RSS-Feed abonnieren
DOI: 10.1055/s-2008-1027150
© Georg Thieme Verlag KG Stuttgart · New York
Medical Prevention and Treatment of Acute and Chronic Radiation Induced Enteritis - Is there any Proven Therapy? A short Review.
Medikamentöse Prophylaxe und Behandlung der akuten und chronischen Strahlenenteritis - Gibt es eine etablierte Therapie?Publikationsverlauf
manuscript received: 15.8.2007
manuscript accepted: 15.1.2008
Publikationsdatum:
07. Mai 2008 (online)

Zusammenfassung
Hintergrund: Die Strahlenenteritis ist eine schwerwiegende Nebenwirkung bei Patienten, die im Rahmen einer Krebstherapie am Abdomen oder Becken bestrahlt werden. Trotzdem fehlen standardisierte Daten für die medikamentöse Prophylaxe und Therapie. Material und Methoden: In einer PubMed-gestützten Literatursuche wurden die aktuellen Veröffentlichungen in deutscher und englischer Sprache zum Thema „Prophylaxe und Therapie der Strahlenenteritis” gesichtet und ausgewertet. Ergebnisse: Es fanden sich vier doppelt verblindete und placebokontrollierte Studien, in denen die prophylaktische Wirkung von 5-Amionosalizylaten bei akuter Strahlenenteritis untersucht wurde. In diesen Studien konnte nur für die Gabe von Sulphasalazin (2 g/Tag) ein positiver Effekt nachgewiesen werden. Die prophylaktische Gabe von Probiotika konnte die Inzidenz der akuten Strahlenenteritis in einer doppelblinden, placebokontrollierten Studie deutlich senken. Die Wirksamkeit von Octreotid bei bereits bestehender akuter Strahlenenteritis wurde in einer randomisierten und einfach verblindeten Studie aufgezeigt. In zwei Arbeiten, eine davon randomisiert, wurde eine Wirksamkeit von Loperamid bei bestehender akuter Strahlenenteritis beschrieben. War Diarrhö auch das Hauptsymptom der chronischen Strahlenenteritis, erwies sich Loperamid in einer doppelt verblindeten, randomisierten und placebokontrollierten Studie als wirksam zur Senkung der Stuhlfrequenz. Eine retrospektive Auswertung von Patientendaten konnte Vorteile einer längerfristigen häuslichen parenteralen Ernährung gegenüber einer chirurgischen Intervention bei schwerer chronischer Strahlenenteritis mit Obstruktion oder Fistelbildung andeuten. Schlussfolgerung: Reduktion der Strahlendosis und des Bestrahlungsfeldes sind nach wie vor die wichtigsten Faktoren in der Prophylaxe der akuten und chronischen Strahlenenteritis. Weitere Untersuchungen der Pathophysiologie insbesondere der chronischen Strahlenenteritis könnten neue therapeutische Perspektiven eröffnen. So scheint beispielsweise eine Hemmung von TGF-β einen neuen Erfolg versprechenden Therapieansatz bei chronischer Strahlenenteritis darzustellen.
Abstract
Background: Radiation enteritis is a severe problem in patients receiving irradiation of the abdomen or pelvis in the course of cancer treatment. Nevertheless, there is a lack of standardised strategies for medical prevention and therapy. Materials and Methods: A PubMed based literature search was performed to address the available data on the prevention of and therapy for acute and chronic radiation enteritis. Results: Four double-blind and placebo-controlled studies used 5-aminosalycilates in the prevention of acute radiation enteritis. Only for sulphasalzine 2 g/d was a positive effect proven. Prophylactic administration of probiotics reduced the incidence of acute radiation enteritis in a large placebo-controlled trial. If acute radiation enteritis was present octreotide ameliorated radiation-induced diarrhoea in a randomised study. Two investigations, only one of them randomised, described the effectiveness of loperamide in the treatment of acute radiation enteritis. If diarrhoea was also the main symptom of chronic radiation enteritis, loperamide reduced stool frequency in a double-blind and placebo-controlled study. A retrospective analysis of severe cases of chronic radiation enteritis with obstruction and fistula indicated that parenteral nutrition at home was more effective than surgery. Conclusion: Reduction of radiation dose and field size are still the most important factors in the prevention of acute and chronic radiation enteritis. Valid data particularly on the treatment of chronic radiation enteritis are lacking. A better understanding of the pathopysiology especially in chronic radiation enteritis might offer new therapeutic perspectives. Inhibition of TGF-β, for example, might be a new promising therapy approach.
Schlüsselwörter
akute Strahlenenteritis - chronische Strahlenenteritis - Prävention - Therapie
Key words
acute radiation enteritis - chronic radiation enteritis - prevention - therapy
References
- 1
Yavuz M N, Yavuz A A, Aydin F. et al .
The efficacy of octreotide in the therapy of acute radiation-induced diarrhea: a randomized
controlled study.
Int J Radiat Oncol Biol Phys.
2002;
54
195-202
MissingFormLabel
- 2
Kozelsky T F, Meyers G E, Sloan J A. et al .
Phase III double-blind study of glutamine versus placebo for the prevention of acute
diarrhea in patients receiving pelvic radiation therapy.
J Clin Oncol.
2003;
21
1669-1674
MissingFormLabel
- 3
Yeoh E K, Horowitz M.
Radiation enteritis.
Surg Gynecol Obstet.
1987;
165
373-937
MissingFormLabel
- 4
Gavazzi C, Bhoori S, Lovullo S. et al .
Role of home parenteral nutrition in chronic radiation enteritis.
Am J Gastroenterol.
2006;
101
374-379
MissingFormLabel
- 5
Kinsella T J, Bloomer W D.
Tolerance of the intestine to radiation therapy.
Surg Gynecol Obstet.
1980;
151
273-284
MissingFormLabel
- 6
Cotti G, Seid V, Araujo S. et al .
Conservative therapies for hemorrhagic radiation proctitis: a review.
Rev Hosp Clin Fac Med Sao Paulo.
2003;
58
284-292
MissingFormLabel
- 7
Martenson J A, Bollinger J W, Sloan J A. et al .
Sucralfate in the prevention of treatment-induced diarrhea in patients receiving pelvic
radiation therapy: A North Central Cancer Treatment Group phase III double-blind placebo-controlled
trial.
J Clin Oncol.
2000;
18
1239-1245
MissingFormLabel
- 8
Tanum G, Tveit K M, Karlsen K O.
Chemoradiotherapy of anal carcinoma: tumour response and acute toxicity.
Oncology.
1993;
50
14-17
MissingFormLabel
- 9
Minsky B D, Kemeny N, Cohen A M. et al .
Preoperative high-dose leucovorin/ 5-fluorouracil and radiation therapy for unresectable
rectal cancer.
Cancer.
1991;
67
2859-2866
MissingFormLabel
- 10
Bosset J F, Collette L, Calais G. et al .
Chemotherapy with preoperative radiotherapy in rectal cancer.
N Engl J Med.
2006;
355
1114-1123
MissingFormLabel
- 11
Bosset J F, Calais G, Mineur L. et al .
Enhanced tumorocidal effect of chemotherapy with preoperative radiotherapy for rectal
cancer: preliminary results - EORTC 22 921.
J Clin Oncol.
2005;
23
5620-5627
MissingFormLabel
- 12
Bosset J F, Calais G, Daban A. et al .
Preoperative chemoradiotherapy versus preoperative radiotherapy in rectal cancer patients:
assessment of acute toxicity and treatment compliance. Report of the 22 921 randomised
trial conducted by the EORTC Radiotherapy Group.
Eur J Cancer.
2004;
40
219-224
MissingFormLabel
- 13
Valencia J, Esco R, Polo S. et al .
Postoperative radiochemotherapy in rectal cancer comparison of two combination schemes:
alternating versus concomitant.
Tumori.
2004;
90
216-224
MissingFormLabel
- 14
Paris F, Fuks Z, Kang A. et al .
Endothelial apoptosis as the primary lesion initiating intestinal radiation damage
in mice.
Science.
2001;
293
293-297
MissingFormLabel
- 15
Cole A.
Elevated rectal leukotriene b4, thromboxane b2 and prostaglandin e2 levels in patients
having pelvic radiotherapy.
Abstracts of the 2nd international conference on eicosanoids and other bioactive lipids
in cancer, inflammation and radiation injury.
1991;
137
MissingFormLabel
- 16
Schneidkraut M J, Kot P A, Ramwell P W. et al .
Regional release of cyclooxygenase products after radiation exposure of the rat.
J Appl Physiol.
1986;
61
1264-1269
MissingFormLabel
- 17
Novak J M, Collins J T, Donowitz M. et al .
Effects of radiation on the human gastrointestinal tract.
J Clin Gastroenterol.
1979;
1
9-39
MissingFormLabel
- 18
Summers R W, Flatt A J, Prihoda M J. et al .
Effect of irradiation on morphology and motility of canine small intestine.
Dig Dis Sci.
1987;
32
1402-1410
MissingFormLabel
- 19
Hwang J M, Chan D C, Chang T M. et al .
Effects of oral arginine and glutamine on radiation-induced injury in the rat.
J Surg Res.
2003;
109
149-154
MissingFormLabel
- 20
Maj J G, Paris F, Haimovitz-Friedman A. et al .
Microvascular function regulates intestinal crypt response to radiation.
Cancer Res.
2003;
63
4338-4341
MissingFormLabel
- 21
Yeoh E K, Horowitz M, Russo A. et al .
Gastrointestinal function in chronic radiation enteritis - effects of loperamide-N-oxide.
Gut.
1993;
34
476-482
MissingFormLabel
- 22
Fernandez-Banares F, Villa S, Esteve M. et al .
Acute effects of abdominopelvic irradiation on the orocecal transit time: its relation
to clinical symptoms, and bile salt and lactose malabsorption.
Am J Gastroenterol.
1991;
86
1771-1777
MissingFormLabel
- 23
Bagrij T, Kralovanszky J, Gyergyay F. et al .
Influence of uridine treatment in mice on the protection of gastrointestinal toxicity
caused by 5-fluorouracil.
Anticancer Res.
1993;
13
789-793
MissingFormLabel
- 24
Pritchard D M, Watson A J, Potten C S. et al .
Inhibition by uridine but not thymidine of p53-dependent intestinal apoptosis initiated
by 5-fluorouracil: evidence for the involvement of RNA perturbation.
Proc Natl Acad Sci USA.
1997;
94
1795-1799
MissingFormLabel
- 25
Kakinuma S, Ohwada S.
Gastric mucosal blood flow and gastric secretion following intravenous administration
of 5-fluorouracil in anesthetized rats.
Cancer Chemother Pharmacol.
1997;
39
357-360
MissingFormLabel
- 26
Prakash A, Spencer C M.
Balsalazide.
Drugs.
1998;
56
83-89; discussion 90
MissingFormLabel
- 27
Greenfield S M, Punchard N A, Teare J P. et al .
Review article: the mode of action of the aminosalicylates in inflammatory bowel disease.
Aliment Pharmacol Ther.
1993;
7
369-383
MissingFormLabel
- 28
Resbeut M, Marteau P, Cowen D. et al .
A randomized double blind placebo controlled multicenter study of mesalazine for the
prevention of acute radiation enteritis.
Radiother Oncol.
1997;
44
59-63
MissingFormLabel
- 29
Baughan C A, Canney P A, Buchanan R B. et al .
A randomized trial to assess the efficacy of 5-aminosalicylic acid for the prevention
of radiation enteritis.
Clin Oncol (R Coll Radiol).
1993;
5
19-24
MissingFormLabel
- 30
Martenson J A, Hyland Jr G, Moertel C G. et al .
Olsalazine is contraindicated during pelvic radiation therapy: results of a double-blind,
randomized clinical trial.
Int J Radiat Oncol Biol Phys.
1996;
35
299-303
MissingFormLabel
- 31
Kilic D, Egehan I, Ozenirler S. et al .
Double-blinded, randomized, placebo-controlled study to evaluate the effectiveness
of sulphasalazine in preventing acute gastrointestinal complications due to radiotherapy.
Radiother Oncol.
2000;
57
125-129
MissingFormLabel
- 32
Rauch K, Weiland H.
Therapy of radiogenic colitis with salicylazosulfapyridine (azulfidine).
Strahlentherapie.
1972;
143
660-663
MissingFormLabel
- 33
Henriksson R, Franzen L, Littbrand B.
Effects of sucralfate on acute and late bowel discomfort following radiotherapy of
pelvic cancer.
J Clin Oncol.
1992;
10
969-975
MissingFormLabel
- 34
Valls A, Pestchen I, Prats C. et al .
Multicenter double-blind clinical trial comparing sucralfate vs placebo in the prevention
of diarrhea secondary to pelvic irradiation.
Med Clin.
1999;
113
681-684
MissingFormLabel
- 35
Stellamans K, Lievens Y, Lambin P. et al .
Does sucralfate reduce early side effects of pelvic radiation? A double-blind randomized
trial.
Radiother Oncol.
2002;
65
105-108
MissingFormLabel
- 36
Klimberg V S, Salloum R M, Kasper M. et al .
Oral glutamine accelerates healing of the small intestine and improves outcome after
whole abdominal radiation.
Arch Surg.
1990;
125
1040-1045
MissingFormLabel
- 37
Souba W W, Klimberg V S, Hautamaki R D. et al .
Oral glutamine reduces bacterial translocation following abdominal radiation.
J Surg Res.
1990;
48
1-5
MissingFormLabel
- 38
Jensen J C, Schaefer R, Nwokedi E. et al .
Prevention of chronic radiation enteropathy by dietary glutamine.
Ann Surg Oncol.
1994;
1
157-163
MissingFormLabel
- 39
Dale P S, Tamhankar C P, George D. et al .
Co-medication with hydrolytic enzymes in radiation therapy of uterine cervix: evidence
of the reduction of acute side effects.
Cancer Chemother Pharmacol.
2001;
47 (Suppl)
S29-S34
MissingFormLabel
- 40
Stauder B, Streichhan.
Strahlentherapeutische Nebenwirkungen bei Abdominalkrebspatienten und deren Reduktion
durch hydrolytische Enzympräparate.
Dtsch Zschr Onkol.
1991;
23
7-16
MissingFormLabel
- 41
Martin T, Uhder K, Kurek R. et al .
Does prophylactic treatment with proteolytic enzymes reduce acute toxicity of adjuvant
pelvic irradiation? Results of a double-blind randomized trial.
Radiother Oncol.
2002;
65
17-22
MissingFormLabel
- 42
Gorbach S L.
Lactic acid bacteria and human health.
Ann Med.
1990;
22
37-41
MissingFormLabel
- 43
Adler U.
On control of radioenteritis by the administration of living lactobacilli in gynecological
carcinoma patients.
Ther Umsch.
1962;
19
283-285
MissingFormLabel
- 44
Haller J, Kraeubig H.
On the modification of the radiation reaction of the intestines by a combination of
living acidophilus, bifidus and coli bacteria.
Strahlentherapie.
1960;
113
272-280
MissingFormLabel
- 45
Salminen E, Elomaa I, Minkkinen J. et al .
Preservation of intestinal integrity during radiotherapy using live Lactobacillus
acidophilus cultures.
Clin Radiol.
1988;
39
435-437
MissingFormLabel
- 46
Delia P, Sansotta G, Donato V. et al .
Use of probiotics for prevention of radiation-induced diarrhea.
World J Gastroenterol.
2007;
13
912-915
MissingFormLabel
- 47
Brouillard M Y, Rateau J G.
Adsorption potency of 2 clays, smectite and kaolin on bacterial enterotoxins. In vitro
study in cell culture and in the intestine of newborn mice.
Gastroenterol Clin Biol.
1989;
13
18-24
MissingFormLabel
- 48
Hombrink J, Voss A C, Frohlich D. et al .
Therapy trends in the prevention of radiation-induced diarrhea after pelvic and abdominal
irradiation. Results of a tricenter study.
Strahlenther Onkol.
1995;
171
49-53
MissingFormLabel
- 49
Hombrink J, Frohlich D, Glatzel M. et al .
Prevention of radiation-induced diarrhea by smectite. Results of a double-blind randomized,
placebo-controlled multicenter study.
Strahlenther Onkol.
2000;
176
173-179
MissingFormLabel
- 50
Borek C.
Antioxidants and radiation therapy.
J Nutr.
2004;
134
3207S-3209S
MissingFormLabel
- 51
Borek C, Ong A, Mason H. et al .
Selenium and vitamin E inhibit radiogenic and chemically induced transformation in
vitro via different mechanisms.
Proc Natl Acad Sci USA.
1986;
83
1490-1494
MissingFormLabel
- 52
Dennert G, Horneber M.
Selenium for alleviating the side effects of chemotherapy, radiotherapy and surgery
in cancer patients.
Cochrane Database Syst Rev.
2006;
3
CD005037
MissingFormLabel
- 53
Housley R M, Morris C F, Boyle W. et al .
Keratinocyte growth factor induces proliferation of hepatocytes and epithelial cells
throughout the rat gastrointestinal tract.
J Clin Invest.
1994;
94
1764-1777
MissingFormLabel
- 54
Spielberger R, Stiff P, Bensinger W. et al .
Palifermin for oral mucositis after intensive therapy for hematologic cancers.
N Engl J Med.
2004;
351
2590-2598
MissingFormLabel
- 55
Farrell C L, Bready J V, Rex K L. et al .
Keratinocyte growth factor protects mice from chemotherapy and radiation-induced gastrointestinal
injury and mortality.
Cancer Res.
1998;
58
933-999
MissingFormLabel
- 56
Hawkey C J, Boughton-Smith N K, Whittle B J.
Modulation of human colonic arachidonic acid metabolism by sulfasalazine.
Dig Dis Sci.
1985;
30
1161-1165
MissingFormLabel
- 57
Montagna W, Wilson J W.
A cytologic study of the intestinal epithelium of the mouse after total-body X-irradiation.
J Natl Cancer Inst.
1955;
15
1703-1735
MissingFormLabel
- 58
Arlow F L, Dekovich A A, Priest R J. et al .
Bile acids in radiation-induced diarrhea.
South Med J.
1987;
80
1259-1261
MissingFormLabel
- 59
Urbancsek H, Kazar T, Mezes I. et al .
Results of a double-blind, randomized study to evaluate the efficacy and safety of
Antibiophilus in patients with radiation-induced diarrhoea.
Eur J Gastroenterol Hepatol.
2001;
13
391-396
MissingFormLabel
- 60
Chapaux J, Chapaux P, Royer E.
Loperamide in patients with radiotherapy-induced diarrhoea.
Arzneimittelforschung.
1978;
28
864-866
MissingFormLabel
- 61
Geginat G, Behdjati F, Green E. et al .
Studies using loperamide in patients with diarrhea following telecobalt irradiation
of malignant abdominal tumors (author’s transl).
Strahlentherapie.
1978;
154
11-15
MissingFormLabel
- 62
Viera A J, Hoag S, Shaughnessy J.
Management of irritable bowel syndrome.
Am Fam Physician.
2002;
66
1867-1874
MissingFormLabel
- 63
Zidan J, Haim N, Beny A. et al .
Octreotide in the treatment of severe chemotherapy-induced diarrhea.
Ann Oncol.
2001;
12
227-229
MissingFormLabel
- 64
Goumas P, Naxakis S, Christopoulou A. et al .
Octreotide acetate in the treatment of fluorouracil-induced diarrhea.
Oncologist.
1998;
3
50-53
MissingFormLabel
- 65
Wang J, Zheng H, Sung C C. et al .
The synthetic somatostatin analogue, octreotide, ameliorates acute and delayed intestinal
radiation injury.
Int J Radiat Oncol Biol Phys.
1999;
45
1289-1296
MissingFormLabel
- 66
Classen J, Belka C, Paulsen F. et al .
Radiation-induced gastrointestinal toxicity. Pathophysiology, approaches to treatment
and prophylaxis.
Strahlenther Onkol.
1998;
174 (Suppl 3)
82-84
MissingFormLabel
- 67
Paulsen F, Hoffmann W, Kortmann R D. et al .
Acute gastrointestinal side effects of radiotherapy. What is certain in the treatment?.
Strahlenther Onkol.
1996;
172
53-63
MissingFormLabel
- 68
Weiss E, Hirnle P, Arnold-Bofinger H. et al .
Therapeutic outcome and relation of acute and late side effects in the adjuvant radiotherapy
of endometrial carcinoma stage I and II.
Radiother Oncol.
1999;
53
37-44
MissingFormLabel
- 69
Donner C S.
Pathophysiology and therapy of chronic radiation-induced injury to the colon.
Dig Dis.
1998;
16
253-261
MissingFormLabel
- 70
Wang C J, Leung S W, Chen H C. et al .
The correlation of acute toxicity and late rectal injury in radiotherapy for cervical
carcinoma: evidence suggestive of consequential late effect (CQLE).
Int J Radiat Oncol Biol Phys.
1998;
40
85-91
MissingFormLabel
- 71
Hauer-Jensen M, Richter K K, Wang J. et al .
Changes in transforming growth factor beta1 gene expression and immunoreactivity levels
during development of chronic radiation enteropathy.
Radiat Res.
1998;
150
673-680
MissingFormLabel
- 72
Nguyen N P, Antoine J E, Dutta S. et al .
Current concepts in radiation enteritis and implications for future clinical trials.
Cancer.
2002;
95
1151-1163
MissingFormLabel
- 73
Haboubi N Y, Schofield P F, Rowland P L.
The light and electron microscopic features of early and late phase radiation-induced
proctitis.
Am J Gastroenterol.
1988;
83
1140-1144
MissingFormLabel
- 74
Regimbeau J M, Panis Y, Gouzi J L. et al .
Operative and long term results after surgery for chronic radiation enteritis.
Am J Surg.
2001;
182
237-242
MissingFormLabel
- 75
Delanian S, Balla-Mekias S, Lefaix J L.
Striking regression of chronic radiotherapy damage in a clinical trial of combined
pentoxifylline and tocopherol.
J Clin Oncol.
1999;
17
3283-3290
MissingFormLabel
- 76
Delanian S, Lefaix J L.
Complete healing of severe osteoradionecrosis with treatment combining pentoxifylline,
tocopherol and clodronate.
Br J Radiol.
2002;
75
467-469
MissingFormLabel
- 77
Fischer M, Wohlrab J, Marsch W.
Crux medicorum ulcerated radiation-induced fibrosis - successful therapy with pentoxifylline
and vitamin E.
Eur J Dermatol.
2001;
11
38-40
MissingFormLabel
- 78
Hille A, Christiansen H, Pradier O. et al .
Effect of pentoxifylline and tocopherol on radiation proctitis/enteritis.
Strahlenther Onkol.
2005;
181
606-614
MissingFormLabel
- 79
Shi H, Noguchi N, Niki E.
Comparative study on dynamics of antioxidative action of alpha-tocopheryl hydroquinone,
ubiquinol, and alpha-tocopherol against lipid peroxidation.
Free Radic Biol Med.
1999;
27
334-346
MissingFormLabel
- 80
Gothard L, Cornes P, Brooker S. et al .
Phase II study of vitamin E and pentoxifylline in patients with late side effects
of pelvic radiotherapy.
Radiother Oncol.
2005;
75
334-341
MissingFormLabel
- 81
Jones K, Evans A W, Bristow R G. et al .
Treatment of radiation proctitis with hyperbaric oxygen.
Radiother Oncol.
2006;
78
91-94
MissingFormLabel
- 82
Girnius S, Cersonsky N, Gesell L. et al .
Treatment of refractory radiation-induced hemorrhagic proctitis with hyperbaric oxygen
therapy.
Am J Clin Oncol.
2006;
29
588-592
MissingFormLabel
- 83
Huddy J E, Patel P, Johnson M W. et al .
Hyperbaric oxygen as a treatment for malabsorption in a radiation-damaged short bowel.
Eur J Gastroenterol Hepatol.
2006;
18
685-688
MissingFormLabel
- 84
Marshall G T, Thirlby R C, Bredfeldt J E. et al .
Treatment of gastrointestinal radiation injury with hyperbaric oxygen.
Undersea Hyperb Med.
2007;
34
35-42
MissingFormLabel
- 85
Scolapio J S, Ukleja A, Burnes J U. et al .
Outcome of patients with radiation enteritis treated with home parenteral nutrition.
Am J Gastroenterol.
2002;
97
662-666
MissingFormLabel
- 86
Gottlober P, Steinert M, Bahren W. et al .
Interferon-gamma in 5 patients with cutaneous radiation syndrome after radiation therapy.
Int J Radiat Oncol Biol Phys.
2001;
50
159-166
MissingFormLabel
Manfred V. Singer, M. D.
Department of Medicine II, Medical Faculty at Mannheim, University of Heidelberg
Theodor Kutzer Ufer 1 - 3
68167 Mannheim
Germany
Telefon: ++ 49/6 21/3 83 32 84
Fax: ++ 49/6 21/3 83 38 05
eMail: manfred.v.singer@med.ma.uni-heidelberg.de