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Article: Hexasodium fytate exposure-response correlations in a randomized, placebo-controlled study of patients on dialysis with cardiovascular calcification.

Perelló, Joan / Alberti, Joan / Torres, Juan Vicente / Ferrer, Miguel D / Perez, M Mar / Bassissi, Firas / Gold, Alex / Raggi, Paolo / Chertow, Glenn M / Salcedo, Carolina

Frontiers in pharmacology

2024 Volume 15, Page(s) 1325186

Abstract: Background: ...

Abstract	Background:
Language	English
Publishing date	2024-02-07
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2587355-6
ISSN	1663-9812
ISSN	1663-9812
DOI	10.3389/fphar.2024.1325186
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Article ; Online: Polyclonal antibodies selectively inhibit tumor growth and invasion and synergize with immune checkpoint inhibitors.

Ciron, Carine / Morice, Pierre / Rousse, Juliette / Roy, Patrice / Royer, Pierre-Joseph / Gauthier, Olivier / Brouard, Sophie / Duvaux, Odile / Bassissi, Firas / Vanhove, Bernard

JCI insight

2024 Volume 9, Issue 3

Abstract: Heterologous polyclonal antibodies (pAb) were shown to possess oncolytic properties a century ago with reported clinical responses. More recent preclinical models confirmed pAb efficacy, though their ability to tackle complex target antigens reduces ... ...

Abstract	Heterologous polyclonal antibodies (pAb) were shown to possess oncolytic properties a century ago with reported clinical responses. More recent preclinical models confirmed pAb efficacy, though their ability to tackle complex target antigens reduces susceptibility to tumor escape. Owing to the recent availability of glyco-humanized pAb (GH-pAb) with acceptable clinical toxicology profile, we revisited use of pAb in oncology and highlighted their therapeutic potential against multiple cancer types. Murine antitumor pAb were generated after repeated immunization of rabbits with murine tumor cell lines from hepatocarcinoma, melanoma, and colorectal cancers. Antitumor pAb recognized and showed cytotoxicity against their targets without cross-reactivity with healthy tissues. In vivo, pAb are effective alone; moreover, these pAb synergize with immune checkpoint inhibitors like anti-PD-L1 in several cancer models. They elicited an antitumor host immune response and prevented metastases. The anticancer activity of pAb was also confirmed in xenografted NMRI nude mice using GH-pAb produced by repeated immunization of pigs with human tumor cell lines. In conclusion, the availability of bioengineered GH-pAb allows for revisiting of passive immunotherapy with oncolytic pAb to fight against solid tumor and cancer metastasis.
MeSH term(s)	Humans ; Rabbits ; Animals ; Mice ; Swine ; Immune Checkpoint Inhibitors ; Mice, Nude ; Immunization ; Melanoma/therapy ; Cell Line, Tumor ; Antibodies, Neoplasm/pharmacology
Chemical Substances	Immune Checkpoint Inhibitors ; Antibodies, Neoplasm
Language	English
Publishing date	2024-02-08
Publishing country	United States
Document type	Journal Article
ISSN	2379-3708
ISSN (online)	2379-3708
DOI	10.1172/jci.insight.166231
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Article: GNS561, a New Autophagy Inhibitor Active against Cancer Stem Cells in Hepatocellular Carcinoma and Hepatic Metastasis from Colorectal Cancer.

Brun, Sonia / Pascussi, Jean-Marc / Gifu, Elena Patricia / Bestion, Eloïne / Macek-Jilkova, Zuzana / Wang, Guanxiong / Bassissi, Firas / Mezouar, Soraya / Courcambeck, Jérôme / Merle, Philippe / Decaens, Thomas / Pannequin, Julie / Halfon, Philippe / Caron de Fromentel, Claude

Journal of Cancer

2021 Volume 12, Issue 18, Page(s) 5432–5438

Abstract: Patients with advanced hepatocellular carcinoma (HCC) or metastatic colorectal cancer (mCRC) have a very poor prognosis due to the lack of efficient treatments. As observed in several other tumors, the effectiveness of treatments is mainly hampered by ... ...

Abstract	Patients with advanced hepatocellular carcinoma (HCC) or metastatic colorectal cancer (mCRC) have a very poor prognosis due to the lack of efficient treatments. As observed in several other tumors, the effectiveness of treatments is mainly hampered by the presence of a highly tumorigenic sub-population of cancer cells called cancer stem cells (CSCs). Indeed, CSCs are resistant to chemotherapy and radiotherapy and can regenerate the tumor bulk. Hence, innovative drugs that are efficient against both bulk tumor cells and CSCs would likely improve cancer treatment. In this study, we demonstrated that GNS561, a new autophagy inhibitor that induces lysosomal cell death, showed significant activity against not only the whole tumor population but also a sub-population displaying CSC features (high ALDH activity and tumorsphere formation ability) in HCC and in liver mCRC cell lines. These results were confirmed
Language	English
Publishing date	2021-07-13
Publishing country	Australia
Document type	Journal Article
ZDB-ID	2573318-7
ISSN	1837-9664
ISSN	1837-9664
DOI	10.7150/jca.58533
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Article ; Online: GNS561, a new lysosomotropic small molecule, for the treatment of intrahepatic cholangiocarcinoma.

Brun, Sonia / Bassissi, Firas / Serdjebi, Cindy / Novello, Marie / Tracz, Jennifer / Autelitano, François / Guillemot, Marie / Fabre, Philippe / Courcambeck, Jérôme / Ansaldi, Christelle / Raymond, Eric / Halfon, Philipe

Investigational new drugs

2019 Volume 37, Issue 6, Page(s) 1135–1145

Abstract: Among the acquired modifications in cancer cells, changes in lysosomal phenotype and functions are well described, making lysosomes a potential target for novel therapies. Some weak base lipophilic drugs have a particular affinity towards lysosomes, ... ...

Abstract	Among the acquired modifications in cancer cells, changes in lysosomal phenotype and functions are well described, making lysosomes a potential target for novel therapies. Some weak base lipophilic drugs have a particular affinity towards lysosomes, taking benefits from lysosomal trapping to exert anticancer activity. Here, we have developed a new lysosomotropic small molecule, GNS561, and assessed its activity in multiple in vitro intrahepatic cholangiocarcinoma models (HuCCT1 and RBE cell lines and patient-derived cells) and in a chicken chorioallantoic membrane xenograft model. GNS561 significantly reduced cell viability in two intrahepatic cholangiocarcinoma cell lines (IC
MeSH term(s)	Animals ; Antineoplastic Agents/pharmacology ; Bile Duct Neoplasms/drug therapy ; Bile Duct Neoplasms/metabolism ; Cell Line, Tumor ; Cell Survival/drug effects ; Chick Embryo ; Cholangiocarcinoma/drug therapy ; Cholangiocarcinoma/metabolism ; Humans ; Lysosomes/metabolism
Chemical Substances	Antineoplastic Agents
Language	English
Publishing date	2019-02-19
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	604895-x
ISSN	1573-0646 ; 0167-6997
ISSN (online)	1573-0646
ISSN	0167-6997
DOI	10.1007/s10637-019-00741-3
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Article: GNS561 acts as a potent anti-fibrotic and pro-fibrolytic agent in liver fibrosis through TGF-β1 inhibition.

Bestion, Eloïne / Jilkova, Zuzana Macek / Mège, Jean-Louis / Novello, Marie / Kurma, Keerthi / Pour, Seyedeh Tayebeh Ahmad / Lalmanach, Gilles / Vanderlynden, Lise / Fizanne, Lionel / Bassissi, Firas / Rachid, Madani / Tracz, Jennifer / Boursier, Jérôme / Courcambeck, Jérôme / Serdjebi, Cindy / Ansaldi, Christelle / Decaens, Thomas / Halfon, Philippe / Brun, Sonia

Therapeutic advances in chronic disease

2020 Volume 11, Page(s) 2040622320942042

Abstract: Background: Hepatic fibrosis is the result of chronic liver injury that can progress to cirrhosis and lead to liver failure. Nevertheless, there are no anti-fibrotic drugs licensed for human use. Here, we investigated the anti-fibrotic activity of ... ...

Abstract	Background: Hepatic fibrosis is the result of chronic liver injury that can progress to cirrhosis and lead to liver failure. Nevertheless, there are no anti-fibrotic drugs licensed for human use. Here, we investigated the anti-fibrotic activity of GNS561, a new lysosomotropic molecule with high liver tropism. Methods: The anti-fibrotic effect of GNS561 was determined Results: GNS561 significantly decreased cell viability and promoted apoptosis. Disrupting the lysosomal pH gradient impaired its pharmacological effects, suggesting that GNS561 lysosomotropism mediated cell death. GNS561 impaired cathepsin activity, leading to defective TGF-β1 maturation and autophagic processes. Moreover, GNS561 decreased HSC activation and extracellular matrix deposition by downregulating TGF-β1/Smad and mitogen-activated proteine kinase signaling and inducing fibrolysis. Finally, oral administration of GNS561 (15 mg/kg per day) was well tolerated and attenuated diethylnitrosamine-induced liver fibrosis in this rat model (decrease of collagen deposition and of pro-fibrotic markers and increase of fibrolysis). Conclusion: GNS561 is a new potent lysosomotropic compound that could represent a valid medicinal option for hepatic fibrosis treatment through both its anti-fibrotic and its pro-fibrolytic effects. In addition, this study provides a rationale for targeting lysosomes as a promising therapeutic strategy in liver fibrosis.
Language	English
Publishing date	2020-07-16
Publishing country	United States
Document type	Journal Article
ZDB-ID	2554816-5
ISSN	2040-6231 ; 2040-6223
ISSN (online)	2040-6231
ISSN	2040-6223
DOI	10.1177/2040622320942042
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Article ; Online: GNS561, a clinical-stage PPT1 inhibitor, is efficient against hepatocellular carcinoma

Brun, Sonia / Bestion, Eloïne / Raymond, Eric / Bassissi, Firas / Jilkova, Zuzana Macek / Mezouar, Soraya / Rachid, Madani / Novello, Marie / Tracz, Jennifer / Hamaï, Ahmed / Lalmanach, Gilles / Vanderlynden, Lise / Legouffe, Raphael / Stauber, Jonathan / Schubert, Thomas / Plach, Maximilian G / Courcambeck, Jérôme / Drouot, Cyrille / Jacquemot, Guillaume /

Serdjebi, Cindy / Roth, Gael / Baudoin, Jean-Pierre / Ansaldi, Christelle / Decaens, Thomas / Halfon, Philippe

Autophagy

2021 Volume 18, Issue 3, Page(s) 678–694

Abstract: Hepatocellular carcinoma is the most frequent primary liver cancer. Macroautophagy/autophagy inhibitors have been extensively studied in cancer but, to date, none has reached efficacy in clinical trials. In this study, we demonstrated that GNS561, a new ... ...

Abstract	Hepatocellular carcinoma is the most frequent primary liver cancer. Macroautophagy/autophagy inhibitors have been extensively studied in cancer but, to date, none has reached efficacy in clinical trials. In this study, we demonstrated that GNS561, a new autophagy inhibitor, whose anticancer activity was previously linked to lysosomal cell death, displayed high liver tropism and potent antitumor activity against a panel of human cancer cell lines and in two hepatocellular carcinoma in vivo models. We showed that due to its lysosomotropic properties, GNS561 could reach and specifically inhibited its enzyme target, PPT1 (palmitoyl-protein thioesterase 1), resulting in lysosomal unbound Zn
MeSH term(s)	Antineoplastic Agents/pharmacology ; Autophagosomes/metabolism ; Autophagy/physiology ; Carcinoma, Hepatocellular/drug therapy ; Carcinoma, Hepatocellular/metabolism ; Humans ; Liver Neoplasms/drug therapy ; Liver Neoplasms/metabolism ; Lysosomes/metabolism ; Membrane Proteins/metabolism ; Sirolimus/pharmacology ; TOR Serine-Threonine Kinases/metabolism ; Thiolester Hydrolases/metabolism ; Thiolester Hydrolases/pharmacology
Chemical Substances	Antineoplastic Agents ; Membrane Proteins ; TOR Serine-Threonine Kinases (EC 2.7.11.1) ; Thiolester Hydrolases (EC 3.1.2.-) ; PPT1 protein, human (EC 3.1.2.22) ; Sirolimus (W36ZG6FT64)
Language	English
Publishing date	2021-11-05
Publishing country	United States
Document type	Journal Article
ZDB-ID	2454135-7
ISSN	1554-8635 ; 1554-8627
ISSN (online)	1554-8635
ISSN	1554-8627
DOI	10.1080/15548627.2021.1988357
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Article: Assessment of a liposomal formulation of ivermectin in rabbit after a single subcutaneous administration

Bassissi, Firas / Lespine, Anne / Alvinerie, Michel

Parasitology research. 2006 Feb., v. 98, no. 3

2006

Abstract: Ivermectin is a member of the macrocyclic lactone family widely used in livestock, pets, and humans as a potent parasiticide. Slight differences in formulation may change the plasma kinetics and efficacy of these compounds. The aim of the study is to ... ...

Abstract	Ivermectin is a member of the macrocyclic lactone family widely used in livestock, pets, and humans as a potent parasiticide. Slight differences in formulation may change the plasma kinetics and efficacy of these compounds. The aim of the study is to evaluate the ability of a liposomal formulation of ivermectin to generate an efficient exposure of the animal to the drug. Ten rabbits were subcutaneously administered with 0.3 mg kg-¹ of ivermectin using Ivomec (n=5) or a liposomal formulation (n=5). The areas under serum concentration-time curve were similar after both treatments, indicating the same bioavailability for the two formulations. However, the liposomal formulation gave a higher C max value (33.33 ng ml-¹) compared with Ivomec (20.82 ng ml-¹) and a significantly faster absorption as indicated by the T max of 0.23 days compared with 1.13 days for the Ivomec formulation. The use of liposomal formulation shows promise as this system improves the efficacy of ivermectin and related drugs.
Keywords	ivermectin ; rabbits
Language	English
Dates of publication	2006-02
Size	p. 244-249.
Publisher	Springer-Verlag
Publishing place	Berlin/Heidelberg
Document type	Article
ZDB-ID	284966-5
ISSN	1432-1955 ; 0932-0113 ; 0044-3255
ISSN (online)	1432-1955
ISSN	0932-0113 ; 0044-3255
DOI	10.1007/s00436-005-0073-z
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Article ; Online: Assessment of a liposomal formulation of ivermectin in rabbit after a single subcutaneous administration.

Bassissi, Firas / Lespine, Anne / Alvinerie, Michel

Parasitology research

2006 Volume 98, Issue 3, Page(s) 244–249

Abstract	Ivermectin is a member of the macrocyclic lactone family widely used in livestock, pets, and humans as a potent parasiticide. Slight differences in formulation may change the plasma kinetics and efficacy of these compounds. The aim of the study is to evaluate the ability of a liposomal formulation of ivermectin to generate an efficient exposure of the animal to the drug. Ten rabbits were subcutaneously administered with 0.3 mg kg(-1) of ivermectin using Ivomec (n=5) or a liposomal formulation (n=5). The areas under serum concentration-time curve were similar after both treatments, indicating the same bioavailability for the two formulations. However, the liposomal formulation gave a higher C(max) value (33.33 ng ml(-1)) compared with Ivomec (20.82 ng ml(-1)) and a significantly faster absorption as indicated by the T(max) of 0.23 days compared with 1.13 days for the Ivomec formulation. The use of liposomal formulation shows promise as this system improves the efficacy of ivermectin and related drugs.
MeSH term(s)	Animals ; Antiparasitic Agents/administration & dosage ; Antiparasitic Agents/blood ; Antiparasitic Agents/pharmacokinetics ; Area Under Curve ; Dosage Forms ; Half-Life ; Injections, Subcutaneous ; Ivermectin/administration & dosage ; Ivermectin/blood ; Ivermectin/pharmacokinetics ; Liposomes ; Male ; Rabbits
Chemical Substances	Antiparasitic Agents ; Dosage Forms ; Liposomes ; Ivermectin (70288-86-7)
Language	English
Publishing date	2006-02
Publishing country	Germany
Document type	Journal Article
ZDB-ID	284966-5
ISSN	1432-1955 ; 0932-0113 ; 0044-3255
ISSN (online)	1432-1955
ISSN	0932-0113 ; 0044-3255
DOI	10.1007/s00436-005-0073-z
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Article: Breed differences in the pharmacokinetics of ivermectin administered subcutaneously to Holstein and Belgian Blue calves.

Vercruysse, Jozef / Deprez, Piet / Everaert, Dries / Bassissi, Firas / Alvinerie, Michel

Veterinary parasitology

2008 Volume 152, Issue 1-2, Page(s) 136–140

Abstract: Belgian Blue (BB) cattle are very sensitive to mange caused by Psoroptes ovis and, in contrast to the case in Holstein cattle, single treatments with ivermectin do not result in complete elimination of the parasite. The objective of the present study was ...

Abstract	Belgian Blue (BB) cattle are very sensitive to mange caused by Psoroptes ovis and, in contrast to the case in Holstein cattle, single treatments with ivermectin do not result in complete elimination of the parasite. The objective of the present study was to determine the concentration of ivermectin in plasma, skin and hair following subcutaneous administration to Holstein and BB calves and to assess the influence of breed on drug pharmacokinetics and availability. Two groups of six healthy female Holstein and BB calves were treated with ivermectin (SC formulation) at a dose of 0.2 mg/kg. Blood, skin and hair were collected before treatment and up to 21 days after treatment. Ivermectin was analyzed in plasma and tissue by high-performance liquid chromatography (HPLC). The peak concentrations (Cmax), time-peak concentrations (Tmax), the area under the plasma concentration-time curves (AUC) and the mean residence time (MRT) were determined. The patterns of plasma and tissue ivermectin concentrations were similar in the two breeds of animals, however, the AUC and Cmax levels for plasma and skin were significantly higher in the BB calves. In hair, ivermectin was detected later than in plasma and skin, with the Tmax ranging between 4 days (Holstein group) and 6 days (BB group). The possible reasons for the significantly higher levels in plasma and skin in BB calves compared to Holstein calves are discussed.
MeSH term(s)	Animals ; Animals, Newborn ; Area Under Curve ; Breeding ; Cattle ; Cattle Diseases/blood ; Cattle Diseases/drug therapy ; Chromatography, High Pressure Liquid/veterinary ; Female ; Hair/chemistry ; Hair/metabolism ; Injections, Subcutaneous/veterinary ; Insecticides/administration & dosage ; Insecticides/blood ; Insecticides/pharmacokinetics ; Ivermectin/administration & dosage ; Ivermectin/blood ; Ivermectin/pharmacokinetics ; Mite Infestations/drug therapy ; Mite Infestations/veterinary ; Psoroptidae/drug effects ; Skin/chemistry ; Skin/metabolism ; Time Factors
Chemical Substances	Insecticides ; Ivermectin (70288-86-7)
Language	English
Publishing date	2008-03-25
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	196831-2
ISSN	1873-2550 ; 0304-4017
ISSN (online)	1873-2550
ISSN	0304-4017
DOI	10.1016/j.vetpar.2007.11.021
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Article: Breed differences in the pharmacokinetics of ivermectin administered subcutaneously to Holstein and Belgian Blue calves

Vercruysse, Jozef / Deprez, Piet / Everaert, Dries / Bassissi, Firas / Alvinerie, Michel

Veterinary parasitology. 2008 Mar. 25, v. 152, no. 1-2

2008

Abstract	Belgian Blue (BB) cattle are very sensitive to mange caused by Psoroptes ovis and, in contrast to the case in Holstein cattle, single treatments with ivermectin do not result in complete elimination of the parasite. The objective of the present study was to determine the concentration of ivermectin in plasma, skin and hair following subcutaneous administration to Holstein and BB calves and to assess the influence of breed on drug pharmacokinetics and availability. Two groups of six healthy female Holstein and BB calves were treated with ivermectin (SC formulation) at a dose of 0.2mg/kg. Blood, skin and hair were collected before treatment and up to 21 days after treatment. Ivermectin was analyzed in plasma and tissue by high-performance liquid chromatography (HPLC). The peak concentrations (C max), time-peak concentrations (T max), the area under the plasma concentration-time curves (AUC) and the mean residence time (MRT) were determined. The patterns of plasma and tissue ivermectin concentrations were similar in the two breeds of animals, however, the AUC and C max levels for plasma and skin were significantly higher in the BB calves. In hair, ivermectin was detected later than in plasma and skin, with the T max ranging between 4 days (Holstein group) and 6 days (BB group). The possible reasons for the significantly higher levels in plasma and skin in BB calves compared to Holstein calves are discussed.
Keywords	breed differences ; pharmacokinetics ; subcutaneous injection ; Holstein ; Belgian Blue ; calves ; drug evaluation ; ivermectin ; chemical concentration ; blood chemistry ; tissue analysis ; skin ; hairs
Language	English
Dates of publication	2008-0325
Size	p. 136-140.
Publishing place	Amsterdam; New York: Elsevier
Document type	Article
ZDB-ID	196831-2
ISSN	1873-2550 ; 0304-4017
ISSN (online)	1873-2550
ISSN	0304-4017
DOI	10.1016/j.vetpar.2007.11.021
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