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  1. Article ; Online: Evaluation of a multiphasic parasite clearance profile after treatment of experimental human infection with the investigational anti-malarial M5717 using segmented mixed effect models.

    Yin, Xiaoyan / Li, Ying / Bagchus, Wilhelmina / Yalkinoglu, Özkan / Bezuidenhout, Deon / Tappert, Aliona / McCarthy, James / Marquart, Louise / Oeuvray, Claude

    Malaria journal

    2023  Volume 22, Issue 1, Page(s) 199

    Abstract: Background: Evaluation of parasite clearance patterns in experimental human infection trials helps increase understanding of drug action. In a previously reported phase Ib trial of a new investigational anti-malarial drug M5717, parasite clearance ... ...

    Abstract Background: Evaluation of parasite clearance patterns in experimental human infection trials helps increase understanding of drug action. In a previously reported phase Ib trial of a new investigational anti-malarial drug M5717, parasite clearance showed a biphasic linear pattern: slow removal phase with a near flat clearance rate followed by a fast clearance phase with a steep slope. In this study three statistical approaches were implemented and compared to estimate the parasite clearance rate for each phase and the time point corresponding to the change of clearance rates (changepoint between the two phases).
    Methods: Data using three M5717 doses 150 mg (n = 6), 400 mg (n = 8), 800 mg (n = 8) were used to estimate biphasic clearance rates. Three models were investigated: firstly, segmented mixed models with estimated changepoint-models with/without random effects in various parameters were compared. Secondly, a segmented mixed model using grid search-this method is similar to the first except that changepoints were not estimated, instead they were selected based on model fit from given candidate values. Thirdly, a two-stage approach whereby a segmented regression model fit to each participant followed by a meta-analysis method. Hourly rate of parasite clearance (HRPC) interpreted as the percentage of parasites removed each hour was calculated.
    Results: The three models generated similar results. Using segmented mixed models, the estimated changepoints after treatment in hours (95% CI) were: 150 mg: 33.9 (28.7, 39.1); 400 mg: 57.4 (52.5, 62.4); and 800 mg: 52.8 (47.4, 58.1). For all three treatment groups, there was nearly no clearance before the changepoints, but rapid clearance in the second phase (HRPC [95% CI]): 150 mg: 16.8% (14.3, 19.1%); 400 mg: 18.6% (16.0, 21.1%); and 800 mg: 11.7% (9.3, 14.1%).
    Conclusions: All three statistical approaches are effective tools to characterize the bi-phasic clearance of M5717 in the phase 1b experimental Plasmodium falciparum malaria human infection study. The statistical approaches produced similar results to estimate the two-phase clearance rates and the changepoint for each treatment dose of M5717. However, the segmented mixed model with random changepoints has several advantages: it is computationally efficient, provides precision for changepoint estimates and is robust concerning outlying datapoints or individuals.
    MeSH term(s) Humans ; Animals ; Parasites ; Antimalarials/therapeutic use ; Malaria, Falciparum/drug therapy ; Kinetics
    Chemical Substances Antimalarials
    Language English
    Publishing date 2023-06-28
    Publishing country England
    Document type Meta-Analysis ; Journal Article
    ZDB-ID 2091229-8
    ISSN 1475-2875 ; 1475-2875
    ISSN (online) 1475-2875
    ISSN 1475-2875
    DOI 10.1186/s12936-023-04627-x
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Reproducibility of malaria sporozoite challenge model in humans for evaluating efficacy of vaccines and drugs: a systematic review.

    Shibeshi, Workineh / Bagchus, Wilhelmina / Yalkinoglu, Özkan / Tappert, Aliona / Engidawork, Ephrem / Oeuvray, Claude

    BMC infectious diseases

    2021  Volume 21, Issue 1, Page(s) 1274

    Abstract: Background: The development of novel malaria vaccines and antimalarial drugs is limited partly by emerging challenges to conduct field trials in malaria endemic areas, including unknown effects of existing immunity and a reported fall in malaria ... ...

    Abstract Background: The development of novel malaria vaccines and antimalarial drugs is limited partly by emerging challenges to conduct field trials in malaria endemic areas, including unknown effects of existing immunity and a reported fall in malaria incidence. As a result, Controlled Human Malaria Infection (CHMI) has become an important approach for accelerated development of malarial vaccines and drugs. We conducted a systematic review of the literature to establish aggregate evidence on the reproducibility of a malaria sporozoite challenge model.
    Methods: A systematic review of research articles published between 1990 and 2018 on efficacy testing of malaria vaccines and drugs using sporozoite challenge and sporozoite infectivity studies was conducted using Pubmed, Scopus, Embase and Cochrane Library, ClinicalTrials.gov and Trialtrove. The inclusion criteria were randomized and non-randomized, controlled or open-label trials using P. falciparum or P. vivax sporozoite challenges. The data were extracted from articles using standardized data extraction forms and descriptive analysis was performed for evidence synthesis. The endpoints considered were infectivity, prepatent period, parasitemia and safety of sporozoite challenge.
    Results: Seventy CHMI trials conducted with a total of 2329 adult healthy volunteers were used for analysis. CHMI was induced by bites of mosquitoes infected with P. falciparum or P. vivax in 52 trials and by direct venous inoculation of P. falciparum sporozoites (PfSPZ challenge) in 18 trials. Inoculation with P. falciparum-infected mosquitoes produced 100% infectivity in 40 studies and the mean/median prepatent period assessed by thick blood smear (TBS) microscopy was ≤ 12 days in 24 studies. On the other hand, out of 12 infectivity studies conducted using PfSPZ challenge, 100% infection rate was reproduced in 9 studies with a mean or median prepatent period of 11 to 15.3 days as assessed by TBS and 6.8 to 12.6 days by PCR. The safety profile of P. falciparum and P.vivax CHMI was characterized by consistent features of malaria infection.
    Conclusion: There is ample evidence on consistency of P. falciparum CHMI models in terms of infectivity and safety endpoints, which supports applicability of CHMI in vaccine and drug development. PfSPZ challenge appears more feasible for African trials based on current evidence of safety and efficacy.
    MeSH term(s) Adult ; Animals ; Humans ; Malaria Vaccines ; Malaria, Falciparum/prevention & control ; Pharmaceutical Preparations ; Reproducibility of Results ; Sporozoites
    Chemical Substances Malaria Vaccines ; Pharmaceutical Preparations
    Language English
    Publishing date 2021-12-20
    Publishing country England
    Document type Journal Article ; Systematic Review
    ZDB-ID 2041550-3
    ISSN 1471-2334 ; 1471-2334
    ISSN (online) 1471-2334
    ISSN 1471-2334
    DOI 10.1186/s12879-021-06953-4
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Efficacy, safety, and palatability of arpraziquantel (L-praziquantel) orodispersible tablets in children aged 3 months to 6 years infected with Schistosoma in Côte d'Ivoire and Kenya: an open-label, partly randomised, phase 3 trial.

    N'Goran, Eliézer K / Odiere, Maurice R / Assandé Aka, Ronald / Ouattara, Mamadou / Aka, N A David / Ogutu, Bernhards / Rawago, Fredrick / Bagchus, Wilhelmina M / Bödding, Matthias / Kourany-Lefoll, Elly / Tappert, Aliona / Yin, Xiaoyan / Bezuidenhout, Deon / Badenhorst, Henk / Huber, Eric / Dälken, Benjamin / Haj-Ali Saflo, Okba

    The Lancet. Infectious diseases

    2023  Volume 23, Issue 7, Page(s) 867–876

    Abstract: Background: WHO has underlined the need for a child-friendly treatment for schistosomiasis, a prevalent parasitic disease in low-income and middle-income countries. After successful phase 1 and 2 trials, we aimed to evaluate the efficacy, safety, ... ...

    Abstract Background: WHO has underlined the need for a child-friendly treatment for schistosomiasis, a prevalent parasitic disease in low-income and middle-income countries. After successful phase 1 and 2 trials, we aimed to evaluate the efficacy, safety, palatability, and pharmacokinetics of arpraziquantel (L-praziquantel) orodispersible tablets for preschool-aged children.
    Methods: This open-label, partly randomised, phase 3 study was conducted at two hospitals in Côte d'Ivoire and Kenya. Children with a minimum bodyweight of 5 kg in those aged 3 months to 2 years and 8 kg in those aged 2-6 years were eligible. In cohort 1, participants aged 4-6 years infected with Schistosoma mansoni were randomly assigned (2:1) to receive a single dose of oral arpraziquantel 50 mg/kg (cohort 1a) or oral praziquantel 40 mg/kg (cohort 1b) using a computer-generated randomisation list. Cohorts 2 (aged 2-3 years) and 3 (aged 3 months to 2 years) infected with S mansoni, and the first 30 participants in cohort 4a (aged 3 months to 6 years) infected with Schistosoma haematobium, received a single dose of oral arpraziquantel 50 mg/kg. After follow-up assessments, arpraziquantel was increased to 60 mg/kg (cohort 4b). Laboratory personnel were masked to the treatment group, screening, and baseline values. S mansoni was detected using a point-of-care circulating cathodic antigen urine cassette test and confirmed using the Kato-Katz method. The primary efficacy endpoint was clinical cure rate at 17-21 days after treatment in cohorts 1a and 1b, measured in the modified intention-to-treat population and calculated using the Clopper-Pearson method. This study is registered with ClinicalTrials.gov, NCT03845140.
    Findings: Between Sept 2, 2019, and Aug 7, 2021, 2663 participants were prescreened and 326 were diagnosed with S mansoni or S haematobium. 288 were enrolled (n=100 in cohort 1a, n=50 in cohort 1b, n=30 in cohort 2, n=18 in cohort 3, n=30 in cohort 4a, and n=60 in cohort 4b), but eight participants received antimalarial drugs and were excluded from the efficacy analyses. The median age was 5·1 years (IQR 4·1-6·0) and 132 (47%) of 280 participants were female and 148 (53%) were male. Cure rates with arpraziquantel were similar to those with praziquantel (87·8% [95% CI 79·6-93·5] in cohort 1a vs 81·3% [67·4-91·1] in cohort 1b). No safety concerns were identified during the study. The most common drug-related treatment-emergent adverse events were abdominal pain (41 [14%] of 288 participants), diarrhoea (27 [9%]), vomiting (16 [6%]), and somnolence (21 [7%]).
    Interpretation: Arpraziquantel, a first-line orodispersible tablet, showed high efficacy and favourable safety in preschool-aged children with schistosomiasis.
    Funding: The Global Health Innovative Technology Fund, the European and Developing Countries Clinical Trials Partnership, and the healthcare business of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: 10.13039/100009945).
    MeSH term(s) Animals ; Child, Preschool ; Male ; Female ; Humans ; Praziquantel/adverse effects ; Cote d'Ivoire ; Kenya ; Schistosomiasis mansoni/drug therapy ; Schistosomiasis mansoni/diagnosis ; Schistosomiasis mansoni/prevention & control ; Anthelmintics/adverse effects ; Schistosoma mansoni ; Schistosomiasis/drug therapy
    Chemical Substances Praziquantel (6490C9U457) ; Anthelmintics
    Language English
    Publishing date 2023-03-06
    Publishing country United States
    Document type Randomized Controlled Trial ; Clinical Trial, Phase III ; Journal Article
    ZDB-ID 2061641-7
    ISSN 1474-4457 ; 1473-3099
    ISSN (online) 1474-4457
    ISSN 1473-3099
    DOI 10.1016/S1473-3099(23)00048-8
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 5743: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
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    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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  4. Article ; Online: Safety, pharmacokinetics, and antimalarial activity of the novel plasmodium eukaryotic translation elongation factor 2 inhibitor M5717: a first-in-human, randomised, placebo-controlled, double-blind, single ascending dose study and volunteer infection study.

    McCarthy, James S / Yalkinoglu, Özkan / Odedra, Anand / Webster, Rebecca / Oeuvray, Claude / Tappert, Aliona / Bezuidenhout, Deon / Giddins, Marla J / Dhingra, Satish K / Fidock, David A / Marquart, Louise / Webb, Lachlan / Yin, Xiaoyan / Khandelwal, Akash / Bagchus, Wilhelmina M

    The Lancet. Infectious diseases

    2021  Volume 21, Issue 12, Page(s) 1713–1724

    Abstract: Background: M5717 is the first plasmodium translation elongation factor 2 inhibitor to reach clinical development as an antimalarial. We aimed to characterise the safety, pharmacokinetics, and antimalarial activity of M5717 in healthy volunteers.: ... ...

    Abstract Background: M5717 is the first plasmodium translation elongation factor 2 inhibitor to reach clinical development as an antimalarial. We aimed to characterise the safety, pharmacokinetics, and antimalarial activity of M5717 in healthy volunteers.
    Methods: This first-in-human study was a two-part, single-centre clinical trial done in Brisbane, QLD, Australia. Part one was a double-blind, randomised, placebo-controlled, single ascending dose study in which participants were enrolled into one of nine dose cohorts (50, 100, 200, 400, 600, 1000, 1250, 1800, or 2100 mg) and randomly assigned (3:1) to M5717 or placebo. A sentinel dosing strategy was used for each dose cohort whereby two participants (one assigned to M5717 and one assigned to placebo) were initially randomised and dosed. Randomisation schedules were generated electronically by independent, unblinded statisticians. Part two was an open-label, non-randomised volunteer infection study using the Plasmodium falciparum induced blood-stage malaria model in which participants were enrolled into three dose cohorts. Healthy men and women of non-childbearing potential aged 18-55 years were eligible for inclusion; individuals in the volunteer infection study were required to be malaria naive. Safety and tolerability (primary outcome of the single ascending dose study and secondary outcome of the volunteer infection study) were assessed by frequency and severity of adverse events. The pharmacokinetic profile of M5717 was also characterised (primary outcome of the volunteer infection study and secondary outcome of the single ascending dose study). Parasite clearance kinetics (primary outcome of the volunteer infection study) were assessed by the parasite reduction ratio and the corresponding parasite clearance half-life; the incidence of recrudescence up to day 28 was determined (secondary outcome of the volunteer infection study). Recrudescent parasites were tested for genetic mutations (exploratory outcome). The trial is registered with ClinicalTrials.gov (NCT03261401).
    Findings: Between Aug 28, 2017, and June 14, 2019, 221 individuals were assessed for eligibility, of whom 66 men were enrolled in the single ascending dose study (eight per cohort for 50-1800 mg cohorts, randomised three M5717 to one placebo, and two in the 2100 mg cohort, randomised one M5717 to one placebo) and 22 men were enrolled in the volunteer infection study (six in the 150 mg cohort and eight each in the 400 mg and 800 mg cohorts). No adverse event was serious; all M5717-related adverse events were mild or moderate in severity and transient, with increased frequency observed at doses above 1250 mg. In the single ascending dose study, treatment-related adverse events occurred in three of 17 individuals in the placebo group; no individual in the 50 mg, 100 mg, or 200 mg groups; one of six individuals in each of the 400 mg, 1000 mg, and 1250 mg groups; two of six individuals in the 600 mg group; and in all individuals in the 1800 mg and 2100 mg groups. In the volunteer infection study, M5717-related adverse events occurred in no participants in the 150 mg or 800 mg groups and in one of eight participants in the 400 mg group. Transient oral hypoesthesia (in three participants) and blurred vision (in four participants) were observed in the 1800 mg or 2100 mg groups and constituted an unknown risk; thus, further dosing was suspended after dosing of the two sentinel individuals in the 2100 mg cohort. Maximum blood concentrations occurred 1-7 h after dosing, and a long half-life was observed (146-193 h at doses ≥200 mg). Parasite clearance occurred in all participants and was biphasic, characterised by initial slow clearance lasting 35-55 h (half-life 231·1 h [95% CI 40·9 to not reached] for 150 mg, 60·4 h [38·6 to 138·6] for 400 mg, and 24·7 h [20·4 to 31·3] for 800 mg), followed by rapid clearance (half-life 3·5 h [3·1 to 4·0] for 150 mg, 3·9 h [3·3 to 4·8] for 400 mg, and 5·5 h [4·8 to 6·4] for 800 mg). Recrudescence occurred in three (50%) of six individuals dosed with 150 mg and two (25%) of eight individuals dosed with 400 mg. Genetic mutations associated with resistance were detected in four cases of parasite recrudescence (two individuals dosed with 150 mg and two dosed with 400 mg).
    Interpretation: The safety, pharmacokinetics, and antimalarial activity of M5717 support its development as a component of a single-dose antimalarial combination therapy or for malaria prophylaxis.
    Funding: Wellcome Trust and the healthcare business of Merck KGaA, Darmstadt, Germany.
    MeSH term(s) Adult ; Antimalarials/pharmacokinetics ; Antimalarials/pharmacology ; Double-Blind Method ; Female ; Humans ; Malaria, Falciparum/drug therapy ; Male ; Middle Aged ; Peptide Elongation Factor 2/antagonists & inhibitors ; Plasmodium falciparum ; Young Adult
    Chemical Substances Antimalarials ; Peptide Elongation Factor 2
    Language English
    Publishing date 2021-10-26
    Publishing country United States
    Document type Journal Article ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
    ZDB-ID 2061641-7
    ISSN 1474-4457 ; 1473-3099
    ISSN (online) 1474-4457
    ISSN 1473-3099
    DOI 10.1016/S1473-3099(21)00252-8
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 5743: Show issues Location:
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    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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  5. Article ; Online: Causal chemoprophylactic activity of cabamiquine against Plasmodium falciparum in a controlled human malaria infection: a randomised, double-blind, placebo-controlled study in the Netherlands.

    van der Plas, Johan L / Kuiper, Vincent P / Bagchus, Wilhelmina M / Bödding, Matthias / Yalkinoglu, Özkan / Tappert, Aliona / Seitzinger, Andrea / Spangenberg, Thomas / Bezuidenhout, Deon / Wilkins, Justin / Oeuvray, Claude / Dhingra, Satish K / Thathy, Vandana / Fidock, David A / Smidt, Lisanne C A / Roozen, Geert V T / Koopman, Jan Pieter R / Lamers, Olivia A C / Sijtsma, Jeroen /
    van Schuijlenburg, Roos / Wessels, Els / Meij, Pauline / Kamerling, Ingrid M C / Roestenberg, Meta / Khandelwal, Akash

    The Lancet. Infectious diseases

    2023  Volume 23, Issue 10, Page(s) 1164–1174

    Abstract: Background: Cabamiquine is a novel antimalarial that inhibits Plasmodium falciparum translation elongation factor 2. We investigated the causal chemoprophylactic activity and dose-exposure-response relationship of single oral doses of cabamiquine ... ...

    Abstract Background: Cabamiquine is a novel antimalarial that inhibits Plasmodium falciparum translation elongation factor 2. We investigated the causal chemoprophylactic activity and dose-exposure-response relationship of single oral doses of cabamiquine following the direct venous inoculation (DVI) of P falciparum sporozoites in malaria-naive, healthy volunteers.
    Methods: This was a phase 1b, randomised, double-blind, placebo-controlled, adaptive, dose-finding, single-centre study performed in Leiden, Netherlands. Malaria-naive, healthy adults aged 18-45 years were divided into five cohorts and randomly assigned (3:1) to receive cabamiquine or placebo. Randomisation was done by an independent statistician using codes in a permuted block schedule with a block size of four. Participants, investigators, and study personnel were masked to treatment allocation. A single, oral dose regimen of cabamiquine (200, 100, 80, 60, or 30 mg) or matching placebo was administered either at 2 h (early liver-stage) or 96 h (late liver-stage) after DVI. The primary endpoints based on a per-protocol analysis set were the number of participants who developed parasitaemia within 28 days of DVI, time to parasitaemia, number of participants with documented parasite blood-stage growth, clinical symptoms of malaria, and exposure-efficacy modelling. The impact of cabamiquine on liver stages was evaluated indirectly by the appearance of parasitaemia in the blood. The Clopper-Pearson CI (nominal 95%) was used to express the protection rate. The secondary outcomes were safety and tolerability, assessed in those who had received DVI and were administered one dose of the study intervention. The trial was prospectively registered on ClinicalTrials.gov (NCT04250363).
    Findings: Between Feb 17, 2020 and April 29, 2021, 39 healthy participants were enrolled (early liver-stage: 30 mg [n=3], 60 mg [n=6], 80 mg [n=6], 100 mg [n=3], 200 mg [n=3], pooled placebo [n=6]; late liver-stage: 60 mg [n=3], 100 mg [n=3], 200 mg [n=3], pooled placebo [n=3]). A dose-dependent causal chemoprophylactic effect was observed, with four (67%) of six participants in the 60 mg, five (83%) of six participants in the 80 mg, and all three participants in the 100 and 200 mg cabamiquine dose groups protected from parasitaemia up to study day 28, whereas all participants in the pooled placebo and 30 mg cabamiquine dose group developed parasitaemia. A single, oral dose of 100 mg cabamiquine or higher provided 100% protection against parasitaemia when administered during early or late liver-stage malaria. The median time to parasitaemia in those with early liver-stage malaria was prolonged to 15, 22, and 24 days for the 30, 60, and 80 mg dose of cabamiquine, respectively, compared with 10 days for the pooled placebo. All participants with positive parasitaemia showed documented blood-stage parasite growth, apart from one participant in the pooled placebo group and one participant in the 30 mg cabamiquine group. Most participants did not exhibit any malaria symptoms in both the early and late liver-stage groups, and those reported were mild in severity. A positive dose-exposure-efficacy relationship was established across exposure metrics. The median maximum concentration time was 1-6 h, with a secondary peak observed between 6 h and 12 h in all cabamiquine dose groups (early liver-stage). All cabamiquine doses were safe and well tolerated. Overall, 26 (96%) of 27 participants in the early liver-stage group and ten (83·3%) of 12 participants in the late liver-stage group reported at least one treatment-emergent adverse event (TEAE) with cabamiquine or placebo. Most TEAEs were of mild severity, transient, and resolved without sequelae. The most frequently reported cabamiquine-related TEAE was headache. No dose-related trends were observed in the incidence, severity, or causality of TEAEs.
    Interpretation: The results from this study show that cabamiquine has a dose-dependent causal chemoprophylactic activity. Together with previously demonstrated activity against the blood stages combined with a half-life of more than 150 h, these results indicate that cabamiquine could be developed as a single-dose monthly regimen for malaria prevention.
    Funding: The healthcare business of Merck KGaA, Darmstadt, Germany.
    MeSH term(s) Adult ; Humans ; Plasmodium falciparum ; Netherlands ; Malaria, Falciparum/drug therapy ; Malaria, Falciparum/prevention & control ; Malaria, Falciparum/parasitology ; Antimalarials ; Healthy Volunteers ; Double-Blind Method
    Chemical Substances Antimalarials
    Language English
    Publishing date 2023-07-03
    Publishing country United States
    Document type Randomized Controlled Trial ; Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2061641-7
    ISSN 1474-4457 ; 1473-3099
    ISSN (online) 1474-4457
    ISSN 1473-3099
    DOI 10.1016/S1473-3099(23)00212-8
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 5743: Show issues Location:
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    ab Jg. 2022: Lesesaal (EG)

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