Vaccine Safety and Immunogenicity in Patients With Multiple Sclerosis Treated With Natalizumab.

Importance: Vaccination in patients with highly active multiple sclerosis (MS) requiring prompt treatment initiation may result in impaired vaccine responses and/or treatment delay. Objective: To assess the immunogenicity and safety of inactivated vaccines administered during natalizumab treatment. Design, Setting, and Participants: This self-controlled, prospective cohort study followed adult patients with MS from 1 study center in Spain from September 2016 to February 2022. Eligible participants included adults with MS who completed immunization for hepatitis B virus (HBV), hepatitis A virus (HAV), and COVID-19 during natalizumab therapy. Data analysis was conducted from November 2022 to February 2023. Exposures: Patients were categorized according to their time receiving natalizumab treatment at the time of vaccine administration as short-term (≤1 year) or long-term (>1 year). Main Outcomes and Measures: Demographic, clinical, and radiological characteristics were collected during the year before vaccination (prevaccination period) and the year after vaccination (postvaccination period). Seroprotection rates and postvaccination immunoglobulin G titers were determined for each vaccine within both periods. Additionally, differences in annualized relapse rate (ARR), new T2 lesions (NT2L), Expanded Disability Status Scale (EDSS) scores, and John Cunningham virus (JCV) serostatus between the 2 periods were assessed. Results: Sixty patients with MS (mean [SD] age, 43.2 [9.4] years; 44 female [73.3%]; 16 male [26.7%]; mean [SD] disease duration, 17.0 [8.7] years) completed HBV, HAV, and mRNA COVID-19 immunization during natalizumab treatment, with 12 patients in the short-term group and 48 patients in the long-term group. The global seroprotection rate was 93% (95% CI, 86%-98%), with individual vaccine rates of 92% for HAV (95% CI, 73%-99%), 93% for HBV (95% CI, 76%-99%), and 100% for the COVID-19 messenger RNA vaccine (95% CI, 84%-100%). Between the prevaccination and postvaccination periods there was a significant reduction in the mean (SD) ARR (0.28 [0.66] vs 0.01 [0.12]; P = .004) and median (IQR) NT2L (5.00 [2.00-10.00] vs 0.81 [0.00-0.50]; P = .01). No changes in disability accumulation were detected (median [IQR] EDSS score 3.5 [2.0-6.0] vs 3.5 [2.0-6.0]; P = .62). No differences in safety and immunogenicity were observed for all vaccines concerning the duration of natalizumab treatment. Conclusions and Relevance: The findings of this cohort study suggest that immunization with inactivated vaccines during natalizumab therapy was both safe and immunogenic, regardless of the treatment duration. Natalizumab may be a valuable option for proper immunization, averting treatment delays in patients with highly active MS; however, this strategy needs to be formally evaluated.

Influenza Vaccine Effectiveness against Hospitalization, Season 2021/22: A Test-Negative Design Study in Barcelona.

BACKGROUND: Vaccination is considered the most effective measure for preventing influenza and its complications. The influenza vaccine effectiveness (IVE) varies annually due to the evolution of influenza viruses and the update of vaccine composition. Assessing the IVE is crucial to facilitate decision making in public health policies. AIM: to estimate the IVE against hospitalization and its determinants in the 2021/22 season in a Spanish tertiary hospital. METHODS: We conducted a prospective observational test-negative design study within the Development of Robust and Innovative Vaccine Effectiveness (DRIVE) project. Hospitalized patients with severe acute respiratory infection (SARI) and an available influenza reverse transcription polymerase chain reaction (RT-PCR) were selected and classified as cases (positive influenza RT-PCR) or controls (negative influenza RT-PCR). Vaccine information was obtained from electronic clinical records shared by public healthcare providers. Information about potential confounders was obtained from hospital clinical registries. The IVE was calculated by subtracting the ratio of the odds of vaccination in cases and controls from one, as a percentage (IVE = (1 - odds ratio (OR)) × 100). Multivariate IVE estimates were calculated using logistic regression. RESULTS: In total, 260 severe acute respiratory infections (SARI) were identified, of which 34 were positive for influenza, and all were subtype A(H3N2). Fifty-three percent were vaccinated. Adjusted IVE against hospitalization was 26.4% (95% CI -69% to 112%). IVE determinants could not be explored due to sample size limitations. CONCLUSION: Our data revealed non-significant moderate vaccine effectiveness against hospitalization for the 2021/2022 season.

Suspected case of monkeypox reinfection versus reactivation in a immunocompetent patient, Barcelona, 2022.

Vaccines against smallpox are known to have cross-protective activity against monkeypox, and smallpox and monkeypox infections are believed to generate permanent immunity. Nevertheless, there are scarce data about the possibility of reinfection or reactivation. Recently, a case of apparent monkeypox reinfection has been reported. We present a suspected case of second episode of monkeypox in a healthy and previously vaccinated man, with a confirmed primary monkeypox infection occurring three months before the second confirmed presentation.

Reactogenicity to the mRNA-1273 Booster According to Previous mRNA COVID-19 Vaccination.

The objective of this study was to assess the local and systemic adverse reactions after the administration of a COVID-19 mRNA-1273 booster between December 2021 and February 2022 by comparing the type of mRNA vaccine used as primary series (mRNA-1273 or BNT162b2) and homologous versus heterologous booster in health care workers (HCW). A cross-sectional study was performed in HCW at a tertiary hospital in Barcelona, Spain. A total of 17% of booster recipients responded to the questionnaire. The frequency of reactogenicity after the mRNA-1273 booster (88.5%) was similar to the mRNA-1273 primary doses (85.8%), and higher than the BNT162b2 primary doses (71.1%). The reactogenicity was similar after receiving a heterologous booster compared to a homologous booster (88.0% vs. 90.2%, p = 0.3), and no statistically significant differences were identified in any local or systemic reactions. A higher frequency of medical leave was identified in the homologous booster dose group vs. the heterologous booster dose group (AOR 1.45; 95% CI: 1.00-2.07; p = 0.045). Our findings could be helpful in improving vaccine confidence toward heterologous combinations in the general population and in health care workers.

Nosocomial COVID-19. Prospective study in a referral hospital.

Background and objective: The objective was to describe the clinical characteristics and prognosis of patients with nosocomial SARS-CoV-2 infection. Methods: An observational and prospective study was performed in a referral hospital. We included all adult patients diagnosed with nosocomial SARS-CoV-2 infection in October 2020. Nosocomial infection was defined as a negative PCR for SARS-CoV-2 on admission and a positive PCR after 7 days of hospitalization. Results: We included 66 cases of nosocomial SARS-CoV-2 infection: 39 (59%) men, median age at diagnosis was 74.5 years (IQR 56.8-83.1) and median Charlson comorbidity index was 3 points (IQR 1-5). Twenty-seven (41%) developed pneumonia and 13 (20%) died during admission. Mortality at 28 days was 33% (22 patients). Mortality at 28 days in the 242 patients with community-acquired SARS-CoV-2 infection who were hospitalized during the same period was 10%. Conclusions: Preventive measures and early detection of nosocomial outbreaks of COVID-19 should be prioritized to minimize the negative impact of this infection.

Antecedentes y Objetivo: El objetivo fue describir las características clínicas y el pronóstico de los pacientes con infección nosocomial por SARS-CoV-2. Métodos: Se realizó un estudio observacional y prospectivo en un hospital de referencia. Se incluyeron todos los pacientes adultos diagnosticados de infección por SARS-CoV-2 nosocomial en octubre de 2020, definida como una PCR para SARS-CoV-2 negativa al ingreso y positiva a partir de los siete días de hospitalización. Resultados: Se diagnosticaron 66 casos de infección por SARS-CoV-2 nosocomial: 39 (59%) hombres, edad mediana al diagnóstico de 74,5 años (RIC 56,8-83,1) y mediana del índice de comorbilidad de Charlson de 3 puntos (RIC 1−5). Veintisiete (41%) presentaron neumonía y 13 (20%) fallecieron durante el ingreso. La mortalidad a los 28 días fue del 33% (22 pacientes). La mortalidad a los 28 días en los 242 pacientes con infección por SARS-CoV-2 adquirida en la comunidad y hospitalizados durante el mismo periodo fue del 10%. Conclusiones: Se deben extremar las medidas de prevención y detección precoz de brotes nosocomiales de COVID-19 para minimizar el impacto negativo de esta infección.

Missed opportunities for vaccination (MOV) in children up to 5 years old in 19 Médecins Sans Frontières-supported health facilities: a cross-sectional survey in six low-resource countries.

OBJECTIVE: To describe missed opportunities for vaccination (MOV) among children visiting Médecins Sans Frontières (MSF)-supported facilities, their related factors, and to identify reasons for non-vaccination. DESIGN: Cross-sectional surveys conducted between 2011 and 2015. SETTING AND PARTICIPANTS: Children up to 59 months of age visiting 19 MSF-supported facilities (15 primary healthcare centres and four hospitals) in Afghanistan, Democratic Republic of the Congo, Mauritania, Niger, Pakistan and South Sudan. Only children whose caregivers presented their vaccination card were included. OUTCOME MEASURES: We describe MOV prevalence and reasons for no vaccination. We also assess the association of MOV with age, type of facility and reason for visit. RESULTS: Among 5055 children's caregivers interviewed, 2738 presented a vaccination card of whom 62.8% were eligible for vaccination, and of those, 64.6% had an MOV. Presence of MOV was more likely in children visiting a hospital or a health facility for a reason other than vaccination. MOV occurrence was significantly higher among children aged 12-23 months (84.4%) and 24-59 months (88.3%) compared with children below 12 months (56.2%, p≤0.001). Main reasons reported by caregivers for MOV were lack of vaccines (40.3%), reason unknown (31.2%) and not being informed (17.6%). CONCLUSIONS: Avoiding MOV should remain a priority in low-resource settings, in line with the new 'Immunization Agenda 2030'. Children beyond their second year of life are particularly vulnerable for MOV. We strongly recommend assessment of eligibility for vaccination as routine healthcare practice regardless of the reason for the visit by screening vaccination card. Strengthening implementation of 'Second year of life' visits and catch-up activities are proposed strategies to reduce MOV.

Characteristics of 24 SARS-CoV-2-Sequenced Reinfection Cases in a Tertiary Hospital in Spain.

Background: Since the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the main concern is whether reinfections are possible, and which are the associated risk factors. This study aims to describe the clinical and molecular characteristics of 24 sequence-confirmed reinfection SARS-CoV-2 cases over 1 year in Barcelona (Catalonia, Spain). Methods: Patients with > 45 days between two positive PCR tests regardless of symptoms and negative tests between episodes were initially considered as suspected reinfection cases from November 2020 to May 2021. Whole-genome sequencing (WGS) was performed to confirm genetic differences between consensus sequences and for phylogenetic studies based on PANGOLIN nomenclature. Reinfections were confirmed by the number of mutations, change in lineage, or epidemiological criteria. Results: From 39 reported suspected reinfection cases, complete viral genomes could be sequenced from both episodes of 24 patients, all were confirmed as true reinfections. With a median age of 44 years (interquartile range [IQR] 32-65), 66% were women and 58% were healthcare workers (HCWs). The median days between episodes were 122 (IQR 72-199), occurring one-third within 3 months. Reinfection episodes were frequently asymptomatic and less severe than primary infections. The absence of seroconversion was associated with symptomatic reinfections. Only one case was reinfected with a variant of concern (VOC). Conclusion: Severe acute respiratory syndrome coronavirus 2 reinfections can occur in a shorter time than previously reported and are mainly found in immunocompetent patients. Surveillance through WGS is useful to identify viral mutations associated with immune evasion.

Nosocomial COVID-19. Prospective study in a referral hospital. / COVID-19 nosocomial. Estudio prospectivo en un hospital de referencia.

BACKGROUND AND OBJECTIVE: The objective was to describe the clinical characteristics and prognosis of patients with nosocomial SARS-CoV-2 infection. METHODS: An observational and prospective study was performed in a referral hospital. We included all adult patients diagnosed with nosocomial SARS-CoV-2 infection in October 2020. Nosocomial infection was defined as a negative PCR for SARS-CoV-2 on admission and a positive PCR after 7 days of hospitalization. RESULTS: We included 66 cases of nosocomial SARS-CoV-2 infection: 39 (59%) men, median age at diagnosis was 74.5 years (IQR 56.8-83.1) and median Charlson comorbidity index was 3 points (IQR 1-5). Twenty-seven (41%) developed pneumonia and 13 (20%) died during admission. Mortality at 28 days was 33% (22 patients). Mortality at 28 days in the 242 patients with community-acquired SARS-CoV-2 infection who were hospitalized during the same period was 10%. CONCLUSIONS: Preventive measures and early detection of nosocomial outbreaks of COVID-19 should be prioritized to minimize the negative impact of this infection.

A year living with SARS-CoV-2: an epidemiological overview of viral lineage circulation by whole-genome sequencing in Barcelona city (Catalonia, Spain).

Herein, we describe the genetic diversity of circulating SARS-CoV-2 viruses by whole-genome sequencing (WGS) in Barcelona city (Catalonia, Spain) throughout the first four pandemic waves. From weeks 11/2020-24/2021, SARS-CoV-2-positive respiratory samples were randomly selected per clinical setting (80% from primary care or 20% from the hospital), age group, and week. WGS was performed following the ARTICv3 protocol on MiSeq or NextSeq2000 Illumina platforms. Nearly complete consensus sequences were used for genetic characterization based on GISAID and PANGOLIN nomenclatures. From 2475 samples, 2166 (87%) were fully sequenced (78% from primary care and 22% from hospital settings). Multiple genetic lineages were co-circulating, but four were predominant at different periods. While B.1.5 (50.68%) and B.1.1 (32.88%) were the major lineages during the first pandemic wave, B.1.177 (66.85%) and B.1.1.7 (83.80%) were predominant during the second, third, and fourth waves, respectively. Almost all (96.4%) were carrying D614G mutation in the S protein, with additional mutations that define lineages or variants. But some mutations of concern, such as E484K from B.1.351 and P.1 lineages are currently under monitoring, together with those observed in the receptor-binding domain or N-terminal domain, such as L452R and T478K from B.1.617.2 lineage. The fact that a predominant lineage was observed in each pandemic wave suggests advantageous properties over other contemporary co-circulating variants. This genetic variability should be monitored, especially when a massive vaccination campaign is ongoing because the potential selection and emergence of novel antigenic SARS-CoV-2 strains related to immunological escapement events.

Local and Systemic Adverse Reactions to mRNA COVID-19 Vaccines Comparing Two Vaccine Types and Occurrence of Previous COVID-19 Infection.

The aim of this study was to assess adverse reactions to COVID-19 vaccines, comparing the BNT162b2 or the mRNA-1273 COVID-19 vaccines and the presence and seriousness of a previous COVID-19 infection. We conducted a cross-sectional online survey of vaccinated healthcare workers at a tertiary hospital in Barcelona (Spain). Thirty-eight percent of vaccine recipients responded to the questionnaire. We compared the prevalence of adverse reactions by vaccine type and history of COVID-19 infections. A total of 2373 respondents had received the BNT162b2 vaccine, and 506 the mRNA-1273 vaccine. The prevalence of at least one adverse reaction with doses 1 and 2 was 41% and 70%, respectively, in the BNT162b2 group, and 60% and 92% in the mRNA-1273 group (p < 0.001). The BNT162b2 group reported less prevalence of all adverse reactions. Need for medical leave was significantly more frequent among the mRNA-1273 group (12% versus 4.6% p < 0.001). Interestingly, respondents with a history of allergies or chronic illnesses did not report more adverse reactions. The frequency of adverse reactions with dose 2 was 96% (95% CI 88-100%) for those with a history of COVID-19 related hospitalization, and 86% (95% CI 83-89%) for those with mild or moderate symptomatic COVID-19, significantly higher than for participants with no history of COVID-19 infections (67%, 95% CI 65-69%). Our results could help inform vaccine recipients of the probability of their having adverse reactions to COVID-19 vaccines.

Epidemiological characteristics and outcomes of COVID-19 cases: mortality inequalities by socio-economic status, Barcelona, Spain, 24 February to 4 May 2020.

BackgroundPopulation-based studies characterising outcomes of COVID-19 in European settings are limited, and effects of socio-economic status (SES) on outcomes have not been widely investigated. AimWe describe the epidemiological characteristics of COVID-19 cases, highlighting incidence and mortality rate differences across SES during the first wave in Barcelona, Catalonia, Spain.MethodsThis population-based study reports individual-level data of laboratory-confirmed COVID-19 cases diagnosed from 24 February to 4 May 2020, notified to the Public Health Agency of Barcelona and followed until 15 June 2020. We analysed end-of-study vital status and the effects of chronic conditions on mortality using logistic regression. Geocoded addresses were linked to basic health area SES data, estimated using the composed socio-economic index. We estimated age-standardised incidence, hospitalisation, and mortality rates by SES.ResultsOf 15,554 COVID-19-confirmed cases, the majority were women (n = 9,028; 58%), median age was 63 years (interquartile range: 46-83), 8,046 (54%) required hospitalisation, and 2,287 (15%) cases died. Prevalence of chronic conditions varied across SES, and multiple chronic conditions increased risk of death (≥ 3, adjusted odds ratio: 2.3). Age-standardised rates (incidence, hospitalisation, mortality) were highest in the most deprived SES quartile (incidence: 1,011 (95% confidence interval (CI): 975-1,047); hospitalisation: 619 (95% CI: 591-648); mortality: 150 (95% CI: 136-165)) and lowest in the most affluent (incidence: 784 (95% CI: 759-809); hospitalisation: 400 (95% CI: 382-418); mortality: 121 (95% CI: 112-131)).ConclusionsCOVID-19 outcomes varied markedly across SES, underscoring the need to implement effective preventive strategies for vulnerable populations.

["Heparjoc-Actúa": educational tool created through a process of participatory action research with vulnerable immigrant groups to improve accessibility to diagnosis of hepatitis B.] / "HEPARJOC-ACTÚA": herramienta educativa creada a través de un proceso de investigación-acción participativa con colectivos inmigrantes vulnerables para mejorar la accesibilidad al diagnóstico de la hepatitis B.

OBJECTIVE: The World Health Organization estimates that 257 million people suffer from chronic infection by the hepatitis B (HB) virus. It is common for diagnosis to be delayed or never given at all. In Spain, immigrants that come from endemic areas present a prevalence of infection of around 8%. In the year 2015, this study was begun with the aiml of improving accessibility to hepatitis B diagnoses in immigrant communities. METHODS: A descriptive qualitative study was carried out, based on participatory action research (IAP). It was divided into two cycles: in the first cycle, after forming a motor group (GIAP), a participatory community assessment (DCP) was performed with the population, through a descriptive-interpretative qualitative study (ECDI) with 3 focal groups (n=17). A narrative analysis was then performed of thematic content. In the second cycle, two collaborative workshops (coworking) were held to create an educational tool (HEPARJOC) and to co-create an action plan (PDA). As a pilot test, the PDA was put into practice through eight workshops (n=56). A knowledge questionnaire was used to compare the median number of correct responses before and after the workshop, using the t of Student for paired data. RESULTS: A GIAP was formed with 8 members of different sectors and community spaces. In the DCP it was observed that there was a lack of knowledge about different aspects of hepatitis B. Visual, interactive materials were proposed as educational tools, and "HEPARJOC" was created as the final product. In the pilot test of the PDA, the median of correct responses to the knowledge questionnaire about HB was 7.7 (DE=3) before the workshop, and 10.6 (DE=0.2) afterward. The improvement of the median was 2.9 points (IC 95% 2.2-3.6), which is statistically significant (p<0.001). 30 people sought screening (53.6% of participants), and 23 of those people were screened (41% of participants). CONCLUSIONS: "HEPARJOC-ACTUA" is a strategy that could contribute to transforming knowledge and improving accessibility to hepatitis B diagnosis in immigrant communities. Key words: Infectious diseases, hepatitis B, community health, community health agents, health education, participatory action research, immigration. Key words: Infectious.

OBJETIVO: La Organización Mundial de la Salud estima que 257 millones de personas padecen infección crónica por el virus de la hepatitis B (HB). Es habitual que el diagnóstico se retrase o que nunca se llegue a realizar. En España, los inmigrantes procedentes de áreas endémicas presentan prevalencias en torno al 8%. En el año 2015, se inició este estudio con el objetivo de mejorar la accesibilidad al diagnóstico de la hepatitis B en colectivos inmigrantes. METODOS: Se realizó un estudio cualitativo descriptivo, basado en la investigación acción participativa (IAP). Se dividió en dos ciclos: en el primer ciclo, después de configurar un grupo motor (GIAP), se realizó un diagnóstico comunitario participativo (DCP) con la población, a través de un estudio cualitativo descriptivo-interpretativo (ECDI) con 3 grupos focales (n=17). Se llevó a cabo un análisis narrativo de contenido temático. En el segundo ciclo, se realizaron 2 talleres de trabajo colaborativo (coworking) para crear una herramienta educativa (HEPAJOC) y coconstruir un plan de acción (PDA). Como prueba piloto se llevó a cabo este PDA a través 8 talleres (n=56). Se utilizó un cuestionario de conocimientos para comparar la media de respuestas correctas pre y post taller utilizando el t de Student para datos apareados. RESULTADOS: Se configuró un GIAP con 8 miembros de diferentes sectores y espacios comunitarios. En el DCP se observó que existía un desconocimiento en diferentes aspectos sobre la hepatitis B. Se propusieron, como herramientas educativas, materiales visuales e interactivos, elaborando como producto final el "HEPARJOC". En la prueba piloto del PDA, la media de las respuestas correctas al cuestionario de conocimientos sobre la HB fue de 7,7 (DE=3) previamente, y de 10,6 (DE=0,2) posteriormente. La mejoría de la media fue de 2,9 puntos (IC 95% 2,2-3,6), siendo estadísticamente significativa (p<0,001). Solicitaron el cribado 30 personas (53,6%), siendo cribadas 23 (41%). CONCLUSIONES: "HEPARJOC-ACTUA" es una estrategia que puede contribuir a transformar conocimientos y a mejorar la accesibilidad al diagnóstico de la hepatitis B en colectivos inmigrantes.

Asymptomatic SARS-CoV-2 Infection in Nursing Homes, Barcelona, Spain, April 2020.

During the coronavirus disease pandemic in Spain, from April 10-24, 2020, a total of 5,869 persons were screened for severe acute respiratory syndrome coronavirus 2 at nursing homes. Among residents, 768 (23.9%) tested positive; among staff, 403 (15.2%). Of those testing positive, 69.7% of residents and 55.8% of staff were asymptomatic.

Infections with Mycobacterium chimaera and open chest surgery. An unresolved problem. / Infecciones por Mycobacterium chimaera y cirugía cardíaca. Un problema no resuelto.

Mycobacterium chimaera (M. chimaera) is a non-tuberculous mycobacterium of the Mycobacterium avium complex. Between 2013 and April 2018, more than 140 cases of severe infection have been identified, all of them in patients who had undergone cardiothoracic surgery with extracorporeal circulation. The epidemiological investigations have shown that the majority of infections have a common source: contaminated normo-hypothermia modules. These devices have a water circuit inside and cooling fans that produce an aerosol, which can be contaminated with M. chimaera, and disperse it into the air in the operating room. The clinical symptoms can take months, even years to appear after the extracorporeal surgery, with an average of 1.5 years. Sarcoidosis is the most frequently described entity as a misdiagnosis in these patients, so it is necessary to maintain a high diagnostic suspicion in all patients with a history of cardiac surgery with extracorporeal circulation.

The dipeptide monoester prodrugs of floxuridine and gemcitabine-feasibility of orally administrable nucleoside analogs.

Dipeptide monoester prodrugs of floxuridine and gemcitabine were synthesized. Their chemical stability in buffers, enzymatic stability in cell homogenates, permeability in mouse intestinal membrane along with drug concentration in mouse plasma, and anti-proliferative activity in cancer cells were determined and compared to their parent drugs. Floxuridine prodrug was more enzymatically stable than floxuridine and the degradation from prodrug to parent drug works as the rate-limiting step. On the other hand, gemcitabine prodrug was less enzymatically stable than gemcitabine. Those dipeptide monoester prodrugs exhibited 2.4- to 48.7-fold higher uptake than their parent drugs in Caco-2, Panc-1, and AsPC-1 cells. Floxuridine and gemcitabine prodrugs showed superior permeability in mouse jejunum to their parent drugs and exhibited the higher drug concentration in plasma after in situ mouse perfusion. Cell proliferation assays in ductal pancreatic cancer cells, AsPC-1 and Panc-1, indicated that dipeptide prodrugs of floxuridine and gemcitabine were more potent than their parent drugs. The enhanced potency of nucleoside analogs was attributed to their improved membrane permeability. The prodrug forms of 5¢-L-phenylalanyl-l-tyrosyl-floxuridine and 5¢-L-phenylalanyl-L-tyrosyl-gemcitabine appeared in mouse plasma after the permeation of intestinal membrane and the first-pass effect, suggesting their potential for the development of oral dosage form for anti-cancer agents.