Digestive Diseases and Sciences, Vol. 37, No. 12 (December 1992), pp. 1890-1897

Spread and Distribution of 5-ASA Colonic Foam and 5-ASA Enema in Patients with Ulcerative Colitis MASSIMO CAMPIERI, MD, CLAUDIO CORBELLI, MD, PAOLO GIONCHETTI, MD, CORRADO BRIGNOLA, MD, ANDREA BELLUZZI, MD, GIULIO DI FEBO, MD, PAOLO ZAGNI, MD, GABRIELE BRUNETTI, MD, MARIO MIGLIOLI, MD, and LUIGI BARBARA, MD

Rectal treatment with enemas, foams, and suppositories is the most efficient method of delivering an adequate quantity of locally active drugs to the distal colon. In a pilot study carried out by colonoscopy in four patients, it was observed that 4 g 5-ASA in 20 ml foam spread up or beyond the splenic flexure and more extens&ely than 2 g 5-ASA in 10 ml foam. Therefore we have undertaken a study in order to compare by scintigraphy the colonic distribution of 4 g 5-ASA foam versus 4 g 5-ASA in 100 ml liquid enemas in lO patients with ulcerative colitis using a crossover randomized design. Both preparations were labeled with 100 MBq [99mTc]sulfur colloid before administration. Anterior scans were taken at intervals for 4 hr. Activity, expressed as a percentage of total radioactivity, was measured in the rectum, sigmoid, descending, transverse, and ascending colon. Six patients had the same extent of spread with the two formulations; in three patients with foam and in one patient with enema a greater spread was observed. The foam reached the upper limit of disease in all cases, while enema failed in two cases. The maximum spread with foam was observed within 30 min in nine of lO patients compared with seven of lO after enema. Compared to enema, foam distributes more uniformly and seems to persist longer in the descending and sigmoid colon. The 5-ASA colonic foam shows some more favorable characteristics than enema for the local treatment of left-sided ulcerative colitis. KEY WORDS: 5-ASA; rectal foam; suspension enema; retrograde spread; biodistribution study; scintigraphic study.

Rectal administration of drugs has become a common approach in the management of patients with Manuscript received September 6, 1991; revised manuscript received March 10, 1992; accepted March 19, 1992. From the Istituto di Clinica Medica e Gastroenterologia, Universifft di Bologna, Servizio di Medicina Nucleare, Policlinico S.Orsola-Maipighi, Bologna, Italy. This work was supported in part by Bracco S.p.A (Milan, Italy). Part of this study was presented at the 92th Annual Meeting of The American Gastrointestinal Association, May 18-24, 1991, in New Orleans, Louisiana. Address for reprint requests: Prof. Massimo Campieri, Clinica Medica e Gastroenterologia, Via Massarenti 9, 40138 Bologna, Italy.

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ulcerative colitis. In fact, this approach provides a direct route for dosing the distal colon and is the most efficient method of delivering an adequate amount of locally active drugs (1, 2) to the inflamed mucosa. Both steroids (3-5) and 5-ASA (6, 7) given rectally have shown a prompt beneficial response in most patients with left-sided colitis and provide less drug absorption into the systemic circulation than oral administration (8-10), thereby reducing the risk of side effects. In recent years the use of rectal suspension enemas has become fairly common as a first-line Digestive Diseases and Sciences, Vol. 37, No. 12 (December 1992)

0163-2116/92/1200-1890506.50/09 1992PlenumPublishingCorporation

5-ASA AND U L C E R A T I V E COLITIS TABLE 1. SPREAD OF Two FOAM PREPARATIONS IN COLONOSCOPIC STUDY Disease

Maximum spread

Patient

Sex

Age

Extent

Activity

Foam 2 g

Foam 4 g

1 2 3 4

F F F m

47 65 42 29

Left-sided Proctosigmoiditis Proctosigmoiditis Left-sided

Moderate Mild Mild Remission

Descending Sigmoid Descending Sigmoid

Ascending Descending Transverse Transverse

therapeutic step in distal ulcerative colitis (11). The acceptance is generally good but a few patients complain of some difficulties related either to selfadministration or to retention. Rectal foams containing steroids have been used for many years and are considered more convenient to administer, easier to retain, and better tolerated than steroid enemas (12, 13). Rectal foams remain in contact with the mucosa for some hours (14), but unfortunately have a limited spread because they cover the mucosa of the rectum and distal sigmoid colon only (15, 16). On the other hand, suspension enemas spread extensively within the colon up to the splenic flexure (17) making it possible to treat satisfactorily most patients with ulcerative colitis. In order to improve the benefits of rectal therapy, even to patients with more widespread colitis, a new colonic foam containing 5-ASA has been developed. This new preparation has been studied in patients with colitis in order to assess the retrograde spread and colonic distribution compared to 5-ASA suspension enema.

At the moment of use, the dispensing valve allows rapid expansion of the propellant, which triggers and enhances the foaming action of the surfactant and makes possible the intrarectal administration in the form of foam. The energy of propellant is absorbed mainly in generating the foam and the ingredients of the vehicle are compatible with rectal and colonic mucosa. In vitro the volumetric expansion of 2 g and 4 g 5-ASA preparations was approx. 100-120 ml and 180-200 ml of foam, respectively. The foam appears creamy, firm, and it takes long time to collapse. In the colonoscopy study the vital dye marker methylene blue (2%) was added to the study preparations. This method enabled the direct observation of the supravital staining in the colonic mucosa. After administration of either 2 g or 4 g foam, patients underwent colonoscopy after 3 hr. The examination was performed by the same endoscopist who was unaware of the dosage used. Seintigraphie Study. This study was carried out in order to compare by scintigraphy the retrograde spread and the colonic distribution of 4 g 5-ASA foam and 4 g 5-ASA enema in patients with ulcerative colitis. The enema preparation consists of 5-ASA aqueous suspension, dispensed in a single plastic squeeze bottle containing 100 mi of liquid enema (ASACOL enema, Giuliani). Ten patients agreed to participate in the study after a full explanation. The study was approved by the Institutional Review Board for clinical studies. Patient characteristics are reported in Table 2.

MATERIALS AND METHODS In order to determine the retrograde spread and colonic distribution of foams and enemas, we carried out two types of investigation: colonoscopic assessment of retrograde spread, and scintigraphic observation of the spread and colonic distribution. Colonoscopic Study. This study was designed to compare the retrograde spread of 2 g 5-ASA in 10 ml foam versus 4 g 5-ASA in 20 ml foam in patients with ulcerative colitis. The study was carried out using a crossover randomized design. Four patients with established ulcerative colitis volunteered to participate in this investigation after having been fully informed of the purpose and nature of the experiment (Table 1). The study was approved by the Institutional Review Board for clinical studies. The preparations contained 5-ASA formulated in a 10 ml or 20 ml aqueous solution able to generate a foam by means of inert gas propellants and a surfactant and were supplied as single-dose aerosol containers fitted with an applicator for rectal delivery of 2 g or 4 g of 5-ASA (ASACOL foam, Giuliani & Bracco, Milan, Italy). Digestive Diseases and Sciences, Vol. 37, No. 12 (December 1992)

TABLE 2. SPREAD OF FOAM ENEMA AND LIQUID ENEMA IN SCINTIGRAPHIC STUDY

Disease Patient

1 2 3 4 5 6 7 8 9 10

Segment* and time (rain) o f maximum spread

Sex

Age

Extent

Activity

Foam

Enema

M M M M M M M M M M

26 58 68 48 60 50 56 57 38 47

Left-sided Transverse Left-sided Left-sided Ascending Sigmoid Left-sided Left-sided Left-sided Left-sided

Remission Moderate Mild Remission Moderate Remission Mild Mild Mild Mild

D5 A 30 T5 D 30 A 60 S5 D5 D5 D 30 D5

T 180 A 30 T 30 S5 T 60 S5 S5 D 30 D 60 D5

*A = ascending; T = transverse; D = descending; S = sigmoid colon.

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CAMPIERI ET AL Both preparations were labeled with 100 MBq [99mTc]sulfur colloid immediately before administration. For the preliminary assessment of tracer distribution in foam and enema preparations, samples of each radiolabeled preparation obtained over a 4-hr period were distributed on 50-cm strips. An uniform distribution of radioactivity was then verified by means of subsequent static images. The stability of 99mTC preparations was confirmed by thinlayer chromatography. The study used a randomized, crossover design. All patients were studied with the second preparation three days after the previous study. Abdominal images were obtained using a large-field-of-view gamma camera (Gamma-diagnost, Philips) equipped with a low-energy, highresolution parallel-hole collimator and linked to a dedicated nuclear medicine computer (PDP11 73 Digital). Patients received either foam or enema at 2 eM, then maintained a supine position on the diagnostic table for 4 hr, after which they were free to move. Anterior scans were taken at 5, 30, 60, 180, and 240 min, with an acquisition matrix of 128 x 128, byte mode. In four patients scans were also taken at 6 and 20 hr. Each scan lasted 6 min; delayed scans were continued up to 300K counts. The abdomen was subdivided into five regions of interest as follows: ascending colon, transverse colon, descending colon, sigmoid colon, and rectum. Radioactivity in each region was expressed as the percentage of total radioactivity in the whole abdomen. Scans were analyzed by three examiners who evaluated individually the anatomic site of progression, the homogeneity of distribution, and the persistence of both preparations in the colonic segments. As regards the homogeneity of distribution, a score from 0 to 2 (0 = absent, 1 = nonhomogeneous, 2 = homogeneous) was used. The persistence of preparations in the colonic segments was evaluated by comparing the images obtained at 4, 6, and 20 hr with the best image obtained within 2 hr for each patient and using a score from 0 to 3 (0 = absent, 1 = poor, 2 = fair, 3 = good). The scoring system proved to be consistent, with low intraand interobserver variability. In less than 10% of cases (32/360) was there discordance among examiners: this was solved by consensus evaluation of the scan. In order to detect possible free 99mTCin blood or in soft tissues due to instability of the radiolabel, blood samples and whole-body scintiscans were taken in the first two patients. Both imaging studies and blood sample assays confirmed uniformity and stability of radiolabeling. Comparison of scores between preparations was performed using the Wilcoxon matched-pairs signed-ranks test. The tests were two-tailed, and P < 0.05 was considered significant. RESULTS

Colonoscopic Study. Table 1 shows individual results. In each case the foam spread to or beyond the extent of disease. The spread of foam was more extensive with the larger dose in all cases. Scintigraphic Study. All patients retained both preparations during the first 2 hr. Partial bowel 1892

evacuations occurred within 4 hr in two patients during the f o a m study and in three patients during the e n e m a study. As can be seen f r o m Table 2, in six patients the same segment was reached with both formulations. A greater spread was o b s e r v e d with f o a m in three patients and with e n e m a in one patient. It is of interest to note that the m a x i m u m spread was reached within 30 rain in nine patients using f o a m as c o m p a r e d with seven using enemas. The regional distribution of f o a m and e n e m a 2 hr after administration is represented in Figure 1. F o a m had better h o m o g e n e i t y scores than e n e m a in the descending colon at 30 rain (P < 0.02) and at 2 hr (P < 0.02) and in the sigmoid colon at 2 hr (P < 0.04) (Table 3). A similar trend was evident for the sigmoid colon at 30 min but did not reach the significance level. N o differences were found between preparations in the h o m o g e n e i t y scores for the rectum. Most scintigraphic images showed a different extent in the c o v e r a g e of the colonic m u c o s a (Figures 2 and 3). The p e r s i s t e n c e scores o f f o a m t a k e n at 4 hr were significantly higher than t h o s e o f e n e m a for the descending colon (P < 0.03) and the sigmoid colon (P < 0.05) (Table 4). T h e r e was no difference in the p e r s i s t e n c e scores o f r e c t u m b e t w e e n preparations. The mean percentage activity in the descending and sigmoid colon calculated at 6 hr in four patients who had fully retained the preparations was o v e r 60% after f o a m c o m p a r e d with 45% after e n e m a administration. Very low activity was found at 20 hr with both preparations. After partial evacuations, there were less m a r k e d changes in the scintigraphic images obtained with f o a m than for enema. DISCUSSION The present study has yielded substantial information about retrograde spread and colonic distribution in the colon of a new dosage f o r m of 5-ASA as foam e n e m a c o m p a r e d with 5-ASA liquid enema. The method of delivering 5-ASA as f o a m is based on the intrarectal administration of a small amount of solution enable to generate in the colon a m u c h larger volume of foam. The aim of this basic study was to assess whether this f o a m preparation could have similar or e v e n better characteristics compared with a large volume of liquid enema. The results of this study d e m o n s t r a t e d that 5-ASA foam has equal or greater retrograde spread Digestive Diseases and Sciences, Vol. 37, No. 12 (December 1992)

5-ASA AND ULCERATIVE COLITIS TABLE 3. HOMOGENEITY SCORES* 30 AND 120 MIN AFTER ADMINISTRATION OF FOAM AND ENEMA

Foam

Sigrnoid

Rectum Patient

30

Enema

Descending

Rectum

Sigmoid

Descending

120

30

120

30

120

30

120

30

120

30

120

1

0

1

2

2

2

2

0

1

1

2

1

1

2 3 4 5 6 7 8 9

0 1 1 2 2 0 1 2 0

1 2 2 2 2 1 I 2 1

2 2 2 2 1 2 2 1 2

2 2 2 2 1 2 2 2 2

2 2 2 2 0 2 2 2 2

2 1 2 2 0 1 2 2 1

0 1 2 0 1 i 2 2 1

1 1 2 1 2 2 1 2 2

1 1 2 1 2 2 1 1 1

1 1 1 1 2 1 1 1 1

1 1 0 i 0 0 1 0 1

1 1 0 1 0 0 1 1 1

10

*Score: 0 = a b s e n t ; 1 = n o n h o m o g e n e o u s ; 2 = homogeneous.

than 5-ASA 100 ml enema containing the same dose and shows a more uniform distribution and longer persistence in the descending and sigmoid colon. From this study, it is evident that within 30 min 30% and 50% of the foam preparation reaches the descending colon and the sigmoid colon, respectively. This means that therapeutic amounts of 5-ASA are delivered in the segments mostly involved by the disease. Spreading of foam and enema is usually complete within an hour and very low residue, if any, is found in active patients after 20 hr from administration. Gamma scintigraphy has provided a particularly suitable noninvasive technique for the evaluation of

the location and distribution of the preparations within the colon. 5-ASA is a locally active drug and therefore its therapeutic activity is related to the presence of adequate concentrations of the drug at the sites of inflammation. The intrarectal route is the best way to deliver topically active drugs to the distal colon; suppositories, retention enemas, and rectal foams have been commonly used in the treatment of distal ulcerative colitis. The extent of spread, the homogeneity of distribution, and the length of persistence of the preparations are all of great importance when drugs are administered rectally for an effective topical action.

80 [~

70

5-ASAFoam 5-ASA Enema

60 _Z,

50

.>_. E o 13.

40 30 20 10 Rectum

Sigmoid

Descending

Trasversum

Ascending

Fig 1. Regional distribution ( - so) of radiolabelled 5-ASA foam and 5-ASA enema 2 hr after administration. Digestive Diseases and Sciences, Vol. 37, No. 12 (December 1992)

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CAMPIERI ET AL

Fig 2. Scintigraphic images taken in the same patient showing clear difference in the homogeneity of distribution 30 min after administration of 5-ASA foam and 5-ASA enema: (a) foam, (b) enema.

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Digestive Diseases and Sciences, Vol. 37, No. 12 (December 1992)

5-ASA AND ULCERATIVE COLITIS

Fig 3. Scintigraphic images taken in the same patient at 60 rain showing clear difference in the homogeneity of distribution between the preparations: (a) foam, (b) enema.

Digestive Diseases and Sciences, Vol. 37, No. 12 (December 1992)

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C A M P I E R I ET AL TABLE 4. PERSISTENCE SCORES* 4 HR AFTER ADMINISTRATION OF FOAM AND ENEMA

Foam Patient 1 2 3 4 5 6 7 8 9 10

Enema

Rectum

Sigmoid

Descending

Rectum

Sigmoid

Descending

3 2 3 3 3 3 3 2 3 3

3 3 2 3 3 2 2 3 3 2

3 3 2 3 3 0 2 3 3 2

3 1 1 3 2 3 3 2 3 3

2 2 2 3 2 2 2 2 2 2

2 2 2 0 3 0 0 2 1 2

*Score: 0 = absent; 1 = poor; 2 = fair; 3 = good.

It is known that the spread of rectal preparations is dependent on the type and volume of preparations. The spread of suppositories is confined within the rectum and distal sigmoid colon (18). Suspension enemas have a spread which is volumedependent, ie, increasing the volume increases the spread into the proximal colon. Enemas of 100 ml usually have a sufficient spread up to the splenic flexure and provide effective topical treatment to the sigmoid and descending colon (17, 19). Other factors related to the patient influence the spread of the preparation into the colon: activity and extent of disease. The more extended and more active the disease, the larger the possibility of reaching the proximal portions of the colon. Our study confirms previous data concerning a volume-dependent retrograde spread (I7), which is much more marked with 100 ml than with only 40-50 ml (20, 21) and also emphasizes further the extent of inflammation as a crucial factor for determining the retrograde progression (22, 23). The reason for this increased retrograde spread seems to be related to a decreased colonic tone, which has been recorded when colitis is active (24). Previous studies have shown that steroid rectal foams have a less extensive retrograde spread than liquid enemas, being mainly limited to the rectum and distal sigmoid colon (14-16). This study indicates a substantial difference between the steroid foams so far clinically employed and the present 5-ASA foam preparation. The reason for this could be the larger volume that is generated within the colon by this new preparation. The foam spreads rapidly in the colon and seems to distribute homogeneously in the entire left colon in a manner different from that of liquid enemas. The tolerance to this preparation proved to be good in patients with active colitis. No major com18 9 6

plaint was reported by patients either in this study or in a large controlled clinical study (25). Further, foam appears to persist longer in the descending and sigmoid colon, even after partial bowel evacuations. In this study both a quantitative and a qualitative evaluation detailing homogeneity of distribution were carried out in parallel, and it is of particular interest to note that the coverage of the colonic mucosa is more uniform when using foam than enema. This could be related to the physical properties of the foam such as greater surface coating, mucosal adhesion, and volumetric expansion with respect to the liquid enemas. In conclusion, 5-ASA foam and enema have favorable characteristics for effective topical action in distal ulcerative colitis. However, colonic foam seems to represent a more suitable preparation to target 5-ASA into the distal colon and a further advancement in the topical treatment of ulcerative colitis. ACKNOWLEDGMENTS The authors wish to thank Dr. Emilia Chiodini, Pharm Sci, for technical assistance in the preparation of radiolabeled 5-ASA foam and enema. REFERENCES 1. Lee DAH, Taylor M, James VHT, Walker G: Rectally administered prednisolone-evidence for a predominantly local action. Gut 21:215-218, 1980 2. Azad Khan AK, Piris J, Truelove SC: An experiment to determine the active therapeutic moiety of sulphasalazine. Lancet 2:892-895, 1977 3. Truelove SC: Treatment of ulcerative colitis with local hydrocortisone. Br Med J 2:1267-1272, 1956 4. Matts SG: Local treatment of ulcerative colitis with prednisolone-21-phosphate retention enemata. Lancet 1:517-519, 1960 5. Spencer JS, Kirsner JB: Experience with short and long

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term courses of local adrenal steroid therapy for ulcerative colitis: Report of 98 cases. Gastroenterology 42:669, 1962. Campieri M, Lanfranchi GA, Bazzocchi G, Brignola C, Sarti F, Franzin G, Battocchia A, Lab6 G, Dal Monte PR: Treatment of ulcerative colitis with high-dose 5-aminosalicylic acid enemas. 2:270-271, 1981 Suthedand LR, Martin F, Greer S, Robinson M, Greenberger N, Saibil F, Martin T, Sparr J, Prokipchuck E, Borgen L: 5-Aminosalicylic acid enema in the treatment of distal ulcerative colitis, proctosigmoiditis, and proctitis. Gastroenterology 92:1894-1898, 1987 Farmer RG, Schumaker OP: Treatment of ulcerative colitis with hydrocortisone enemas: Relationship of hydrocortisone absorption, adrenal suppression, and clinical response. Dis Colon Rectum 13:355-361, 1970 Lee DAH, Taylor GM, James VHT, Walker G: Plasma prednisolone levels and adrenocortical responsiveness after administration of prednisolone-21-phosphate as a retention enema. Gut 20:349-355, 1979 Campieri M, Lanfranchi GA, Boschi S, Brignola C, Bazzocchi G, Gionchetti P, Minguzzi MR, Belluzzi A, Lab6 G: Topical administration of 5-aminosalicylic acid enemas in patients with ulcerative colitis. Studies on rectal absorption and excretion. Gut 26:400-405, 1985 Hanauer SB: 5-ASA enema therapy. Neth J Med 35:Sll$20, 1989 Ruddell WS, Dickinson RJ, Dixon MF, Axon AT: Treatment of distal ulcerative colitis (proctosigmoiditis) in relapse: Comparison of hydrocortisone enemas and rectal hydrocortisone foam. Gut 21:885-889, 1980 Sommerville KW, Langman MJ, Kane SP, MacGilchrist AJ, Watkinson G, Salmon P: Effect of treatment on symptoms and quality of life in patients ulcerative colitis: Comparative trial of hydrocortisone acetate foam and prednisolone 21phosphate enemas. Br Med J 291:886, 1985 Farthing MJG, Rutland MD, Clark ML: Retrograde spread of hydrocortisone containing foam given intrarectally in ulcerative colitis. Br Med J 2:822-824, 1979

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15. Hay DJ, Sharma H, Irving MH: Spread of steroid-containing foam after intrarectal administration. Br Med J 1:175l-1753, 1979 16. Wood E, Wilson CG, Hardy JG: The spreading of foam and solution enemas. Int J Pharmacol 25:191-197, 1985 17. Campieri M, Lanfranchi GA, Brignola C, Bazzocchi G, Gionchetti P, Minguzzi MR, Cappello IP, Corbelli C, Boschi S: Retrograde spread of 5-aminosalicylic enemas in patients with active colitis. Dis Colon Rectum 29:108-110, 1986 18. Williams CN, Haber G, Aquino GA: Double-blind, placebo-controlled evaluation of 5-ASA suppositories in active distal colitis and measurement of extend of spread using 99mTc-labeled 5-ASA suppositories. Dig Dis Sci 32:71S75S, 1987 19. Kruis W, Bull U, Eisenburg J, Paumgartner G: Retrograde colonic spread of sulfasalazine enemas. Scand J Gastroenterol 17:933-938, 1982 20. Van Buul MMC, Mulder CJJ, Wiltink EHH, Van Royen EA, Tytgat GNJ: Retrograde spread of therapeutic enemas in patients with inflammatory bowel disease. HepatoGastroenterol 36:199-201, 1989 21. Hardy JG, Lee SW, Clark AG, Reynolds JR: Enema volume and spreading. Int J Pharmacol 31:151-155, 1986 22. Jay M, Digenis GA, Foster TS, Antonow DR: Retrograde spreading of hydrocortisone enema in inflammatory bowel disease. Dig Dis Sci 31:139-144, 1986 23. Vitti RA, Meyers F, Knight LC, Siegel JA, Malmud LS, Fisher RS: Quantitative distribution of radiolabeled 5-aminosalicylic acid enemas in patients with left-sided ulcerative colitis. Dis Colon Rectum 29:108-110, 1986 24. Hardy JG, Wood E, Clark AG, Reynolds JR: Colonic motility and enema spreading. Eur J Nucl Med 12:176-178, 1986 25. Campieri M, Bianchi P, Bianchi Porto G, Brunetti G, D'Albasio G, Capurso L, Cottone M, De Franchis R, Miglioli M, PaUone F, Paoluzi P, Pera A, Prantera C, Sturniolo GC: Therapeutic evaluation of mesalazine foam (Asacol) versus mesalazine enema in the treatment of distal ulcerative colitis. Gastroenterology 100:A200, 1991

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Spread and distribution of 5-ASA colonic foam and 5-ASA enema in patients with ulcerative colitis.

Rectal treatment with enemas, foams, and suppositories is the most efficient method of delivering an adequate quantity of locally active drugs to the ...
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