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RESUMEN Los inhibidores de la bomba de protones (IBP) son los medicamentos más potentes para inhibir la secreción gástrica ácida, y se utilizan en el tratamiento de la mayor parte de las afecciones inflamatorias de la mucosa gástrica. Forman parte de los fármacos más recetados y sobreprescritos en todo el mundo; por ejemplo, en los Estados Unidos, según la Encuesta nacional de salud y nutrición, casi duplicaron su uso en los adultos de 40 años de un 4,9 % hasta un 8,3 %, entre los años 1999 a 2012. Aunque, en general, se consideran bien tolerados, algunos estudios epidemiológicos ―que extraen información a partir de grandes bases de datos― han reportado una serie de efectos adversos asociados con su uso prolongado, entre los cuales están el deterioro cognitivo, la enfermedad renal crónica, el infarto de miocardio, el accidente cerebrovascular, las fracturas óseas e incluso la muerte, entre otros. El objetivo fue realizar una revisión narrativa de la literatura acerca de los efectos del uso crónico de los IBP sobre el deterioro cognitivo en los adultos mayores. Se revisaron artículos a partir de una búsqueda en las bases de datos Pudmed, Scopus y Scielo con las palabras clave y términos Mesh/DeCS relacionados tanto en inglés como en español. Los efectos secundarios a nivel neurológico inducidos por el uso crónico de los IBP pueden estar relacionados indirectamente con la presencia de alteraciones sistémicas secundarias (deficiencia de magnesio y vitamina B12) o con efectos directos sobre el funcionamiento neuronal después de pasar a través de la barrera hematoencefálica. Si bien se han descrito varios mecanismos neurobiológicos por medio de los cuales los IBP podrían favorecer el desarrollo de la demencia ―que comprenden el funcionamiento de la proteína tau, la acumulación de beta amiloide (βA) y la deficiencia de cobalamina, entre otros―, la mayor parte de la evidencia clínica disponible no ha encontrado una asociación significativa entre el uso de los IBP y el riesgo de demencia o el deterioro cognitivo. Para establecer de una manera más clara los efectos clínicos adversos del uso crónico de los IBP, en especial, en el funcionamiento cerebral, se necesitan estudios de cohorte bien diseñados, con tamaños de muestra grandes y periodos de seguimiento prolongados, con un método confiable para ajustar los factores de confusión estandarizados y, además, realizar análisis por subgrupos.

ABSTRACT Proton pump inhibitors (PPIs) are the most potent drugs to inhibit gastric acid secretion, being used in the treatment of most inflammatory conditions of the gastric mucosa. They are among the most prescribed and overprescribed medications worldwide; for example, in the United States, according to the National Health and Nutrition Examination Survey, they almost doubled their use in adults aged 40 years and older from 4.9 % to 8.3 % between 1999 and 2012. Although they are generally considered well tolerated, some epidemiological studies extracting information from large databases have reported a number of adverse effects associated with their prolonged use, including cognitive impairment, chronic kidney disease, myocardial infarction, stroke, bone fractures and even death, among others. The objective was to conduct a narrative review of the literature on the effects of chronic use of PPIs on cognitive impairment in older adults. Articles were reviewed based on a search in the PubMed, Scopus and SciELO databases using both English and Spanish keywords and related MeSH/DeCS terms. Neurological side effects induced by chronic PPI use may be indirectly related to secondary systemic disorders (magnesium and vitamin B12 deficiency) or to direct effects on neuronal functioning after passing through the blood-brain barrier. Although several neurobiological mechanisms by which PPIs could favor the development of dementia-which involve Tau protein function, beta-amyloid [βA] accumulation and cobalamin deficiency, among others-have been described, most of the available clinical evidence has not shown a significant association between PPI use and the risk of dementia or cognitive impairment. To establish the adverse clinical effects of chronic PPI use more clearly, especially on brain functioning, well-designed cohort studies with large sample sizes and long follow-up periods, with a reliable method to adjust for standardized confounders, as well as subgroup analyses are needed.

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Abstract Objective To investigate the effects of combination therapy with cholecalciferol and lansoprazole on residual β-cell function and glycemic control in children with new-onset type 1 diabetes. Methods Children aged 6-12 years with type 1 diabetes were allocated to receive cholecalciferol and lansoprazole (Group 1) or no treatment (Group 2). Children were maintained on their respective insulin regimens and kept records of blood sugar and insulin doses taken. Children were followed at three-month intervals for six months. Changes in mean fasting C-peptide and HbA1c levels, daily insulin doses, fasting blood glucose and mean blood glucose levels from baseline to end of the study were analyzed. Results Twenty-eight children (14 per group) met the eligibility criteria. Fasting C-peptide levels decreased significantly from baseline to study end in both groups (mean decrease -0.19±0.09ng/mL and -0.28±0.08ng/mL, p=0.04 and p=0.001; Group 1 and Group 2 respectively). However, fasting C-peptide level drop was significantly smaller in Group 1 compared to Group 2 (30.6% and 47.5% respectively; p=0.001). Likewise, daily insulin doses decreased significantly in both groups (-0.59±0.14units/kg and -0.37±0.24units/kg respectively; p=0.001). All patients recruited completed the study. No adverse events were reported. Conclusion Combined therapy with cholecalciferol and lansoprazole for six months was associated with smaller decline in residual β-cell function and lower insulin requirements in children with new-onset type 1 diabetes. Preliminary findings of this small-scale study need to be confirmed by larger studies. Registry of Clinical Trials (www.ctri.nic.in) under number REF/2021/03/041415 N.

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Development of positron emission tomography (PET) imaging agents capable of quantifying tau aggregates in neurodegenerative disorders such as Alzheimer's disease (AD) is of enormous importance in the field of dementia research. The aim of the present study was to conduct first-in-man imaging studies with the potential novel tau imaging agent [18F]N-methyl lansoprazole ([18F]NML). Herein we report validation of the synthesis of [18F]NML for clinical use by labeling the trifluoromethyl group via radiofluorination of the corresponding gem-difluoro enol ether precursor. This is the first use of this method for clinical production of PET radiotracers and confirmed that it can be readily implemented at multiple production facilities to provide [18F]NML in good noncorrected radiochemical yield (3.4 ± 1.5 GBq, 4.6% ± 2.6%) and molar activity (120.1 ± 186.3 GBq/µmol), excellent radiochemical purity (>97%), and suitable for human use (n = 15). With [18F]NML in hand, we conducted rodent biodistribution, estimates of human dosimetry, and preliminary evaluation of [18F]NML in human subjects at two imaging sites. Healthy controls (n = 4) and mildly cognitively impaired (MCI) AD patients (n = 6) received [18F]NML (tau), [18F]AV1451 (tau), and [18F]florbetaben or [18F]florbetapir (amyloid) PET scans. A single progressive supranuclear palsy (PSP) patient also received [18F]NML and [18F]AV1451 PET scans. [18F]NML showed good brain uptake, reasonable pharmacokinetics, and appropriate imaging characteristics in healthy controls. The mean ± SD of the administered mass of [18F/19F]NML was 2.01 ± 2.17 µg (range, 0.16-8.27 µg) and the mean administered activity was 350 ± 62 MBq (range, 199-403 MBq). There were no adverse or clinically detectable pharmacologic effects in any of the 11 subjects, and no significant changes in vital signs were observed. However, despite high affinity for tau in vitro, brain retention in MCI/AD and PSP patients was low, and there was no evidence of specific signals in vivo that corresponded to tau. Although it is still unclear why clinical translation of the radiotracer was unsuccessful, we nevertheless conclude that further development of [18F]NML as a tau PET imaging agent is not warranted at this time.

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abstract The aim of this study was to evaluate the effects of caffeine, tea polyphenol and daidzein on the pharmacokinetics of lansoprazole and its metabolites. Rats were intragastrically administered caffeine (30 mg·kg-1, once per day), tea polyphenol (400 mg·kg-1, once per day) or daidzein (13.5 mg·kg-1, once per day) for 14 days, followed by an intragastric administration of lansoprazole (8 mg·kg-1) on the 15th day. The plasma concentrations of lansoprazole and its two primary metabolites, 5-hydroxylansoprazole and lansoprazole sulfone, were determined by high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS). Tea polyphenol significantly elevated the Area Under the Curve (AUC) of lansoprazole from 680.29 ± 285.99 to 949.76 ± 155.18 μg/L.h and reduced that of lansoprazole sulfone from 268.82 ± 82.37 to 177.72 ± 29.73 μg/L.h. Daidzein increased the AUC of lansoprazole from 680.29 ± 285.99 to 1130.44 ± 97.6 μg/L.h and decreased that of lansoprazole sulfone from 268.82 ± 82.37 to 116.23 ± 40.14 μg/L.h. The pharmacokinetics of 5-hydroxylansoprazole remained intact in the presence of tea polyphenol or daidzein. Caffeine did not affect the pharmacokinetics of lansoprazole and its metabolites. The results imply that tea polyphenol and daidzein may inhibit the in vivo metabolism of lansoprazole by suppressing CYP3A.

resumo O objetivo deste estudo foi avaliar os efeitos da cafeína, do polifenol do chá e da daidzeína na farmacocinética do lansoprazol e de seus metabólitos. Administraram-se, intragastricamente, aos ratos cafeína (30 mg·kg-1, uma vez ao dia), polifenol do chá(400 mg·kg-1, uma vez ao dia) ou daidzeína (13,5 mg·kg-1, uma vez ao dia), por 14 dias, seguindo-se a administração de lansoprazol (8 mg·kg-1) no 15º. dia. As concentrações plasmáticas do lansoprazol e de seus dois metabólitos primários, 5-hidroxilansoprazol e sulfona de lansoprazol, foram determinadas por cromatografia líquida de alta eficiência acoplada com espectrometria de massas (CLAE-EM/EM). O polifenol do chá elevou, significativamente, a Área Sob a Curva (ASC) do lansoprazol de 680,29 ± 285,99 para 949,76 ± 155,18 μg/L.h e reduziu a da sulfona de lansoprazol de 268,82 ± 82,37 para 177,72 ± 29,73 μg/L.h. A daidzeína aumentou a ASC do lansoprazol de 680,29 ± 285,99 para 1130,44 ± 97,6 μg/L.h e reduziu a da sulfona de lansoprazol de 268,82 ± 82,37 para 177,72 ± 29,73 μg/L.h. A farmacocinética do 5-hidroxilansoprazol permaneceu intacta na presença de polifenol do chá ou daidzeína. A cafeína não afetou a farmacocinética do lansoprazol e de seus metabólitos. Os resultados sugerem que o polifenol do chá e a daidzeína podem inibir o metabolismo in vivo do lansoprazol por supressão da CYP3A.

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The effect of proton pump inhibitors and Helicobacter pylori infection on the bioavailability of antibiotics is poorly understood. We determined the effects of 5-day oral administration of 60 mg lansoprazole on the bioavailability of clarithromycin in individuals with and without H. pylori infection. Thirteen H. pylori-infected and 10 non-infected healthy volunteers were enrolled in a study with an open-randomized two-period crossover design and a 21-day washout period between phases. Plasma concentrations of clarithromycin in subjects with and without lansoprazole pre-treatment were measured by liquid chromatography coupled to a tandem mass spectrometer. Clarithromycin Cmax and AUC0-10 h were significantly reduced after lansoprazole administration. In addition, lansoprazole treatment of the H. pylori-positive group resulted in a statistically significant greater reduction in Cmax (40 vs 15 percent) and AUC0-10 h (30 vs 10 percent) compared to lansoprazole-treated H. pylori-negative subjects. Thus, treatment with lansoprazole for 5 days reduced bioavailability of clarithromycin, irrespective of H. pylori status. This reduction, however, was even more pronounced in H. pylori-infected individuals.

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