Efficacy of Tigecycline Pleurodesis: A Comparative Experimental Study

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Journal of Surgical Research 169, e109ee118 (2011) doi:10.1016/j.jss.2010.07.001

Efficacy of Tigecycline Pleurodesis: A Comparative Experimental Study Niccolo` Daddi, M.D., Ph.D.,*,1 Jacopo Vannucci, M.D.,* Chiara Maggio, D.V.M.,† Andrea Giontella, Banim Sci,† Ilaria Bravi, M.D.,‡ Fiovo Marziani, M.D.,‡ Rosanna Capozzi, M.D.,* Mark Ragusa, M.D.,* Antonello Bufalari, D.V.M.,† and Francesco Puma, M.D.* *Thoracic Surgery Unit in Perugia and Terni; †Department of Veterinary Pathology, Diagnostic and Clinic in Perugia; and ‡Institute of Pathologic Anatomy and Histology in Terni; University of Perugia, Italy Submitted for publication April 8, 2010

Background. We investigated whether tigecycline (TIGE) is more effective than talc in inducing pleurodesis in rabbits. Methods. Fifty-six New Zealand rabbits were utilized in a two-phase study: Effects at 14 d (phase I) and at 28 d (phase II) were assessed. Saline solution (SAL n [ 3), talc slurry (TALC 200 mg/kg, n [ 5), and TIGE at different concentrations (mg/kg): TIGE0.5 (n [ 5); TIGE1 (n [ 5); TIGE3 (n [ 5); TIGE25 (n [ 5); TIGE50 (n [ 5) were randomly injected, for each phase, through a right chest drainage. TIGE0.5 and TIGE1 were ineffective during phase I and were thus excluded from further investigation. At post mortem examination, pleurodesis was graded grossly and microscopically by three observers blinded to treatment groups. Results. Phase I: pleurodesis was more effective in TIGE25 and TIGE50 (P < 0.001); TALC was better than TIGE0.5 (P < 0.001), and TIGE1 (P [ 0.49), macroscopically. Pleural thickness was significantly higher in TIGE25 compared with SAL, TALC, TIGE0.5, TIGE1, and TIGE3 (P < 0.01). No significant differences were evident between TALC and TIGE3, both macroscopically (P [ 0.90) and microscopically (inflammation P [ 0.99, fibrosis P [ 0.96, pleural thickness P [ 0.99). Phase II: better effectiveness of TIGE50 compared with all other groups (P < 0.001) except TIGE 25 (P [ 0.29); results similar to phase I for TALC and TIGE3 (P [ 0.99), macroscopically. Microscopically greater inflammation in TALC compared with TIGE3 (P < 0.05) and in TIGE50 to TIGE3 (P [ 0.05). Significant complications occurred in all TIGE50 group. One of TIGE25 and one of TIGE50 died of respiratory distress and of right hemothoraxDascites, respectively. 1 To whom correspondence and reprint requests should be addressed at Thoracic Surgery Unit, Perugia University School of Medicine, S. Maria della Misericordia Hospital, S. Andrea delle Fratte, 06126 Perugia, Italy. E-mail: [email protected].

Conclusions. Intrapleural TIGE3 mg/kg is as effective as talc in inducing pleurodesis in rabbits. The intrapleural TIGE toxicity threshold was reached at TIGE25 mg/kg concentration. Ó 2011 Elsevier Inc. All rights reserved.

Key Words: drainage; pleurodesis; tetracycline; minocycline; tigecycline; talc; antibiotic; malignant pleural effusion; pneumothorax.

INTRODUCTION

In the mid 1960s, intrapleural instillation of tetracycline combined with chest drainage was the preferred method of chemical pleurodesis, mainly for patients with malignant pleural effusions [1, 2] and for recurrent pneumothorax [3e5]. Unfortunately, the production of injectable tetracycline hydrochloride was discontinued in the United States and in Europe at the beginning of the 1990s [1]. Over 30 agents, several of them already in use before tetracycline [6, 9], were considered acceptable in pleurodesis armamentarium since 1935 with variable results, side effects, and complications [7e9]. Furthermore, the suggested newer alternatives, to date, have not been rigorously compared with conventional agents [10, 11]. Recently a new antibiotic with molecular characteristics similar to tetracycline has been developed, namely tigecycline (TIGE). This molecule, approved by the Food and Drug Administration in 2005, and 1 y later also in Europe, is the first drug in the glycylcycline class of antibiotics structurally related to minocycline [12, 13]. TIGE (GAR-936, 9-t-butylcyclamido-minocycline) shows the same spectrum of activity as tetracyclines analogs derived from minocycline and remains active against many pathogens resistant to tetracyclines [14].

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The aim of this study is to investigate whether TIGE is more effective than talc, commonly used in clinical practice to induce pleurodesis [9, 15, 16]. MATERIALS AND METHODS The study protocol was approved by the University of Perugia Bioethics Committee and the Italian Animal Care Committee. The methods used were similar to those described in previous studies in literature [9, 16]. Fifty-nine white New Zealand male rabbits (Charles River Laboratories, Lyon, France) weighing 1.750 to 2.466 kg were utilized in a two phase study: Effects at 14 d (phase I) and effects at 28 d (phase II) were assessed. Different concentrations of TIGE were evaluated in order to identify the minimum effective dose and the toxicity threshold. In phase I, 33 animals, divided in seven groups, randomly received intrapleural injections with 2 mL saline solution (saline: n ¼ 3, pH 5.84), 2 mL saline solution containing talc (Steritalc F2; Novatech SA, La Ciotat, France), 200 mg/kg (TALC: n ¼ 5, pH 7.04) or tigecycline (Tygacil; Wyeth-Pfizer, Maidenhead, UK), 0.5 mg/kg (TIGE0.5: n ¼ 5, pH 7.94), 1 mg/kg (TIGE1: n ¼ 5, pH 7.91), 3 mg/kg (TIGE3: n ¼ 5, pH 7.89), 25 mg/kg (TIGE25: n ¼ 5, pH 7.77), and 50 mg/kg (TIGE50: n ¼ 5, pH 7.82). All animals were euthanized on d 14. In phase II, effects at 28 d, the same groups were utilized, except TIGE0.5 and TIGE1, which proved to be ineffective during phase I and were excluded for further investigation. Furthermore, three animals were missing from the study due to intraoperative or postoperative problems. Two animals died during the surgical procedure for iatrogenic pneumothorax due to accidental position of the tip of the drainage contralaterally through the pulmonary ligament. One was suppressed 24 h later for paralysis of the hind legs due to an incorrect handling of the animal during the nursing procedure.

Chest Tube Insertion General anesthesia was induced using medetomidine (20 mg/kg, s.c., Domitor; Pfizer Animal Health, Rome, Italy), followed 15 min later by 7 mg/kg, s.c., ketamine (Ketavet 100; Intervet Italia, Aprilia, LT, Italy). During induction, rabbits were oxygenated by facial masks. Maintenance of anesthesia was achieved by isoflurane (Isoflo; Esteve, Milan, Italy) in 100% of oxygen at 2l/min by a coaxial Mapleson D respiratory system. During the procedure, heart rate, respiratory rate, temperature, and pulse oximetry were evaluated in all rabbits (AS3/CS3; Datex-Engstro¨m Division, Instrumentarium Corp., Helsinki, Finland). Saline solution (10 mL/kg/h, EV) was administered during surgery. In order to achieve a good level of intraoperative analgesia, 2 mg/kg of lidocaine (lidocaine 2%; Esteve) was infiltrated locally (subcutaneous and muscular fascia). In all rabbits, postoperative analgesia was by administration of 15 mg/kg, s.c. of buprenorphine (Temgesic 300 mg; Schering Plough SpA, Milan, Italy) at the end of the surgical procedure. A buprenorphine patch (3.8 mg/h total or 1.85 mg/kg/h) (Transtec, Formenti, Milan, Italy) was also added to subcutaneous buprenorphine as an analgesic treatment in 10 cases randomly assigned. A 10 Fr chest tube was inserted into the pleural space through a small right incision and all air was aspirated to prevent pneumothorax. The tube was then tunneled under the skin to the vertebral line and connected to a three-way stopcock. A randomly selected solution was then injected into the pleural space through the chest tube. Following the solution injection, the chest tube was closed via the stopcock for 24 h. The drainage was then opened and connected to a suction drain (Mini-Redon 50 OP-Set, Primed Halberstadt, Medizintechnik GmbH, Halberstadt, Germany) for the next 72 h. Pleural effusion, if present, was collected every 24 h. On d 4 the tube was removed. Blood samples were taken after 24, 48, 72, 96, 168 h and just before sacrifice (14 and 28 d).

Clinical Evaluation and Pain Assessment All rabbits underwent clinical evaluation (heart rate, respiratory rate, temperature, weight, food, and water intake) and only the animals in good general condition were included in the study. At least 4 d of adaptation in the animal care facility was considered necessary to reduce the level of stress before surgery. The same clinical evaluations were performed at 24, 48, 72, 96, 168 h after surgery, and just before sacrifice. Lethargic or dehydrated rabbits were given, in the postoperative period, 10 mL saline solution subcutaneously every 12 h for the first 48 h. Assessment of pain after surgery was carried out in all rabbits using the pain scale (Table 1) proposed by Jones et al. [17] and modified by the authors. The rabbits were killed by the injection of 4 mg/kg of a mixture of embutramide (20%) mebenzone (5%), and tetracaine (0.5%) (Tanax; Intervet Italia SRL, Milan, Italy) into the marginal ear vein. Necropsy was done carefully by four of the investigators (ND, JV, CM, and RC) blinded to the treatment. Immediately after the rabbits’ sacrifice, attempts were made to aspirate all fluid from the peritoneal cavity. Liver, kidneys, and spleen were harvested and weighed. Organomegaly of the liver or spleen was recorded. In addition, attempts were made to aspirate all fluid from both pleural spaces using a posterior transdiaphragmatic approach. The volume of aspirated pleural fluid was recorded. Small incisions were made in the diaphragm to allow better access of the fixative (10% formaldehyde solution) to the pleural cavities. Efforts were made to expand the lung with an intratracheal injection of 10% formaldehyde solution through a plastic catheter (6-mm diameter). The trachea was then ligated with silk and the entire thorax was submerged in 10% formaldehyde solution for at least 48 h. Macroscopic evaluation was performed by one pathologist (SA) (see acknowledgements) who was blinded to the treatment the animal had received and the day of killing. The gross pleurodesis was graded, according to the literature [20], from 1 (none) to 8 (>50% symphysis). Samples were taken from the visceral pleura of anterior lower lobes and parietal pleura of each hemithorax. Specimens were processed routinely and stained with hematoxylin and eosin and with Weigert Van Gieson staining (Bio-Optica S.p.a., Milano, Italy) in order to obtain differential staining of collagen. The microscopic slides were evaluated blindly by two of the investigators (IB and FM) for the presence of inflammation, fibrosis, and thickness in the parietal and visceral pleura. The degree of microscopic inflammation and fibrosis was graded as described in literature: none (0), equivocal (1), mild (2), moderate (3), or marked (4) [20, 28, 29]. Samples of thymus, liver, kidney, and spleen were microscopically analyzed for tigecycline systemic toxicity by two of the investigators blinded to the treatment (IB and FM).

Statistical Analysis Two-way analysis of variance (ANOVA) and Tukey test were used to compare the values between control and pleurodesis groups, using the agent and the time after injection as the two independent factors for analysis. If the data failed the normality test or if they were ordinal data, the results were compared using Kruskal-Wallis rank sum test and multiple Behrens-Fisher test. Statistical analysis was carried out by “R” software (R Development Core Team, 2007, Vienna, Austria) [19]. All data are expressed as mean 6 SD except for nonparametric results and numbers that failed the normal distribution (ShapiroWilk test). The significance level was established when P < 0.05.

RESULTS Clinical Evaluation and Pain Assessment

Clinical evaluation following pain scale by Jones et al. [17], demonstrated that the TIGE50 group had higher

TABLE 1 Scale of Pain in Rabbits Proposed by Jones et al. [17] Modified by Authors

Absent

Mild

Moderate

Substantial

No loss Normal Normal

Up to 10% weight loss 40%e75% of normal for 72 h 40%e75% of normal for 72 h

10%e25% weight loss 48 h 48 h

>25% weight loss 72 h 72 h

Normal

Normal

Poor coat condition, reduced grooming

Normal

Transiently hunched, especially after dosing

Intermittenly hunched

Very poor coat condition, absence of grooming, plus additional signs, e.g., hunched posture, unresponsive behavior Persistently hunched

Normal None None None

Normal Transient Transient None

Intermittent abnormal pattern Intermittent with wetting of fur under chin Intermittent Intermittent (but 30 min (euthanize if >1 h duration)

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Body weight

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FIG. 1. Differential of body weight change between study groups (TIGE3, TIGE25, and TIGE50) and control groups (saline and talc) from d 1 to d 28 after pleurodesis. Dg ¼ differential grams; PO ¼ post-operative. Significant data are expressed as *P < 0.05 and ***P < 0.001.

pain values compared with all other groups (P < 0.005). Their body weight was significantly lower compared with saline, TIGE25, and TALC groups at 7, 14, and 28 d control (Fig. 1). Moreover, the Buprenorphine patch (3.8 mg/h total or 1.85 mg/kg/h) did not provide any significant pain relief compared with nontreated rabbits. Clinical parameters such as body temperature and heart rate were not significant between study groups and controls. Pleural Fluid Analysis

Pleural fluids collected at 24 h after the injection of TALC, TIGE3, TIGE25, and TIGE50 were compared in Fig. 2A. The TIGE50 produced significantly (P < 0.01) more fluid at 24 h than did the TALC and TG3 groups. No significant data were detected between TIGE50 and TIGE25 (P ¼ 0.46). Intrapleural injection of each of the four preparations elicited an exudative pleural effusion. The amount of exudates produced after 24 h by TIGE25 and TIGE50, as well as the other two groups, decreased rapidly over the following days. The same increased values were evident at 24 h for the protein in pleural fluid (Fig. 2B) and lactic acid dehydrogenase (LDH) in pleural fluid (Fig. 2C). During the following days, protein and LDH markedly increased in TIGE50, whilst they decreased in TIGE 25,

TIGE3, and TALC. None of the other groups (saline, TIGE0.5, and TIGE1) produced pleural fluid. The incidence of hemothorax in the animals receiving TIGE50 was 100% in phase I and 50% in phase II. No presence of hemothorax or blood clots in the pleural space at the time of post mortem examination was detected in TIGE25 at 14 and 28 d. Pleurodesis Score

The intrapleural injection of TIGE25 and TIGE50 produced a more rapid pleurodesis than did all other study and control groups in phase I at macroscopic analysis (P < 0.001; Fig. 3). Furthermore, the mean pleurodesis scores were significantly higher in rabbits receiving TIGE25 and TIGE50 than those injected with saline, talc slurry, and TIGE3. Better effectiveness in phase II was confirmed only by TIGE50 compared with all other groups (P < 0.001) whilst TIGE 25 was not significant (P ¼ 0.29; Fig. 4). No significant difference was seen between TALC and TIGE3 at 28 d phase II (P ¼ 0.99). The left pleurodesis scores were 1.00 in all 56 rabbits. At autopsy, liver and kidney were reduced in weight in TIGE50 groups at 14 and 28 d compared with all other groups (Table 2). Microscopically, pleural inflammation, fibrosis, and thickness are described in Table 3 (Fig. 5). Higher

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FIG. 2. Total pleural effusion between study groups (TIGE3, TIGE25 and TIGE50) and control groups (saline and talc) from d 1 to d 28 after pleurodesis (A). Total of protein (B) and LDH (C) in pleural effusion with their pleural fluid/serum ratio are also shown. Significant data are expressed as *P < 0.05, **P < 0.01, ***P < 0.001.

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TABLE 2

8

Liver and Kidney Weights, Expressed as Mean ± SD, of the Control Groups and the Main Study Groups at 14 d (phase I) and 28 d (phase II)

PLEU URODESIS SCORES

7 6

***

***

5

Phase I 14 d

4

Saline TALC TIGE3 TIGE25 TIGE50

3 2

1 SALINE

TALC

TIGE0.5 TIGE1

TIGE3 TIGE25 TIGE50

TREATMENT FIG. 3. Macroscopic grading of pleurodesis of all groups after 14 d (phase 1). Note the inefficacies of TIGE0.5 and TIGE1 compared with control groups (talc and saline). Significant data are expressed as ***P < 0.001.

values of TIGE25 groups were judged in phase I for pleural thickness compared with all other groups (P < 0.01). TALC had a significant pleurodesis effect only when compared with TIGE0.5 (P < 0.001). No differences were noted between TALC and TIGE3 (P ¼ 0.91) either macroscopically or microscopically (inflammation P ¼ 0.99, fibrosis P ¼ 0.96, pleural thickness P ¼ 0.99). In phase II, TIGE0.5 and TIGE1 had no effect and were thus excluded. We observed, macroscopically, a better pleurodesis from TIGE50 compared with all other groups (P < 0.05). Results were similar to phase TALC

TIGE3

TIGE25

TIGE50

8 7

PLEU URODESIS SCORES

Liver

*** 6

*** 5 4 3 2 1 14

28

14

28

14

28

14

28

DAYS FROM TREATMENT FIG. 4. Macroscopic pleurodesis grading comparison of phase 1 (14 d) and phase II (28 d) between study groups (TIGE3, TIGE25, and TIGE50) and control groups (saline and talc). Significant data are expressed as ***P < 0.001.

Kidney

a Phase II 28 d

Phase I 14 d

Phase II 28 d

89,71 6 20,42 105,09 6 18,26 9,28 6 0,65 10,01 6 0,48 80,07 6 9,5 88,85 6 11,59 8,1 6 1,27 8,47 6 0,85 96,30 6 9,08 90,07 6 10,89 8,76 6 1,01 8,24 6 0,58 90,42 6 13,78 90,72 6 14,30 9,004 6 1,11 7,66 6 0,67 60,15 6 15,85 79,77 6 14,71 7,21 6 0,97 7,64 6 0,92

I for TALC and TIGE3 (P ¼ 0.99). There was microscopically greater inflammation in TALC compared with TIGE3 (P < 0.05). Tigecycline Systemic Toxicity

Blood samples for systemic toxicity of TIGE shows alanine transaminase (ALT) over the normal range for TIGE50 groups at 24 and 48 h after the intrapleural instillation. Furthermore, urea was detected over the maximum limit in TIGE25 groups at 4 and 7 d after administration (Fig. 6) whilst for TIGE50 only at 7 d. The aspartate transaminase (AST) and creatinine were in the physiologic range (Fig. 6). High incidence of diarrhea was evident in the TIGE50 group in the first 3 d. Complications occurred only in TIGE50 (n ¼ 3 right hemothoraxþascites and n ¼ 2 hemothorax at d 14; n ¼ 1 massive ascites at d 28). One rabbit of TIGE25 (acute respiratory distress at day 11 postop) and one of TIGE50 (massive right hemothorax and ascites at day 14 postop) died. Right chest wall retraction with ipsilateral mediastinal shift of the mediastinum was markedly evident in all TIGE50 treated animals in phase I and phase II. Furthermore, in 44% of the TIGE50 (n ¼ 2 in phase I and n ¼ 2 in phase II), a trapped lung was present. Lymphocitic chronic pericarditis (LCP) with focal miocarditis was discovered microscopically in 2 out of 5 animals (40%) in each phase of TIGE50 treated groups. Only in one animal (20%) of phase II TIGE25 group was focally detected a LCP without any signs of miocardium involvement. Lymphoid tissues such as thymus showed, microscopically, a dramatic involution of its tissue structures in the TIGE50 group compared with all other groups in phase I and phase II. DISCUSSION

Since the introduction of tigecycline, several research works and clinical trials have demonstrated its antibacterial activity [21, 22]. The tigecycline mechanism of

2.80 6 0.45 3.20 6 0.84 0.24 6 0.11 1.80 6 1.09 2.40 6 0.55 0.22 6 0.16 1.20 6 1.09 1.80 6 1.64 0.13 6 0.11 3.00 6 1.00 2.00 6 1.41 0.29 6 0.28 0.00 6 0.00 0.00 6 0.00 0.03 6 0.01 2.80 6 0.84 3.20 6 1.09 0.31 6 0.24 3.00 6 1.00 3.40 6 0.89 0.65 6 0.26** Significant data are expressed as *P < 0.05 **

2.00 6 1.87 2.20 6 1.30 0.19 6 0.09 Pleural infiammation (0e4) Pleural fibrosis (0e4) Pleural thickness (mm)

0.67 6 1.15 0.67 6 0.58 0.23 6 0.01

2.00 6 0.00 2.00 6 0.00 0.14 6 0.11

Tige50 Tige25 Tige3 TALC Saline

Tige3

Tige25

Tige50

Saline

TALC

Phase II (28 d) Phase I (14 d)

Histologic Comparisons, Expressed as Mean ± SD, of the Control Groups and the Main Study Groups at 14 d (Phase I) and 28 d (Phase II)

TABLE 3

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action allows for a broad spectrum of activity, avoiding many common antibiotic resistance mechanisms, including those that inactivate the other tetracycline and tetracycline-modified antibiotics [13, 14]. The molecular structure of tigecycline is similar to the tetracyclines. In the recent past, tetracycline had a key role among pleurodesis agents due to its proven safety, effectiveness, low cost, and few side effects (e.g., pain) [23e27]. As injectable tetracycline was withdrawn from clinical use, talc gained more success as a pleurodesis agent in the clinical setting and, today, is still the most commonly used. Because of its similarity to tetracycline and its derivatives, we investigated whether tigecycline produced the same pleurodesis effects, and the results were compared with those obtained by a talc slurry. The present study demonstrates that tigecycline is an effective pleurodesis agent: in our study this effect was apparent from 3 mg/kg, and proved to be dosedependent. If we consider that the intrapleural TIGE toxicity threshold was reached at TIGE25mg/kg concentration, we can state that intrapleural administration can be reiterated several times until the desirable pleurodesis effect has been achieved. Tigecycline pleurodesis in rabbits involves a sequential mechanism, starting with inflammation followed by neoangiogenesis and fibrosis. (1) Inflammation: the intrapleural injection of tigecycline induces a dosedependent intrapleural inflammation with formation of exudative pleural effusion within the first 24 h (Fig. 2). The intrapleural injection of talc slurry also produces an acute exudative effusion after 24 h and the inflammation is as intense at 28 d as TIGE at higher dosages (25 and 50 mg/kg). Other effects of talc slurry were significant foreign body granulomas (Fig. 5). The activation of the mesothelial cells, extensively investigated in previous studies on chemical pleurodesis, leads to a pro-inflammatory cascade where coagulation and fibrinolysis are the main steps in pleural organization and fibrosis [30]. (2) Neovascularization: in the TIGE groups the intrapleural inflammatory reaction continues at a high level for at least 4 wk with a dosedependent curve (Table 2). As the inflammation continues, neovascularization becomes more prominent in all TIGE groups than in talc control on the surfaces of both the visceral and the parietal pleurae [31]. (3) Fibrosis: mediators of pleural fibrosis activated by the mesothelial cells such as transforming growth factor beta (TGF-b), Platelet-derived Growth Factor (PDGF), tumor necrosis factor alfa (TNF-a), and interleukin 1 (IL-1) are only part of a large number of locally produced peptides that have been identified and shown to play a key role in the pro-fibrotic activity [32]. Wall retraction and mediastinal shift are probably associated

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FIG. 5. Pleura treated at 28 d from instillation. Ematossilin and eosin (E.E.) staining (1A, 20x) and Weigert Van Gieson (W.V.G., 1B, 20x) of control saline. The talc treated control (2A, 20x, E.E) shows a nodular granulomatosis inflammation from crystals deposits (asterisk) with mild fibrosis of the alveolar septa. WVG (2B, 20x) highlights in pink the collagenous deposit of fibers on the visceral pleura (asterisk). TIGE3 (3A, 20x) shows an immature fibroblasts proliferation and neoangiogenesis (asterisks) with a mild eosinophilic component (arrow). Clearly present is a mild congestion of the alveolar septa. The WVG (3B, 10x) confirm the collagenous deposits nonuniformly distributed with areas with more cellularity (arrows). TIGE25 (4A, 20x) shows adhesions (arrow) between parietal and visceral pleura with neoangiogenesis (asterisk). Atelectasic area of lung parenchyma below the visceral pleura is evident. WVG (4B, 20x) clearly demonstrates, in yellow, a dense proliferation of connective tissue (asterisk) and minimal deposits of collagenous tissues in pink (double asterisk). TIGE50 (5A, 20x) with severe fibrosis of the pleura; area of neoangiogenesis (asterisk) and chondroid metaplasia (double asterisk). Mild fibrosis of the alveolar septa of the lung parenchyma below. Collagenous deposits uniformly distributed (asterisk) on the pleura at the WVG staining (5B, 20x).

with the persistent activation of the pro-fibrotic cascade, which generates an inflammatory peel that freezes the pleura reducing its compliance. The contralateral lung is thus physiologically stimulated to overinflate, with consequent mediastinal shifting. In our study, right chest wall retraction with ipsilateral mediastinal shift of the mediastinum was markedly evident in all TIGE50 treated animals in phase I and phase II. Furthermore, in 44% of the TIGE50 trapped lung was present whilst all other TIGE treated groups and talc control did not have any of those signs. In order to better define TIGE toxicity, the pharmacokinetics and pharmacodynamics of tigecycline administration were studied in a few animal models [33]. In humans, tigecycline administered intravenously has an elimination half-life of approximately 36 h [34]. It is mainly eliminated as unchanged drug and metabolites in the bile and feces (59%). Another 22% of the drug is excreted as unchanged drug in the urine [33, 34]. An increased concentration of alanine transaminase (ALT) was detected in our study after 24 h from the intrapleural treatment only in the TIGE50, both in phase I and phase II.

Comparing the pleurodesis effect of tigecycline with talc, chronic inflammation is a typical finding of the latter. In the literature, the presence of talc particles has been observed for up to 12 y after intrapleural instillation. This might explain why, in our study, after 14 d the pleura appears inflamed, with foreign body granulomas on visceral and parietal pleura, and the inflammatory reaction may persist or even increase in time, as shown, up to 28 d after pleural instillation. This confirms that talc is nonbiodegradable, and many authors advice not to repeat any other instillation after reaching the maximum dosage of 5 g [9, 16]. Talc pleurodesis entails some advantages (effectiveness, low cost) [6, 15], side-effects (pleural granulomas, fibrosis) [6, 23], and possible severe complications (increased risk of mesothelioma, adult respiratory distress syndrome) [7, 16]. Talc is not biodegradable and is responsible for long-term persistent pleural inflammation that can be detected by PET scan many years after the procedure [35, 36]. A possible advantage of tigecycline pleurodesis is the biodegradability of the molecule that might be administered several times, reaching a dosage level < 25 mg/kg. Drawbacks of tigecycline are the severe pain, also resistant to

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FIG. 6. Liver and kidney indices of functional activity. n.v. ¼ normal values [18]; AST ¼ aspartate transaminase; ALT ¼ alanine transaminase; P.O. ¼ postoperative.

analgesics in the 25 mg/kg and 50 mg/kg tigecycline study groups, and its high commercial price. Further studies are necessary to delineate the optimal dosage of intrapleural tigecycline for producing pleurodesis in humans: similarly to the previous pleurodesic experiences with tetracyclines and minocyclines, the initial dosage could be around 3e4 mg/kg, might be repeated every 24 h several times, and included among the acceptable toxicity levels (below 25 mg/Kg). In conclusion, tigecycline can be valuably used as a pleurodesis agent in the clinical field, especially where it is necessary to reduce to the minimum the toxicity of the treatment and long-term complications, as could happen in the case of primary spontaneous pneumothorax. Tigecycline might be used as an alternative pleurodesis agent in patients with malignant pleural effusions that do not respond properly to talc instillation. ACKNOWLEDGMENTS This study was supported by a Research Grant from CARIT Bank Foundation for Polo Ternano of the University of Perugia, Terni

(TR), Italy. The authors acknowledge the contributions of Francesco Rao DVM in helping to randomize the study groups and caring for the animals before and after the intrapleural injection of the sclerosants; Stefano Ascani MD for macroscopically grading the anatomical chest specimens blinded to the study; Camillo Pieramati DVM for reviewing our statistical analysis; and Claudia Floridi BSc for her invaluable laboratory technical assistance.

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