ratio of viscosity to elasticity is important. The viscoelasticity of many of the sputum samples studied was in this range, but unlike the Puchelle et al[29] study, we did not find an "optimum" for transport. In fact, there was little relationship between viscoelasticity and transport, as we have previously reported.[4,24] In this study, for MCTR, [R.sup.2] was [is less than] 0.02, and for CTR, [R.sup.2] was [is less than] 0.01 for both G' and G" by linear regression analysis (data not shown).

In our studies of sputum transportability, only in vitro exposure to IPG increased MCTR, suggesting a direct effect on the ciliated epithelium. This is consistent with the direct effects of potassium iodide on the ciliated epithelium.[30] Although albuterol has been consistently shown to increase ciliary beat frequency, there is no dear evidence that this is reflected in an increase in mucus transport, with some investigators[9] finding improved in vivo mucociliary transport after [Beta]-agonist administration, while other groups[31,32] found no such increase. The fact that we did not see any increase in MCTR in vitro strongly suggests that any in vivo improvement on mucociliary clearance after albuterol administration is not mediated by a direct effect on the cilia, but may instead be secondary to increased mucociliary activity induced by mucus secretion.[10]

However, the topical administration of guaifenesin, even mixed with sputum, seems to paralyze cilia irreversibly. This may well be due to the oily and hypertonic nature of the guaifenesin that we tested, as indicated by the significant increase in the solids content of the secretions after exposure. However, because guaifenesin is meant to be orally administered and not topically applied or inhaled, the effects of guaifenesin therapy on sputum clearance could be different when the medication is administered as directed. Because both guaifenesin and IPG are thought to be secreted unchanged into the airway surface liquid, and sputum concentrations of these agents have been directly measured, we presumed that in vitro exposure of mucus to these agents would mimic airway exposure in vivo. It is likely that this is an oversimplification, and thus the clinical efficacy or lack of efficacy of these medications after oral dosing cannot be extrapolated from the data presented herein.

In conclusion, it is known that classic mucolytic agents can reduce the viscosity of abnormally viscous secretions. It is useful to evaluate this action both in vitro and in vivo to prevent the over thinning of secretions with a concomitant reduction in mucus clearance.[33] Possibly some nonmucolytic, mucoactive agents can alter the transportability properties of sputum by acting directly on the secretions. However, these data strongly suggest that in vitro assessments cannot be a substitute at this time for clinical trials in evaluating the effectiveness of these agents.

ACKNOWLEDGMENTS: The author acknowledges the help of Ms. Titik Dian and Dr. Oscar Ramirez in conducting these studies; the author is also grateful to Dr. Jill A. Ohar for providing the sputum specimens from the St. Louis University Pulmonary Clinic.

REFERENCES

[1] Task Group on Mucoactive Drugs. Recommendations for guidelines on clinical trials of mucoactive drugs in chronic bronchitis and chronic obstructive pulmonary disease. Chest 1994; 106:1532-1537

[2] Rubin BK, Tomkiewicz RP, King M. Mucoactive agents: old and new. In: Wilmott RW, ed. The pediatric lung. Basel, Switzerland: Birkhauser, 1997; 155-179

[3] King M, Rubin BK. Mucus physiology and pathophysiology: therapeutic aspects. In: Derenne JP, Similowski T, Whitelaw WA, eds. Acute respiratory failure in chronic obstructive pulmonary disease. New York, NY: Marcel Dekker, 1996; 391-411

[4] King M, Rubin BK. Mucus rheology, relationship with transport. In: Takishima T, ed. Airway secretion: physiological bases for the control of mucus hypersecretion. New York, NY: Marcel Dekker, 1994; 283-314

[5] Hirsch SR, Viernes PF, Kory RC. The expectorant effect of glyceryl guaiacolate in patients with chronic bronchitis: a controlled in vitro and in vivo study. Chest 1973; 63:9-14

[6] Rubin BK, Ramirez OE, Ohar JA. Iodinated glycerol has no effect on pulmonary function, symptom score, or sputum properties in patients with stable chronic bronchitis. Chest 1996; 109:348-3,52

[7] Seltzer A. A superior iodide preparation for respiratory tract disease, iodopropylidene glycerol (Organidin). Med Ann DC 1961; 10:130-132

[8] Anzueto A, Jubran A, Ohar JA, et al. Effects of aerosolized surfactant in patients with stable chronic bronchitis: a prospective randomized controlled trial. JAMA 1997; 278:1426-1431

[9] Lafortuna CL, Fazio F. Acute effect of inhaled salbutamol on mucociliary clearance in health and chronic bronchitis. Respiration 1984; 45:111-123

[10] Webber SE, Widdicombe JG. The actions of methacholine, phenylephrine, salbutamol and histamine on mucus secretion from the ferret in-vitro trachea. Agents Actions 1987; 22:82-85

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[12] Puchelle E, Tournier JM, Zahm JM, et al. Rheology of sputum collected by a simple technique limiting salivary contamination, J Lab Clin Med 1984; 103:347-353

[13] Charman J, Reid L. The effect of freezing, storing, and thawing on the viscosity of sputum. Biorheology 1973; 10: 295-301

[14] Adler K, Dulfano M J, Wooten O. Physical properties of sputum: V. The effects of time, freezing, and thawing on viscoelasticity measurements. Am Rev Respir Dis 1974; 109: 490-493

[15] Puchelle E, Zahm JM, Jacquot J, et al. Effect of air humidity on spinability and transport capacity of canine airway secretions. Biorheology 1989; 26:315-322

[16] Agarwal M, King M, Rubin BK, et al. Mucus transport in a miniaturized simulated cough machine: effect of constriction and serous layer simulant. Biorheology 1989; 26:977-988

[17] Rubin BK, Ramirez O, King M. Mucus-depleted frog palate as a model for the study of mucociliary clearance. J Appl Physiol 1990; 69:424-429

[18] Rubin BK. Surface properties of respiratory secretions: relationship to mucus transport. In: Baron G, ed. Cilia, mucus, and mucociliary interactions. New York, NY: Marcel Dekker, 1998; 317-324

[19] Hills BA. Water repellency induced by pulmonary surfactants. J Physiol (Lond) 1982; 325:175-186

[20] Albers GM, Tomkiewicz RP, May MK, et al. Ring distraction technique for measuring the surface tension of sputum and relationship of the work of adhesion to clearability. J Appl Physiol 1996; 81:2690-2695

[21] King M. Relationship between mucus viscoelasticity and ciliary transport in guaran gel/frog palate model system. Biorheology 1980; 17:249-254

[22] Giordano A, Shih CK, Holsclaw DS, et al. Mucus clearance: in vivo canine tracheal versus in vitro bullfrog palate studies. J Appl Physiol 1977; 42:761-766

[23] Tomkiewicz RP, Albers GM, Ramirez OE, et al. Rheologic properties of airway secretions in cystic fibrosis, chronic bronchitis, and fatal asthma. Biorheology 1995; 32:364-365

[24] King M, Zahm JM, Pierrot D, et al. The role of mucus gel viscosity, spinability, and adhesive properties in clearance by simulated cough. Biorheology 1989; 26:737-745

[25] Allegra L, Bossi R, Braga PC. Influence of surfactant on mucociliary transport. Prog Respir Dis 1985; 19:441-460

[26] Girod de Bentzmann S, Pierrot D, Fuchey C, et al. Distearoyl phosphatidylglycerol liposomes improve surface and transport properties of CF mucus. Eur Respir J 1993; 6:11561161

[27] Braga PC, Bossi R, Allegra L. Evaluation of the elastic and viscous components of bronchial mucus before and after S-carboxymethylcysteine-Lys treatment. Int J Clin Pharmacol Res 1984; 4:121-127

[28] Thomson ML, Pavia D, Jones CJ, et al. No demonstrable effect of S-carboxymethylcysteine on clearance of secretions from the human lung. Thorax 1975; 30:669-673

[29] Puchelle E, Zahm JM, Girard F, et al. Mucociliary transport in vivo and in vitro: relations to sputum properties in chronic bronchitis. Eur J Respir Dis 1980; 61:254-264

[30] Melville GN, Ismail S, Sealy C. Tracheobronchial function in health and disease: effect of mucolytic substances. Respiration 1980; 40:329-336

[31] Isawa T, Teshima T, Hirano T, et al. Effect of bronchodilation on the deposition and clearance of radioaerosol in bronchial asthma in remission. J Nucl Med 1987; 28:1901-1906

[32] Isawa T, Teshima T, Hirano T, et al. Does a beta 2 stimulator really facilitate mucociliary transport in the human lungs in vivo? A study with procaterol. Am Rev Respir Dis 1990; 141:715-720

[33] Rubin BK, MacLeod PM, Sturgess JM, et al. Recurrent respiratory infections in a child with fucosidosis: is the mucus too thin (or effective transport? Pediatr Pulmonol 1991; 10:304-309

(*) From the Department of Pediatrics, Wake Forest University School of Medicine, Winston-Salem, NC

Manuscript received September 15, 1998; revision accepted January 15, 1999.

Correspondence to: Brace K. Rubin, MD, FCCP, Professor and Vice Chair for Research, Department of Pediatrics, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157-1081; e-mail: brubin@wfubmc.edu

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