Appendix Die Blut-Hirn-Schranke von Edwin H. Bessai - Die Blut-Hirn-Schranke der Gehirnkapillaren. Prodrugs, das Prodrug „Levodopa“ und „Levodopa-Präparate“ Warum die Ernährung bei der Einnahme von Levodopa-Präparaten eine Rolle spielt, wie deshalb die Ernährung gestaltet werden muss und wie Levodopa-Präparate eingenommen werden müssen. Das Gehirn mu
Guided Treatment of Hydatid
Cysts in Sheep
Direct Injection of Mebendazole and Albendazole
Yahya Paksoy, MD, Kemal Ödev, MD, Mustafa S¸ahin, MD,Bilal Dik, VMD, Recep Ergül, VMD, Ahmet Arslan, PhD Objective. The purpose of this study was to investigate the scolicidal effect of intracystic injection of
benzimidazolic solutions in naturally infected sheep with hydatid disease. Methods. Twenty-four sheep
with 37 hydatid cysts were included in this study for percutaneous treatment with benzimidazolic solu-
tions. The animals were divided into 3 groups: group I, treatment group with mebendazole; group II,
treatment group with albendazole; and group III, control group with distilled water. All solutions were
given percutaneously under sonographic guidance. Cyst contents were aspirated with a needle, and
then scolicidal solutions were injected into the cysts; reaspiration was not done. Routine follow-up sono-
graphic images were taken on the 15th day after treatment, then once per month for 3 months, and
then at 3-month intervals thereafter. At the 1-month follow-up, the percutaneous aspirate yielded
orange juice–like material containing necrotic debris without living scolices. Results. Sonography
showed a reduction in cyst size in the benzimidazolic groups (groups I and II) and progressive changes
in echo patterns. An anaphylactic reaction was observed during the procedure in 1 animal. After 12
months of sonographic follow-up, the animals in all groups were killed, and macroscopic and micro-
scopic changes in tissue samples were evaluated. At autopsy, no cysts with living scolices were found in
the benzimidazolic groups, and the appearance of the treated cysts was different from that of those in
the control group. Microscopic examination showed the degeneration, necrosis, and thickening of the
cyst walls in the treatment groups. Conclusions. Intracystic injection of benzimidazolic solutions as scol-
icidal agents may be used for percutaneous treatment of hepatic hydatid cysts in sheep. Key words:
benzimidazole; hydatid cyst; percutaneous treatment; scolicidal; sonographic guidance.
PAI, puncture, aspiration, and injection
Received February 25, 2003, from UltraGörüntüleme Merkezi (private practice), Konya, ydatid disease is a parasitic infection caused by Turkey (Y.P.); Departments of Radiology (K.Ö.) and the larval stage of the tapeworm Echinococcus General Surgery (M.S.), Selcuk University, School of granulosus.1 The definitive hosts of E granulosus Medicine, Konya, Turkey; Department of Para-sitology, Veterinary Faculty, Selcuk University, Konya, are mainly dogs or other carnivores carrying the Turkey (B.D.); Institute of Veterinary Research, adult tapeworm in their intestines. Humans and sheep Konya, Turkey (R.E.); and Department of Medical (intermediate hosts) are contaminated by ingestion of Biology and Genetics, Gaziantep University, Schoolof Medicine, Gaziantep, Turkey (A.A.). Revision parasite eggs, which reach the liver via the portal system to requested March 12, 2003. Revised manuscript form hydatid cysts. The disease is endemic in regions such accepted for publication March 24, 2003. as the Mediterranean countries and the Middle East. Until We thank Hüsamettin Vatansev, MD, for help with statistical analysis of the data and Evren recent years, treatment of this disease had been limited to Burakgazi, MD, for grammatical support. surgery, but systemic chemotherapeutic agents and percu- Address correspondence and reprint requests to taneous treatment have been reported. Drainage of cysts Yahya Paksoy, MD, Ultra Görüntüleme Merkezi,Serafettin Cad 11, 1-A, Konya 42000, Turkey. by percutaneous needle puncture is contraindicated because of potential seeding of living scolices.2–4 2003 by the American Institute of Ultrasound in Medicine • J Ultrasound Med 22:797–803, 2003 • 0278-4297/03/$3.50 Sonographically Guided Treatment of Hydatid Cysts in Sheep
Several types of sclerosing agents, such as (n = 7 sheep) in group I, 11 cysts (n = 7 sheep) in group II, and 14 cysts (n = 10 sheep) in group III hydrogen peroxide, alcohol, and silver nitrate, are commonly used for percutaneous treatment The procedure was performed as follows.
of hepatic hydatid cysts.2,5–9 Scolicidal solutions The cyst was located, and the percutaneous (e.g., formalin and hypertonic saline) have toxic approach was selected with the aid of sonogra- effects on the biliary tree.10–12 Benzimidazole phy. The maximal cyst diameter was measured, derivatives (albendazole and mebendazole) are and the approximate cyst volume was estimated.
the most preferred chemotherapeutic agents, Prilocaine hydrochloride (Citanest; AstraZeneca although the efficacy of systemic administra- International, London, England) was injected at tion is limited.13–16 When they are taken orally, the chosen puncture site after sedation with a only small amounts are transported to the cyst 2% xylazine hydrochloride solution (Rompun, fluid.17 We thought that direct injection of the 0.1–0.2 ml intramuscularly; Bayer Animal Health, benzimidazole solutions into the cyst cavities Monheim, Germany). Puncture was performed might overcome this obstacle. The aim of this with 18- to 22-gauge, 13- to 16-cm-long poly- experiment was to investigate the efficacy of ethylene needles (Secalon-T; Ohmeda, Swindon, benzimidazole solutions in the treatment of England) under sonographic guidance. When the needle tip was visualized in the correct positionin the cyst cavity, the hydatid fluid was aspirated Materials and Methods
as much as possible, and the scolicidal solutionwas injected into the cyst. The approximate vol- ume of the injected solution was equal to half the research ethics regulations of our institute. We prior cystic volume. The solution was left in the screened and selected infected sheep from 475 cyst. Microscopic examination of the aspirates sheep in herds at the Institute of Veterinary from the cysts revealed living scolices, laminated Research in Konya. The sonographic scanning membranes, hooklets, or combinations thereof was performed with a real-time gray scale in all cysts after the first aspirations. The appear- B-mode scanner and probes of 3.5 MHz (RT- ance of living daughter vesicles proved the sono- X200; GE Medical Systems, Milwaukee, WI) and Routine follow-up sonographic images were Netherlands). According to the classification of taken on the 15th day after treatment, then once per month for 3 months, and then at 3-month revealed 37 unilocular (type 1) hydatid liver intervals thereafter. At the 1-month follow-up, cysts in 24 sheep (8 ewes and 16 White Karaman cystic contents were reaspirated, and the via- sheep). Mebendazole tablets (Vermazol, 100 mg; bility of scolices was examined under light IE Ulagay, Istanbul, Turkey) were liquefied with microscopy with eosin Y dye. In each sheep, isotonic saline, and a solution of 10 g/mL was only 1 cyst cavity was reaspirated for micro- prepared. Pure albendazole was obtained as a scopic examination. Oral antihelmintic agents solution containing isotonic saline (Andazol, were not administered to the animals before the 10 g/mL; Biofarma, Istanbul, Turkey). Both solu- PAI procedure. At the end of the study, the ani- mals in all 3 groups were given a lethal overdose Before the procedure, blood samples were taken of xylazine hydrochloride. Specimens taken from for serum aspartate aminotransferase, alanine the groups of animals were examined and com- aminotransferase, alkaline phosphatase, and pared microscopically and macroscopically.
total bilirubin levels to test liver functions.
A Kruskal-Wallis test and Mann-Whitney U test were used for statistical analysis. P < .05 was group I, treated with mebendazole; group II, treated with albendazole; and group III, treatedwith distillated water. Group III was kept as a control group. Thirty-seven cysts from the 24sheep were subjected to echo-guided percuta- Serial sonographic examinations performed dur- neous treatment with the puncture, aspiration, ing the follow-up period of 1 year revealed a and injection (PAI) technique. There were 12 cysts gradual decrease in cyst volume and changes in Paksoy et al
cyst appearance (Figs. 1 and 2 and Table 1). In the evaluation of all groups’ posttreatment cystvolumes, the differences between the groupswere significant according to the nonparamet-ric Kruskal-Wallis test (P < .0001). According tothe Mann-Whitney U test, there was a signifi-cant decrease in the cyst volumes in groups Iand II in comparison with group III (P < .0001).
There was no significant difference betweenthe cyst volumes in groups I and II (P < .05). Acomparison of pretreatment and posttreat-ment cyst volumes in groups I and II showed asignificant decrease in cyst volumes after treat-ment (P < .002 and .003, respectively). In groupIII, however, there was an increase in cyst vol-umes after PAI, which was statistically signifi-cant (P < .001).
Figure 1. Serial sonograms from a sheep with a nonvesicular
hepatic hydatid cyst (type I) treated with PAI. A, Liver cyst with
well-defined borders and a pure fluid collection during instilla-
tion of a benzimidazolic solution. The needle tip is shown in the
cystic lesion. B, Follow-up sonogram 1 month after PAI showing
collapse of the laminar membrane and disappearance of the
anechoic area. C, Follow-up sonogram 6 months after PAI
showing obliteration of the cystic cavity by folded membranes
Sonographically Guided Treatment of Hydatid Cysts in Sheep
Animals were followed up for 12 months after PAI. In 1 experiment, an anaphylactic reactionoccurred after cyst puncture just before scolicidalagent injection; that animal died and thus wasexcluded from the treatment with scolicidalagents. We considered the death to be due to ananaphylactic reaction caused by cyst contentseeding during cyst puncture, a result of strug-gling by the animal, which did not have adequatesedation. There were no other complicationsduring the procedure.
After PAI, the endocyst separated from the pericyst in groups I and II. During the follow-up, sonography showed that the cyst cavity wasobliterated by folded membranes and debris(pseudotumor appearance). Living scolices(eosin Y dye) were found in all animals after thefirst aspiration. One month later, cystic con-tents were reaspirated and centrifuged, and theviability of scolices was examined under light Figure 2. Serial sonograms from a sheep with a type I hydatid
cyst. A, Before PAI. B, Sonogram 15 days after PAI showing a
partially collapsed cyst cavity. C, One year after PAI, the cyst cav-
ity was almost obliterated.
Paksoy et al
Table 1. Changes in Cyst Volumes in All Groups
Cyst Volumes, mL
No. of Sheep
No. of Cysts
microscopy with eosin Y. One month after percu- mortality, morbidity, and high recurrence rates.
taneous drainage, no living scolices were Successful percutaneous treatment of hydatid observed microscopically in groups I and II; on liver disease with scolicidal agents also has been the contrary, living scolices were seen in group III. These findings imply that both scolicidal Recently, results of medical treatment with agents were effective 1 month after percuta- reported.22–24 Benzimidazole derivatives (fluben- Because a reduction in cyst size, solidification dazole, albendazole, and mebendazole) are of the cyst, absence of a fluid component, and commonly used for the treatment of hydatid dis- decreased posterior wall enhancement have ease in high-risk patients, to prevent secondary been accepted as healing, as stated in the litera- hydatidosis, or both.1,2,25,26 However, the results ture,13,19,20 a postmortem examination of the of enteric medical therapy are still controversial entire abdominal cavity was done to check for and of limited effectiveness.22–24,27–29 Direct cystic dissemination of the disease. The liver was injection of these drugs offers the advantage of a high intracystic drug concentration. Therefore, microscopically for changes in cyst morphologic high scolicidal activity can be obtained, and sys- characteristics. Dissemination of the cysts was temic side effects can be reduced or avoided. We not observed in any sheep. The walls of the treat- hope that pharmaceutical companies can pro- ed hydatid cysts were hard and solid. Calci- duce sterile intracystic forms of these agents.
fication of the cyst walls was seen in all but 3 sheep. Microscopic examination of the treated been treated percutaneously.3,5,6,20,25,26,30,31 The cysts showed that there were no daughter vesi- cysts are sterilized with a scolicidal agent, such cles or living scolices. Hyalinization, thickening, as hypertonic saline, silver nitrate, 90% alcohol, and necrosis of the cyst walls were predominant cetrimide, hydrogen peroxide, benzimidazolic in the treated cysts. In contrast to those in the solutions, or formalin.2,3,6,25,32 Unfortunately, treatment groups, the cysts in the control groups clinical and experimental studies have shown had clear fluid with living scolices and thin, that intracystic injection of scolicidal agents intact walls. Microscopic examination did not may cause sclerosing chemical cholangitis.33,34 show any evidence of hepatobiliary toxicity. Liver Moreover, 1 report described fatal cholangi- function test results were within the normal tis.35 Unlike other scolicidal agents, albenda- zole is not toxic to the liver and biliarystructures at the applied concentration, which Discussion
potentially decreases the possibility of chemi-cal sclerosing cholangitis.13 Erzurumlu et al10 Hydatid disease caused by E granulosus is a com- reported that direct application of albendazole and mebendazole solutions to the biliary sys- Turkey, and other Mediterranean countries. The tem of rabbits did not cause any side effects.
conventional treatment of hydatid liver disease Our study did not reveal any injury to the is surgery, which is associated with considerable Sonographically Guided Treatment of Hydatid Cysts in Sheep
In the course of follow-up, sonographically Ödev K, Paksoy Y, Arslan A, et al. Sonographically guided reaspiration was performed on 6 cysts in guided percutaneous treatment of hepatic hydatid each group. There were no living scolices in the cysts: long-term results. J Clin Ultrasound 2000; treated cysts of groups I and II. Living scolices were found in the control group. Serial sono- Aygün E, S¸ahin M, Ödev K, et al. The management graphic examinations over 1 year revealed a of liver hydatid cysts by percutaneous drainage. Can marked reduction in lesion size in the treated groups but not in the control group. A solid pat-tern or a heterogeneous echo pattern was seen in Ödev K, Aygün E, Kartal A, et al. Percutaneous treat- the cysts of all animals treated with albendazole ment of hydatid disease. Turk J Intervent Radiol 1997; or mebendazole. Postmortem histopathologic examination of the cysts showed thickening of 10. Erzurumlu K, Özdemir M, Mihmanlı M, Çevikbap U.
the cyst walls, hyalinization, necrosis of the walls, The effect of intra-operative mebendazole-albenda- and local calcification. There was no evidence of zole application on the hepatobiliary system. Eur Surg biliary toxicity in the liver, such as ductal epithe- lial proliferation, ductal dilatation, or fibrosis. Inthis study, we observed that there was a correla- 11. Belghiti J, Benhamou TB, Houry S, Grenier P, Hugucer tion between the follow-up sonographic appear- M, Fekete F. Caustic sclerosing cholangitis. Arch Surg We conclude that sonographically guided intra- 12. Polo JR, Garcia-Sabrido JL. Sclerosing cholangitis cystic injection of benzimidazolic solutions is associated with hydatid liver disease. Arch Surg 1989; effective in the treatment of hepatic hydatid cysts in sheep. In experimental models, intracysticinjection of benzimidazolic solutions as scolici- 13. Deg˘er E, Hökelek M, Deg˘er BA, Tutar E, Asil M, dal agents should be considered for treating hep- Pakdemirli E. A new therapeutic approach for the atic hydatid cysts. Well-designed human studies treatment of cystic echinococcosis: percutaneous are needed to establish the efficacy of the PAI albendazole sulfoxide injection without reaspiration.
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DIREKTORAT JENDERAL PELAYANAN KEFARMASIAN DAN ALAT KESEHATAN UNDANG – UNDANG REPUBLIK INDONESIA NOMOR 5 TAHUN 1997 P S I K O T R O P I K A DENGAN RAHMAT TUHAN YANG MAHA ESA PRESIDEN REPUBLIK INDONESIA, Menimbang : a. bahwa pembangunan nasional bertujuan untuk mewujudkan suatu masyarakat adil dan makmur yang merata materil dan spiritual berdasarkan Pancasila dan Undang