Leigh M. Vaughan

Chemical Pleurodesis for Malignant Pleural Effusions

Malignant pleural effusions can be the first clinical manifestation of malignancy [1], as well as the first sign of recurrence of tumor. At the time that malignant effusion is diagnosed, three of four patients have respiratory symptoms [2]. The standard treatment of these recurrent, symptomatic pleural effusions is intrapleural instillation of a chemical agent in an attempt to produce pleurodesis [3-6]. We review the medicinal agents currently available for chemical pleurodesis but defer discussion of less considered and unavailable agents such as CalmetteGurin bacillus cell-wall skeleton [7, 8], nitrogen mustard [9], quinacrine [10, 11], and thiotepa [12]. Although not currently available for this use in the United States, tetracycline and Corynebacterium parvum are included in this review because many studies have been done on these agents. Methods Using MEDLINE (1966 to October 1992), we searched the English-language medical literature (with the addition of reference 33 translated from Japanese) that describes the treatment of malignant pleural effusions. We found reports of 1168 patients who were treated with intrapleural agents for pleurodesis. The following information was extracted from each article: pleurodesis regimen, number of patients, success rate (complete response), and adverse effects. Because criteria for success varied, we defined success as complete response only: the absence of reaccumulation of the effusion determined by clinical examination or chest radiograph. Partial response criteria differed among trials and were not included in some reports. We did not compare response duration for the various treatment regimens because of variability and inconsistency in reporting. Chemical Agents Tetracycline Hydrochloride Although it has not been approved by the Food and Drug Administration for pleurodesis, intrapleural administration of intravenous tetracycline (Achromycin, American Cyanamid; Pearl River, New York), with or without intrapleural lidocaine [13], gained acceptance in the last two decades as the pleurodesis agent of choice [4, 14]. It has been proven to be safe, effective, inexpensive, and easily administered, with reported adverse effects limited to pain (14%) and fever (10%) [3, 15] (Table 1). Intrapleural administration of the tetracyclines is usually in 30 to 50 mL of 0.9% saline, with an indwelling time of 2 to 6 hours. Its mechanism of action has been attributed to growth-factor-like activity on fibroblasts from both direct mesothelial cell activation [16] and indirect mesothelial cell activation through stimulated pleural macrophages [17]. Table 1. Success Rates and Adverse Effects in Patients Treated with Nonantineoplastic Agents for Malignant Pleural Effusions* Results of early studies [1, 18-25] using tetracycline in doses of 500 mg reported complete response in 52 (45%) of 115 patients. Subsequent studies [26-29], using doses of 1 g to 20 mg/kg body weight, reported response rates of 77%. Gravelyn and colleagues [25] treated 20 patients with 500 mg of intrapleural tetracycline and 12 patients with 1 g or more. A complete response was seen in only 5 (16%) of 32 patients, with 4 of the 5 patients receiving 1 g or more of tetracycline. Adverse effects did not differ according to dosage. In a randomized trial in 50 patients with malignant pleural effusions, 25 patients received a single dose of tetracycline, 20 mg/kg, and 25 received two doses of 20 mg/kg on consecutive days [28]. No significant difference was found in complete response between single-dose (88%) and double-dose (96%) groups. Doxycycline Intrapleural doxycycline (Vibramycin, Pfizer; Groton, Connecticut) produced a complete response in 43 (72%) of 60 patients (see Table 1). However, only 6 [10%] patients had a complete response after a single 500-mg dose of doxycycline, 6 (10%) patients after two doses, 14 (23%) patients after three doses, and 6 (10%) patients after four doses. More than four doses were required for a complete response in the remaining 11 (18%) patients [30]. Pain was reported in 40% of patients and fever occurred in 7%. Kitamura and colleagues [31] administered intrapleural doxycycline hyclate, 500 mg, to 15 patients with malignant pleural effusions twice weekly for 1 to 2 weeks. Complete response was seen in 10 (67%) patients, with a response duration of 2 to 10 months (average, 6.3 months). Mild chest pain, not requiring analgesics, was the only reported adverse effect and occurred in 5 (33%) patients. Mansson [32] reported a complete response in 11 of 18 (61%) patients with doxycycline HCl, 500 mg, for an average duration of 8.9 months (range, 1 to 27 months). Twelve patients received intravenous morphine, 10 mg, before instillation of doxycycline. Chest pain was reported in 4 (22%) patients, and 2 of the 4 patients with chest pain had received morphine. Fever occurred in 4 (22%) patients during the first 24 hours after instillation. Muir and associates [30] treated 27 patients who had malignant pleural effusions with doxycycline, 500 mg, through a chest tube; the tube was clamped for 24 hours. The procedure was repeated every 24 hours until tube drainage approximated the amount of fluid instilled; an average of 11 days was required. Complete response was reported in 22 (81%) patients. Two patients responded after a single dose of doxycycline, 1 patient after two doses, 4 (15%) patients after three doses, and 4 (15%) patients after four doses. Eight patients required 2.5 to 5.0 g of doxycycline, 6 patients required 6.0 to 9.5 g, and 2 patients required 10.5 g and 28 g. Even though larger doses of doxycycline were administered, adverse effects were similar to those in previously published studies on doxycycline. Pain occurred in 5 (19%) patients, fever in 10 (37%) patients, and an urticarial rash in 1 patient. Minocycline Intrapleural minocycline (Minocin, American Cyanamid), 300 mg with 1% lidocaine, was given to seven patients with malignant pleural effusions [33] (see Table 1). Six of the seven [86%] patients responded completely after a single dose of minocycline. However, the small number of patients, unspecified success rate criteria, and response duration make comparisons with other agents problematic. One patient reported pain. Serum minocycline concentrations were not measured and may be of concern because vestibular symptoms have occurred in 30% to 90% of patients at usual 200-mg intravenous daily doses [3, 34]. Vertigo, dizziness, ataxia, nausea, vomiting, and tinnitus have been reported in patients 1 to 3 days after receiving intravenous minocycline, 100 mg every 12 hours, with the symptoms resolving 48 hours after withdrawal of the drug. Symptoms appear to be related to the dose regimen and possibly to female sex. When receiving the same dose as men, women tend to have higher serum concentrations and are at a two to three times higher risk for developing vestibular toxicities than are men [35]. Studies with intrapleural minocycline and tetracycline in the rabbit pleural model suggest an inflammatory dose-response relation [36-40]. Extrapolating from experimental and human data on tetracycline, doses of minocycline, 300 mg or 4 to 5 mg/kg body weight, appear to be rational starting points. Bleomycin Intrapleural administration of bleomycin (Blenoxane, Bristol-Myers; Princeton, New Jersey), 1 unit/kg or 1 mg/kg [41] (15 to 240 units), produced a complete response in 108 (54%) of 199 patients with malignant pleural effusions [24, 29, 42-47] (Table 2). Pain, fever, and nausea were reported in 28%, 24%, and 11% of patients, respectively. Other adverse effects reported include hemoptysis [29], fluid accumulation and septic shock [29], rash [42], and diarrhea [45]. Forty-five percent of an intrapleural bleomycin dose is absorbed into the systemic circulation; however, alopecia and pulmonary fibrosis have rarely been reported [48]. The technique of intrapleural bleomycin administration is similar to that for tetracycline: The pleural effusion is drained by chest tube; bleomycin is instilled through the tube; and the chest tube is clamped for 2 to 6 hours and then reconnected to suction. The mechanism of action of bleomycin and the other cytotoxic antineoplastic agents is unknown. It may be caused by a combination of antineoplastic and fibrogenic effects and appears to operate differently than that of tetracycline [16]. Table 2. Success Rates and Adverse Effects in Patients Treated with Antineoplastic Agents for Malignant Pleural Effusion Ruckdeshel and colleagues [29] conducted a multicenter, randomized trial comparing intrapleural bleomycin, 60 units (37 patients), with intrapleural tetracycline, 1 g (36 patients). Ninety days after the agents were instilled, 30% of the patients in the bleomycin group and 53% in the tetracycline group had recurrent effusions (P = 0.05). Reported adverse effects were similar in the groups: 36 percent with bleomycin and 37% with tetracycline. The major disadvantage of bleomycin is its cost, approximately

The effect of theophylline on respiratory muscle contractility and fatigue.

1104 for a 70-unit dose [49] (Table 3). Table 3. Charges for Agents Used for Chemical Pleurodesis* Cisplatin and Cytarabine Markman and associates [50] first reported the use of intrapleural cisplatin (Platinol, Bristol-Myers) and cytarabine (Cytosar-U, Upjohn; Kalamazoo, Michigan) in seven patients with malignant pleural effusions (see Table 2). Fluid was removed from the pleural cavity by a percutaneous thoracentesis catheter. One liter of intravenous hydration was administered 1 to 2 hours before administration of intrapleural cisplatin and cytarabine. Sodium thiosulfate was given as an intravenous bolus of 4 g/m2 body surface area and followed by 12 g/m2 for a period of 6 hours beginning at the time of pleurodesis. Cisplatin, 100 mg/m2, and cytarabine, 600 mg/m2, were administered through the intrapleural catheter. Four hours after instillation, the chest cavity was drained as completely as possible and the catheter was removed. Patients with fluid

Clinical comparability of albuterol delivered by the breath-actuated inhaler (Spiros) and albuterol by MDI in patients with asthma

The traditional role of theophylline as a bronchodilator has been expanded by recent findings that suggest this drug has more than smooth muscle relaxant properties. Several investigators indicate that theophylline has an inotropic effect on respiratory muscle, causing enhanced muscular contraction and prevention of muscle fatigue. In animal studies, the drug enhanced respiratory muscle contraction by 15–20%, with levels in the upper end of the therapeutic range (15–20 mg/L). Results of studies in healthy volunteers and patients with lung disease, however, are conflicting. Five clinical trials demonstrated increased diaphragmatic contractility, whereas seven trials showed no effect, with five referring to the diaphragm and the remaining two to the sternomastoid muscle. Disparity in outcomes may be attributed to differences in patient populations, study designs, and techniques used to determine diaphragmatic contractility. Few long‐term trials exist that document significant clinical benefit. Theophylline may prove to be of value in selected populations, such as adults with hypercapnic obstructive lung disease.

Comparison of different methods to evaluate population dose-response and relative potency : Importance of interoccasion variability

STUDY OBJECTIVE This study compares the efficacy and safety of one and two actuations of albuterol sulfate powder delivered via a breath-actuated, effort-assisted, investigational inhaler (Spiros, Dura Pharmaceuticals, Inc) and albuterol delivered via a conventional propellant-driven metered dose inhaler (Ventolin, Glaxo, Inc). DESIGN Randomized, double-blind, placebo-controlled, 5-way crossover study. PARTICIPANTS Sixty patients with mild-to-moderate asthma (FEV1 59% predicted) were enrolled and 44 completed the study. MEASUREMENTS AND RESULTS FEV1 values over 6 hours were analyzed by ANCOVA and the Finney relative potency model. The relative potency of the inhalers (albuterol MDI: albuterol DPI) was 1.132 (90% CI, 0.680 to 2.252) indicating 1.132 actuations of albuterol MDI provided the same bronchodilation as one actuation of albuterol DPI. ANCOVA analyses further indicated that there were no significant differences between the two delivery systems with respect to FEV1, FVC, FEF25-75%, or PEF. Both inhalers had similar effects on serum potassium levels, QTc interval, blood pressure, and heart rate. CONCLUSIONS In patients with mild-to-moderate asthma in this study, the albuterol DPI was determined to be therapeutically comparable to albuterol MDI in the delivery of one and two actuations of albuterol.

Pilot Study of Bronchodilator Response to Inhaled Albuterol Delivered by Metered-Dose Inhaler and a Novel Dry Powder Inhaler

Different mixed-effects models were compared to evaluate the population dose–response and relative potency of two albuterol inhalers. Bronchodilator response was measured after ascending doses of each inhaler in 37 asthmatic patients. A linear mixed-effects model was developed based on the approach proposed by Finney for the evaluation of bioassay data. A nonlinear mixed-effects (Emax) model with interindividual and interoccasion variability (IOV) in the different pharmacodynamic parameters was also fit to the data. Both methods produced a similar estimate of relative potency. However, the estimate of relative potency was 22% lower with the nonlinear mixed-effects model if IOV was not taken into account. Monte Carlo simulations based on a similar study design demonstrated that more biased and variable estimates of ED50and relative potency were obtained when the nonlinear mixed-effects model ignored the presence of IOV in the data. Furthermore, the linear mixed-effects model that did not account for IOV produced confidence intervals for relative potency that were too narrow and thus could lead to erroneous conclusions. These problems were avoided when the estimation model could account for IOV. Results of the simulations were consistent with those of the experimental data. Although the linear or the nonlinear mixed-effects model may be used to evaluate population dose–response and relative potency, there are important differences in the assumptions made by each method.

Stability of Ceftazidime and Vancomycin Alone and in Combination in Heparinized and Nonheparinized Peritoneal Dialysis Solution

BACKGROUND The metered-dose inhaler is currently one of the most prescribed methods of delivering drugs to the lungs. In the United States, most currently marketed metered dose inhalers use chlorofluorocarbons as the system propellant and require patient breath coordination. These factors lead to the need for a delivery system that is independent of propellants and patient coordination. OBJECTIVE To compare the magnitude and time course of bronchodilation between albuterol delivered by Ventolin metered dose inhaler and albuterol sulfate powder (Rotacaps) delivered by a novel dry powder inhaler that generates a respirable drug aerosol over a range of inspiratory flow rates. METHODS A single-center, single-dose, randomized, placebo-controlled, partial-blind, 3-way crossover study was conducted in an outpatient asthma Clinical Research Center. Twelve mild to moderate asthmatic patients 12 to 36 years of age participated in this study that involved three treatments, each separated by three to eight days, consisting of 2 puffs (90 micrograms/puff) albuterol by Ventolin metered-dose inhaler, two inhalations (100 micrograms/puff) albuterol sulfate powder (Rotacaps) by dry powder inhaler, and two inhalations (12.5 mg/inhalation) lactose powder by dry powder inhaler. Spirometry, blood pressure, and heart rate were measured at 30 minutes, 15 minutes, and immediately before treatment and then at 15, 30, 45, 60, 90, 120, 180, 240, and 300 minutes after each treatment. Serum potassium and glucose, and electrocardiograms were measured at 30 minutes before, and 30, 60, 90, and 180 minutes after each treatment. Endpoints were compared with analysis of variance. RESULTS Five patients (one metered-dose inhaler and four dry powder inhaler) did not respond with > 15% FEV1 increase over baseline within 30 minutes. Metered-dose inhaler and dry powder inhaler mean FEV1 results, respectively, for 11 and 8 responders were 15 minutes in onset, 202.9 and 185.4 minutes in duration, 24.8% and 25.1% maximum change, and 18.6 and 18.2 area-under-FEV1-bronchodilation-curve. Statistical analysis of all patients and responders-only revealed both active treatments to be different from placebo (P = .0018), but not different from each other (P = .1291). No safety endpoints were significantly different among all three treatments (P > .10 for all safety endpoints). CONCLUSIONS In this study, the dry powder inhaler safely and effectively delivered a commercially available albuterol sulfate powder (Rotacaps) into human lungs with bronchodilation comparable to Ventolin metered-dose inhaler.

Penetration of Intravenous and Oral Ciprofloxacin into Sterile and Empyemic Human Pleural Fluid

OBJECTIVE: To examine the stability of ceftazidime, vancomycin, and heparin, alone and in combination, in dialysis solution over six days at three temperatures. DESIGN: Nine 250-mL Dianeal PD-2 dextrose 1.5% bags were prepared with ceftazidime, vancomycin, and heparin alone and in combination at set concentrations of 100 μg/mL, 50 μg/mL, and 1 unit/mL, respectively. Three bags of each mixture were stored at 4, 25, and 37°C. Duplicate samples for analysis were removed from each bag at the following time points: premix, 0, 12, 24, 48, 72, 96, 120, and 144 hours. MAIN OURCOME MEASURES: Each sample was examined visually for signs of cloudiness and precipitation. Each sample was analyzed by stability-indicating HPLC assay for ceftazidime and vancomycin, with stability defined as less than 10 percent degradation of drug overtime. RESULTS: No color change or precipitation was observed in any bag. Vancomycin with or without heparin was stable for 5–6 days at 4, 25, and 37°C. Ceftazidime with and without heparin was stable for 6 days at 4°C, 4 days at 25°C, and less than 12 hours at 37 °C. Vancomycin plus ceftazidime with and without heparin was stable for 6 days at 4 °C and 25°C, and 4–5 days at 37 °C, Ceftazidime plus vancomycin with or without heparin was stable for 6 days at 4°C, 2–3 days at 25°C, and 12 hours at 37 °C. CONCLUSIONS: Bulk preparations of ceftazidime and vancomycin, alone and in combination and with or without heparin in Dianeal PD dextrose 1.5% solution, are sufficiently stable for use up to 6 days under refrigeration or 48 hours at room temperature.

Compatibility of Ceftazidime and Aminophylline Admixtures for Different Methods of Intravenous Infusion

OBJECIVE: To compare the penetration of oral and intravenously administered ciprofloxacin into infected (empyemic) and noninfected(sterile) human pleural fluid. DESIGN: Eleven men and 5 women (aged 29–76) were consecutivelyselected from adult patients referred to the respiratory unit forpleural effusion. In this open-label, prospective trial, 13 patients withsterile pleural effusions were nonrandomly assigned to receive eitherciprofloxacin 200 mg (single intravenous dose), 750 mg (single oraldose), or 750 mg (two oral doses per day for 3 days); 3 patients withinfected pleural effusions received 750 mg oral doses for 10 days. Simultaneous pleural fluid and venous blood specimens were drawnover 5 hours after single dose or when steady-state was attained, andciprofloxacin concentrations were measured by HPLC. RESULTS: Pleural fluid concentrations of ciprofloxacin equaledplasma concentrations 1.5 hours after 200 mg was givenintravenously and the pleural/plasma ratio remained ∼ 0.9 for 4hours. After a single 750-mg oral dose, pleural ciprofloxacinconcentrations rose from 0 to 1.4 ug/ml, over 5 hours with thehighest pleural fluid/plasma ratio (0.7) at 5 hours. Average steadystateciprofloxacin concentrations in sterile pleural fluid after 750mg administered twice daily for 3 days, ranged between 1.1 and 1.8ug/rnl, with ratios between 0.3 and 0.9 over 4 hours. In empyemicpleural fluid at the same dosage, average steady-state ciprofloxacinconcentrations ranged between 1.9 and 3.4 ug/ml, with ratiosbetween 1.0 and 2.0 over 5 hours. CONCLUSIONS: Oral ciprofloxacin penetrates into sterile andempyemic pleural fluid with concentrations 30–90 percent and100–200 percent of plasma concentrations, respectively.

Heparin Inhalation for Asthma

OBJECTIVE: Aminophylline and ceftazidime are sometimes used concurrently in patients with respiratory disorders. Parenteral aminophylline usually is administered as a constant infusion, and ceftazidime is given intermittently or less commonly as a constant infusion. We evaluated the stability and compatibility of the two drugs when aminophylline is given as a constant intravenous infusion and ceftazidime is administered simultaneously either through a y-site (piggyback method) or as a continuous infusion (constant infusion method). DESIGN: The chemical stability of intravenous aminophylline and ceftazidime in dextrose 5% and NaCl 0.9% for both methods was studied. Three different formulations of ceftazidime from the same manufacturer were studied (minibag using reconstituted ceftazidime, premixed minibag, and ceftazidime arginine). For the piggyback and constant infusion methods, samples were collected at 0,1, and 2 hours; and 0,6, and 24 hours, respectively. All experiments were conducted in triplicate. Samples were analyzed in duplicate by a stability-indicating HPLC assay method. OUTCOME MEASURE: Ceftazidime and aminophylline were considered stable if concentrations remained above 90 percent of the original concentrations over the time periods studied. RESULTS: Ceftazidime was determined to be compatible with aminophylline in the piggyback method. In contrast, when aminophylline and ceftazidime were admixed in the same intravenous container (constant infusion method), the two drugs were not stable. CONCLUSIONS: These data indicate that aminophylline and ceftazidime admixtures are incompatible when prepared in the same intravenous container, which may occur if both are given as a constant infusion. The two drugs are compatible when the ceftazidime is piggybacked into a primary intravenous set in which aminophylline is administered as a constant infusion.

Effect of Xanthine-Related Compounds on a Theophylline Assay Using Theophylline Oxidase:

The study of inhaled heparin in asthma has resurfaced recently in the medical literature. Although the above mentioned investigations have helped us better understand the pathologic processes of asthma, the results are too scant and preliminary to enable us to recommend the use of inhaled heparin in acute or chronic asthma. If the antiinflammatory properties of inhaled heparin prove to be of clinical value in asthma, it would represent a considerable advantage over steroids, which cause immunosuppression and other significant adverse reactions. Future trials will need to address such issues as: (1) What is the asthma subpopulation in which heparin is likely to be beneficial? (2) What is the optimal dose for inhalation? (3) What are the long-term adverse effects of inhaled heparin? (4) What is the optimal timing of administration with regard to allergen exposure? (5) If proven useful, what is the ideal delivery mode? Additional well-designed human trials will be necessary before we can define the place of inhaled heparin in the therapy or prevention of asthma.