RESUMO
SCOPE: This review represents a focus on the structure and properties of the common nutritional disaccharides (lactose, maltose, and sucrose) in health and disease. The aim is to provide a comprehensive reference source related to the role of disaccharides in human nutrition. METHODS AND RESULTS: Key reference sources are searched, including Web of Science, PubMed, Science Direct, and Wiley Online, and key reference works are selected to support the factual basis of the text where interpretations and relevance of the works are discussed in the review. There are key nutritional health benefits of receiving dietary energy in the form of sugars, but equally life-threatening issues exist associated with constant/excess consumption. These issues are discussed together with genetic disorders, which impact upon health associated with consumption of the disaccharides (e.g., specific disaccharide intolerance due to deficiency of relevant digestive enzymes). CONCLUSIONS: As the three common dietary disaccharides (lactose, maltose, and sucrose) are consumed on a very regular basis in the human diet, it is critical to understand insofar as possible their role in health and disease. This review provides an insight into the structure and properties of these molecules in health and disease.
Assuntos
Lactose/efeitos adversos , Maltose/efeitos adversos , Sacarose/efeitos adversos , Transtorno do Deficit de Atenção com Hiperatividade/etiologia , Doenças Cardiovasculares/etiologia , Diabetes Mellitus/etiologia , Dissacarídeos/farmacocinética , Produtos Finais de Glicação Avançada/metabolismo , Índice Glicêmico , Humanos , Lactose/química , Lactose/farmacocinética , Lipídeos/sangue , Maltose/química , Maltose/farmacocinética , Hepatopatia Gordurosa não Alcoólica/etiologia , Obesidade/etiologia , Sacarose/química , Sacarose/farmacocinéticaRESUMO
PURPOSE: Iron deficiency (ID) is one of the most commonly known nutritional deficiencies and is considered the primary cause of anemia (iron-deficiency anemia). Ferric carboxymaltose (FCM), an intravenous iron preparation, has been widely used for >10 years for iron-deficiency anemia treatment worldwide because of its many advantages. METHODS: This single-center, open-label, single dose escalation study in Chinese subjects was designed to assess the pharmacokinetic/pharmacodynamic parameters and safety of FCM in this population. The first 12 subjects received a 500-mg dose; after assessing safety data from the first 6 subjects in this cohort, another 12 subjects were assigned to the 1000-mg dose cohort. FINDINGS: After an infusion of FCM over 15 min, a rapid dose-dependent increase in total serum iron levels was observed with a median Tmax of 30 min following the start of the infusion for both cohorts. The Cmax and AUC for the 1000-mg dose were ~1.8-fold (p = 0.2929) and 2.3-fold (p = 0.0318) those associated with the 500-mg dose, respectively. Mean terminal t1/2 values were 12.3 and 10.5 h for the 2 cohorts. The renal elimination of FCM was negligible (<0.1%). Increase in mean serum iron levels and ferritin concentrations showed dose dependency. Iron-binding capacity was transiently well utilized after dosing, as indicated by transferrin saturation >88% with 500-mg FCM and >90% with 1000-mg FCM. Hemoglobin levels did not show significant changes during the 7-day observation period, whereas mean reticulocyte counts significantly increased in both cohorts, suggesting activation of the hematopoietic system. FCM was well tolerated in these Chinese subjects. No new or unexpected treatment-emergent adverse events were attributable to FCM. IMPLICATIONS: The pharmacokinetic/pharmacodynamic and safety profiles in Chinese subjects seemed comparable to those in white and Japanese populations. ChinaDrugTrials.org.cn identifier: CTR20160863.
Assuntos
Anemia Ferropriva/sangue , Compostos Férricos/farmacologia , Compostos Férricos/farmacocinética , Ferritinas/sangue , Ferro/sangue , Maltose/análogos & derivados , Administração Intravenosa , Adulto , Povo Asiático , Feminino , Compostos Férricos/efeitos adversos , Humanos , Masculino , Maltose/efeitos adversos , Maltose/farmacocinética , Maltose/farmacologiaRESUMO
BACKGROUND: Iron is administered intravenously (IV) to many dialysis patients at regular intervals and iron stores are evaluated through periodic measurements of ferritin and transferrin saturation (TSAT). In patients without kidney diseases, large single doses of IV iron lead to a transient rise in serum ferritin that does not reflect iron stores. It is not known whether and to what extent smaller IV iron doses used to maintain adequate stores in hemodialysis patients lead to transient spurious elevations of ferritin and TSAT. METHODS: Ferritin and TSAT were serially determined over four weeks after the administration of ferric carboxymaltose (FCM) in hemodialysis patients on a stable maintenance FCM dosing regimen of 100 mg or 200 mg every four weeks. RESULTS: Ferritin values increased by 113 ± 72.2 µg/l (P < 0.001) from baseline to the peak value and remained significantly elevated until two weeks after the administration of 100 mg FCM (n = 19). After the administration of 200 mg FCM (n = 12), ferritin values increased by 188.5 ± 67.56 µg/l (P < 0.001) and remained significantly elevated by the end of week three. TSAT values increased by 12.0 ± 9.7% (P < 0.001) and 23.1 ± 20.4% (P = 0.002) in patients receiving 100 or 200 mg FCM, respectively, and returned to baseline within four days. CONCLUSIONS: IV administration of FCM at doses of 100 or 200 mg in hemodialysis patients leads to dose-dependent transient ferritin elevations of extended duration. Temporal coordination of blood sampling for iron status evaluation with the maintenance IV iron dosing schedule is advisable. TRIAL REGISTRATION: ISRCTN12825165 (retrospectively registered 01/02/2019).
Assuntos
Anemia Ferropriva , Compostos Férricos , Ferritinas/sangue , Maltose/análogos & derivados , Diálise Renal , Insuficiência Renal Crônica , Transferrina/análise , Anemia Ferropriva/sangue , Anemia Ferropriva/diagnóstico , Anemia Ferropriva/tratamento farmacológico , Anemia Ferropriva/etiologia , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos/métodos , Feminino , Compostos Férricos/administração & dosagem , Compostos Férricos/farmacocinética , Hematínicos/administração & dosagem , Hematínicos/farmacocinética , Humanos , Infusões Intravenosas/métodos , Ferro/metabolismo , Masculino , Maltose/administração & dosagem , Maltose/farmacocinética , Pessoa de Meia-Idade , Estudos Prospectivos , Diálise Renal/efeitos adversos , Diálise Renal/métodos , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/terapia , Fatores de TempoRESUMO
IV iron is indicated in clinical conditions, where rapid anaemia alleviation and repletion of iron stores are required. The acute toxicity of IV iron is ascribed to the presence of labile iron in plasma. Thus, shorter plasma residence time might improve the safety profile, even for compounds holding-on the iron tightly. In this single-centre, open-label, single-dose escalation study, we evaluated the elimination kinetics of ferric bepectate (FBP) compared to those of ferric carboxymaltose (FCM). Thirty-three iron-depleted anaemic patients who had undergone cardiac surgery were included and received 200, 500 or 1500 mg FBP or 500 mg FCM. Plasma drug curves were subjected to model-free analysis. Because saturation kinetics was found, a compartmental model with limited elimination capacity was applied. Urinary iron excretion was also analysed. The initial non-compartmental analysis revealed an increasing AUC/dose ratio for FBP. For both drugs, the central distribution compartment corresponded to plasma volume, and elimination followed Michaelis-Menten saturation kinetics. Maximal elimination rates (Vmax ) were 224 mg/h and 81 mg/h for FBP 500 mg and FCM 500 mg, respectively; drug concentrations at half Vmax (Km ), 99 mg/L and 212 mg/L, respectively; and terminal plasma half-life (T½), 3.05 h and 8.96 h, respectively. Both drugs were equally effective in eliciting an early ferritin rise. Urinary iron excretion was measurable in all patients receiving FCM but not in those receiving FBP, which was well tolerated. Intravenous iron drugs are subject to capacity-limited elimination with different saturation thresholds. Urinary iron excretion can be used as a surrogate for labile plasma iron.
Assuntos
Anemia Ferropriva/tratamento farmacológico , Compostos Férricos/farmacocinética , Ferro/urina , Maltose/análogos & derivados , Idoso , Anemia Ferropriva/sangue , Anemia Ferropriva/urina , Relação Dose-Resposta a Droga , Compostos Férricos/administração & dosagem , Compostos Férricos/efeitos adversos , Humanos , Infusões Intravenosas , Ferro/sangue , Masculino , Maltose/administração & dosagem , Maltose/efeitos adversos , Maltose/farmacocinética , Pessoa de Meia-Idade , Estudos Prospectivos , Eliminação RenalRESUMO
Poly(propylene imine) dendrimers have been shown to be promising 3-dimensional polymers for the use in the pharmaceutical and biomedical applications. Our aims of this study were first, to synthesize a novel type of dendrimer with poly(propylene imine) core and maltose-histidine shell (G4HisMal) assessing if maltose-histidine shell can improve the biocompatibility and the ability to cross the blood-brain barrier, and second, to investigate the potential of G4HisMal to protect Alzheimer disease transgenic mice from memory impairment. Our data demonstrate that G4HisMal has significantly improved biocompatibility and ability to cross the blood-brain barrier in vivo. Therefore, we suggest that a maltose-histidine shell can be used to improve biocompatibility and ability to cross the blood-brain barrier of dendrimers. Moreover, G4HisMal demonstrated properties for synapse and memory protection when administered to Alzheimer disease transgenic mice. Therefore, G4HisMal can be considered as a promising drug candidate to prevent Alzheimer disease via synapse protection.
Assuntos
Histidina/uso terapêutico , Maltose/uso terapêutico , Transtornos da Memória/prevenção & controle , Fármacos Neuroprotetores/uso terapêutico , Polipropilenos/uso terapêutico , Doença de Alzheimer/complicações , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Animais , Linhagem Celular , Dendrímeros/química , Dendrímeros/farmacocinética , Dendrímeros/uso terapêutico , Histidina/análogos & derivados , Histidina/farmacocinética , Humanos , Maltose/análogos & derivados , Maltose/farmacocinética , Transtornos da Memória/complicações , Transtornos da Memória/patologia , Camundongos , Camundongos Transgênicos , Nanopartículas/química , Nanopartículas/uso terapêutico , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacocinética , Polipropilenos/química , Polipropilenos/farmacocinética , Sinapses/efeitos dos fármacos , Sinapses/patologiaRESUMO
Based on its high affinity for µ opiate receptors and reported half-life after oral administration, the pharmacokinetic properties of intranasal naltrexone were examined to evaluate its potential to treat opioid overdose. This study was prompted by the marked rise in overdose deaths linked to synthetic opioids like fentanyl, which may require more potent, longer-lived opiate antagonists than naloxone. Both the maximum plasma concentration (Cmax ) and the time (Tmax ) to reach Cmax for intranasal naltrexone (4 mg) were comparable to values reported for a Food and Drug Administration-approved 4-mg dose of intranasal naloxone. The addition of the absorption enhancer dodecyl maltoside (Intravail) increased Cmax by â¼3-fold and reduced the Tmax from 0.5 to 0.17 hours. Despite these very rapid increases in plasma concentrations of naltrexone, its short half-life following intranasal administration (â¼2.2 hours) could limit its usefulness as a rescue medication, particularly against longer-lived synthetic opioids. Nonetheless, the ability to rapidly attain high plasma concentrations of naltrexone may be useful in other indications, including an as-needed dosing strategy to treat alcohol use disorder.
Assuntos
Maltose/análogos & derivados , Naltrexona/sangue , Naltrexona/farmacocinética , Alcaloides Opiáceos/antagonistas & inibidores , Administração Intranasal , Administração Oral , Adulto , Área Sob a Curva , Linhagem Celular , Estudos Cross-Over , Overdose de Drogas , Feminino , Meia-Vida , Humanos , Concentração de Íons de Hidrogênio , Injeções Intramusculares , Masculino , Maltose/farmacocinética , Pessoa de Meia-Idade , Naltrexona/administração & dosagem , Absorção Nasal , Permeabilidade/efeitos dos fármacos , Adulto JovemRESUMO
This paper presents the design and fabrication of a multi-layer and multi-chamber microchip system using thiol-ene 'click chemistry' aimed for drug transport studies across tissue barrier models. The fabrication process enables rapid prototyping of multi-layer microfluidic chips using different thiol-ene polymer mixtures, where porous Teflon membranes for cell monolayer growth were incorporated by masked sandwiching thiol-ene-based fluid layers. Electrodes for trans-epithelial electrical resistance (TEER) measurements were incorporated using low-melting soldering wires in combination with platinum wires, enabling parallel real-time monitoring of barrier integrity for the eight chambers. Additionally, the translucent porous Teflon membrane enabled optical monitoring of cell monolayers. The device was developed and tested with the Caco-2 intestinal model, and compared to the conventional Transwell system. Cell monolayer differentiation was assessed via in situ immunocytochemistry of tight junction and mucus proteins, P-glycoprotein 1 (P-gp) mediated efflux of Rhodamine 123, and brush border aminopeptidase activity. Monolayer tightness and relevance for drug delivery research was evaluated through permeability studies of mannitol, dextran and insulin, alone or in combination with the absorption enhancer tetradecylmaltoside (TDM). The thiol-ene-based microchip material and electrodes were highly compatible with cell growth. In fact, Caco-2 cells cultured in the device displayed differentiation, mucus production, directional transport and aminopeptidase activity within 9-10 days of cell culture, indicating robust barrier formation at a faster rate than in conventional Transwell models. The cell monolayer displayed high TEER and tightness towards hydrophilic compounds, whereas co-administration of an absorption enhancer elicited TEER-decrease and increased permeability similar to the Transwell cultures. The presented cell barrier microdevice constitutes a relevant tissue barrier model, enabling transport studies of drugs and chemicals under real-time optical and functional monitoring in eight parallel chambers, thereby increasing the throughput compared to previously reported microdevices.
Assuntos
Dextranos , Insulina , Absorção Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Dispositivos Lab-On-A-Chip , Maltose/análogos & derivados , Manitol , Técnicas Analíticas Microfluídicas , Rodamina 123 , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Células CACO-2 , Dextranos/farmacocinética , Dextranos/farmacologia , Humanos , Insulina/farmacocinética , Insulina/farmacologia , Mucosa Intestinal/citologia , Maltose/farmacocinética , Maltose/farmacologia , Manitol/farmacocinética , Manitol/farmacologia , Técnicas Analíticas Microfluídicas/instrumentação , Técnicas Analíticas Microfluídicas/métodos , Rodamina 123/farmacocinética , Rodamina 123/farmacologiaRESUMO
Although parenteral iron products have been established to medicinal use decades before, their structure and pharmacokinetic properties are not fully characterized yet. With its' second reflection paper on intravenous iron-based nano-colloidal products (EMA/CHMP/SWP/620008/2012) the European Medicine Agency provided an extensive catalogue of methods for quality, non-clinical and pharmacokinetic studies for the comparison of nano-sized iron products to an originator (EMA, 2015). For iron distribution studies, the reflection paper assumed the use of rodents. In our tests, we used a turkey fetus model to investigate time dependent tissue concentrations in pharmacological and toxicological relevant tissues liver, heart and kidney. We found turkey embryos to be a suitable alternative to rodents with high discriminatory sensitivity. Clear differences were found between equimolar doses of iron products with hydroxyethyl amylopectin, sucrose, dextrane and carboxymaltose shell. A linear dose dependency for the tissue accumulation was also demonstrated.
Assuntos
Amilopectina/análogos & derivados , Amilopectina/farmacocinética , Embrião não Mamífero/metabolismo , Compostos Férricos/farmacocinética , Ácido Glucárico/farmacocinética , Complexo Ferro-Dextran/farmacocinética , Maltose/análogos & derivados , Nanopartículas , Amilopectina/administração & dosagem , Animais , Compostos Férricos/administração & dosagem , Óxido de Ferro Sacarado , Ácido Glucárico/administração & dosagem , Complexo Ferro-Dextran/administração & dosagem , Rim/metabolismo , Fígado/metabolismo , Maltose/administração & dosagem , Maltose/farmacocinética , Modelos Animais , Miocárdio/metabolismo , Nanopartículas/administração & dosagem , Equivalência Terapêutica , TurquiaRESUMO
Iron-deficiency anemia (IDA) is the most common form of anemia. Iron replacement therapy is an effective treatment, but oral and previously available intravenous (IV) formulations in Japan have disadvantages such as side effects, immunogenic reactions, low dose per tablet/vial, and the need for continuous administration. Ferric carboxymaltose (FCM), which overcomes these limitations, is widely used as an IV iron preparation outside of Japan. In this single-center, open-label, single-dose escalation study, we investigated the pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability of FCM in Japanese subjects. Twenty-four Japanese IDA patients, diagnosed by hemoglobin, serum ferritin, and transferrin saturation, were assigned in equal groups to the 100, 500, 800, and 1000 mg iron dose arms. All subjects completed the study without important protocol deviations. Mean total serum iron concentrations showed a rapid, dose-dependent increase after FCM injection, reaching a maximum within 1 h. Mean reticulocyte counts significantly increased in all arms, suggesting improved hematopoietic function. Fourteen of 24 subjects experienced adverse events, but these were neither serious nor led to drug interruption. The PK/PD and safety profiles were similar in Japanese and European subjects. Ferric carboxymaltose is safe for administration in Japanese patients with IDA.
Assuntos
Anemia Ferropriva/tratamento farmacológico , Compostos Férricos/administração & dosagem , Compostos Férricos/farmacocinética , Maltose/análogos & derivados , Adolescente , Adulto , Anemia Ferropriva/sangue , Povo Asiático , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Hematopoese , Humanos , Infusões Intravenosas , Ferro/sangue , Masculino , Maltose/administração & dosagem , Maltose/farmacocinética , Pessoa de Meia-Idade , Contagem de Reticulócitos , Segurança , Adulto JovemRESUMO
In non-dialysis-chronic kidney disease (CKD), iron deficiency is a frequent nutritional disorder due to either the greater tendency to occult gastrointestinal bleeding or to the chronic inflammatory state resulting in a reduced intestinal iron reabsorption through an increased synthesis of hepcidin. These phenomenon are responsible for a negative iron balance that compromises erythropoiesis and contributes to the pathogenesis of anemia in CKD. Several laboratory tests are now available to allow an adequate diagnosis of iron deficiency. Among the new parameters, the percentage of hypochromic red cells (% HYPO) and the reticulocyte hemoglobin content (CHr) are now considered as the most specific markers for diagnosing iron-deficiency erythropoiesis. Unfortunately, their implementation in clinical practice is limited by the scarce availability. In non-dialyzed CKD , subjects intolerant or non-responsive to oral iron therapy, can be effectively treated with novel intravenous iron preparations, such as iron carboxymaltose, that allow a complete and rapid correction of iron deficient anemia. Furthermore, this iron compound is associated with lower rate of adverse effects since the carbohydrate shell (carboxymaltose) is more stable than gluconate and saccarate thus reducing the release of free iron in the bloodstream. Of note, the possibility of administering this drug at high doses and reduced frequency decreases the risk of infusion reactions. Finally, a substantial economic saving mainly dependent on a reduction in indirect costs represents a further advantage in the use of iron carboxymaltose in this population.
Assuntos
Anemia Ferropriva/etiologia , Deficiências de Ferro , Insuficiência Renal Crônica/complicações , Anemia Ferropriva/diagnóstico , Anemia Ferropriva/tratamento farmacológico , Anemia Ferropriva/fisiopatologia , Biomarcadores , Exame de Medula Óssea , Eritropoese , Compostos Férricos/administração & dosagem , Compostos Férricos/farmacocinética , Compostos Férricos/uso terapêutico , Ferritinas/sangue , Hemorragia Gastrointestinal/etiologia , Hematínicos/uso terapêutico , Hemoglobinas/análise , Hepcidinas/metabolismo , Humanos , Absorção Intestinal , Ferro/sangue , Ferro/farmacocinética , Maltose/análogos & derivados , Maltose/farmacocinética , Maltose/uso terapêutico , Estudos Multicêntricos como Assunto , Guias de Prática Clínica como Assunto , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/fisiopatologia , Reticulócitos/química , Transferrina/análiseRESUMO
The diagnosis and treatment of malignant melanoma by means of the formulation of active principles with dendrimeric nanoparticles is an area of great current interest. The identification and understanding of molecular mechanisms which ensure the integration of particular dendrimeric nanostructures in tumor cellular environment can provide valuable guidance in their coupling strategies with antitumor or diagnostic agents. Two structurally distinct maltose-shell modified 5th generation (G5) poly(propylene imine) (PPI) glycodendrimers fluorescently labeled, (a) with open maltose shell, cationic charged G5-PPI-OS and (b) with dense maltose shell and nearly neutral G5-PPI-DS, were tested in relation with several melanoma cell lines. We found that three melanoma cell lines internalize G5-PPI-DS structure more efficiently than non tumoral HEK297T cells. Furthermore, the internalization pathways of G5-PPI-OS and G5-PPI-DS are characteristic for each tumor cell phenotype and include more than one mechanism. As a general trend, large amounts of both G5-PPI-OS and G5-PPI-DS are internalized on cholesterol-dependent pathway in MJS primary melanoma cells and on non conventional pathways in SK28 metastatic melanoma cells. G5-PPI-OS, temporarily retained at plasma membrane in both cell lines, is internalized slower in metastatic than in primary phenotype. Unlike G5-PPI-OS, G5-PPI-DS is immediately endocytosed in both cell lines. The unconventional internalization pathway and trafficking, exclusively used by G5-PPI-DS in metastatic cells, is described at molecular level. The decay kinetics of fluorescent labeled G5-PPI-OS and G5-PPI-DS is distinct in the two cellular phenotypes. Both cationic and neutral maltose G5-PPI glycodendrimeric structures represent molecules based on which designing of new formulations for therapy or/and diagnosis of melanoma can be further developed.
Assuntos
Dendrímeros/farmacocinética , Maltose/farmacocinética , Melanoma/metabolismo , Polipropilenos/farmacocinética , Animais , Linhagem Celular Tumoral , Células Cultivadas , Dendrímeros/química , Humanos , Maltose/química , Camundongos , Polipropilenos/químicaRESUMO
OBJECTIVE: Intravenous (IV) iron has been used as a treatment to reduce Restless Legs Syndrome (RLS) symptoms, but two double-blinded trials of a frequently prescribed IV iron formulation, iron sucrose, failed to show lasting efficacy. This study evaluates efficacy and safety of a new IV iron formulation (ferric carboxymaltose, FCM) with molecular properties that may make iron more available for uptake to the brain than iron sucrose does. METHODS: In this 28-day, multi-centre, randomised, placebo-controlled trial 46 RLS patients were discontinued from all RLS treatment. Twenty-four received 500 mg FCM in two doses 5 days apart and 22 received a matching placebo. At day 28, those on placebo were given a single 1000 mg IV FCM and those not responding to initial treatment were given a third dose of 500 mg FCM. Patients were followed up for 24 weeks or until needing added RLS treatment. RESULTS: FCM significantly improved primary and secondary outcomes compared to placebo: International Restless Legs Syndrome study group severity scale (IRLS) average (SD) decrease of 8.9 (8.52) versus 4.0 (6.11), p=0.040; Clinical Global Inventory of Change (CGI-1) very much or much improved 48.3% versus 14.3%, p=0.004. Quality of life was also significantly improved. Of the 24 with initial iron treatment 45% responded and 29% remitted (IRLS ≤ 10) at day 28, and 25% continued free of other RLS medications at 24 weeks after treatment. The single 1000 mg dose on day 28 produced the same degree of treatment response as the divided dose, but the added 500 mg dose for those not responding to the initial treatment showed little benefit. There were no significant adverse events. CONCLUSIONS: IV FCM provided a safe and effective treatment for RLS that lasted for at least 24 weeks for some patients. Larger studies are needed to confirm these results.
Assuntos
Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Compostos Férricos , Maltose/análogos & derivados , Síndrome das Pernas Inquietas/tratamento farmacológico , Adulto , Idoso , Feminino , Compostos Férricos/administração & dosagem , Compostos Férricos/efeitos adversos , Compostos Férricos/farmacocinética , Ferritinas/sangue , Seguimentos , Humanos , Ferro/sangue , Masculino , Maltose/administração & dosagem , Maltose/efeitos adversos , Maltose/farmacocinética , Pessoa de Meia-Idade , Projetos Piloto , Placebos , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
An in vitro perfusion model of human placenta was used to study the transplacental passage of iron applied in the form of the drug compound ferric carboxymaltose (FCM) which had been radio-labelled with 59Fe. In four placental perfusion experiments, two simulated circuits for the maternal and fetal sides of the placenta were set up with two experimental phases each lasting 3 h. FCM was added to the maternal circuit at the beginning of each phase to a final iron concentration of 11 mM, which is at least 10 times higher than the maximal predicted level in blood after an administration of 200 mg iron as FCM. The effects of adding transferrin at a physiological concentration of 1.67 mg/ ml were also tested. The concentration profiles of 59Fe showed a 10% decrease within the first 30 min of perfusion on the maternal side. Thereafter the radioactivity levels remained unchanged. The addition of transferrin had no effect on the tissue uptake of 59Fe-FCM. No transferred iron radioactivity could be detected in the fetal circuit. Despite a loss of approximately 10% of the radio-labelled iron observed on the maternal side, only 0.5-2% of the radioactivity was detected in the placental tissue after perfusion. No free iron could be detected at the end of perfusion on the maternal side using ultrafiltration or acid precipitation methods. In addition, the production of transferrin receptor remained unchanged, with similar concentrations in placental tissue before and after perfusion. No effects of FCM on placental viability were observed in terms of energy metabolism (glucose consumption and lactate production), hormone release or placental permeability (assessed by the transfer rates of creatinine and antipyrine). However, two additional observations were made: firstly, a significant reduction in the rate of cell death compared to control conditions was observed in the presence of FCM; secondly, the integrity of the fetal capillary system was improved on the fetal side of the perfusion system. It is concluded that the iron compound FCM does not cross the placenta and may increase the integrity of placental tissue (at least under in vitro conditions), but this latter observation needs further investigation.
Assuntos
Compostos Férricos/farmacologia , Maltose/análogos & derivados , Permeabilidade/efeitos dos fármacos , Placenta/fisiologia , Artérias/efeitos dos fármacos , Artérias/fisiologia , Feminino , Compostos Férricos/farmacocinética , Humanos , Ferro/metabolismo , Radioisótopos de Ferro/análise , Maltose/farmacocinética , Maltose/farmacologia , Perfusão/métodos , Placenta/efeitos dos fármacos , Gravidez , Transferrina/farmacologia , Veias/efeitos dos fármacos , Veias/embriologia , Veias/fisiologiaRESUMO
Iron-deficiency anaemia (IDA) represents a major burden to public health worldwide. The therapeutic aim for patients with IDA is to return iron stores and haemoglobin (Hb) levels to within the normal range using supplemental iron therapy and erythropoiesis-stimulating agents. Oral and previous intravenous (i.v.) iron formulations have a number of disadvantages, including immunogenic reactions, oxidative stress, low dosages, long administration times and the requirement for a test dose. Ferric carboxymaltose (FCM, Ferinject) is a novel, next-generation i.v. iron formulation with the potential to overcome these limitations. In this single-centre, randomized, double-blind, placebo-controlled study, the pharmacokinetics (PK), pharmacodynamics (PD), safety and tolerability of single, escalating doses of FCM were investigated. Four ascending doses were investigated in a total of 24 patients with mild IDA (defined as serum ferritin < 20 microg/l and transferrin saturation [TfS] < 16%): 100 mg iron as FCM given as an i.v. bolus injection, and 500, 800 and 1000 mg iron as FCM given as an i.v. infusion over 15 min. At each dose level six patients received FCM and two received placebo. The decision to escalate to the next dose was based on evaluation of safety and tolerability data from the previous dose. The maximum duration of the study was 5 weeks from screening to final assessment. Assessments were made of PK iron-status parameters up to 168 h post-dose. Safety assessments included incidence of adverse events (AEs), clinical laboratory parameters and vital signs. PK and PD parameters were analysed using descriptive statistics. All analyses were performed on the safety population, which included all patients who received > or = 1 dose of study medication. Seventy-seven patients were screened and, of these, 32 male and female patients with pre-study Hb between 9.2 and 11.9 g/dl and serum ferritin < 20 microg/l were included in the study. Two patients had TfS > 16% (19.2% and 17.2%); both patients were considered by the investigator to be eligible for inclusion. Compared with placebo, a rapid, dose-dependent increase in total serum iron was observed across all dose groups. Mean (standard deviation) maximum total serum iron levels ranged between 36.9 (4.4) and 317.9 (42.3) microg/ml in the 100 and 1000 mg groups. Concentration-time curves of total serum iron continuously declined for up to 24 and 72 h post-dose in the 100 and 500-1000 mg groups, respectively. Non-compartmental analysis of PK parameters was truncated at 24 h (100 mg) and 72 h (500-1000 mg doses). A dose-dependent, but not dose-linear, increase in serum ferritin was seen in all treatment groups compared with placebo, with peak levels of a 23-210-fold increase above baseline occurring 48-120 h postdose. Iron-binding capacity was transiently almost fully utilized after doses of 500, 800 and 1000 mg (TfS > 95%). No meaningful changes in serum transferrin or serum transferrin receptor concentrations were observed during this study. The elimination pattern for FCM appeared to be mono-exponential; FCM was cleared from serum with a terminal halflife of approximately 7.4-12.1 h. The percentage of FCM excreted in urine was negligible (0.0005%). FCM was well tolerated; a total of 19 AEs were reported by 8/32 patients (25%), of which three were considered by the investigator to be related to FCM: nausea and vomiting (one patient [100 mg]), and headache (one patient [1000 mg]). The incidence of AEs did not increase with dose. No severe or serious AEs, or deaths occurred. FCM had no significant effect on laboratory safety parameters or vital signs. This study satisfactorily characterized the PK/PD parameters of single doses of 100, 500, 800 and 1000 mg iron as FCM. The majority of FCM was utilized or eliminated within 24 h of administration of a 100 mg dose and within 72 h of a 500-1000 mg dose. FCM was generally well tolerated across all doses in patients with mild IDA.
Assuntos
Anemia Ferropriva/tratamento farmacológico , Compostos Férricos/farmacocinética , Maltose/análogos & derivados , Adolescente , Adulto , Pressão Sanguínea/efeitos dos fármacos , Temperatura Corporal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Eletrocardiografia , Feminino , Compostos Férricos/administração & dosagem , Compostos Férricos/uso terapêutico , Frequência Cardíaca/efeitos dos fármacos , Humanos , Infusões Intravenosas , Masculino , Maltose/administração & dosagem , Maltose/farmacocinética , Maltose/uso terapêutico , Pessoa de Meia-IdadeRESUMO
This multiple-dose Phase I/II study provided pharmacodynamics and pharmacokinetics data on the therapeutic benefit of ferric carboxymaltose (FCM, Ferinject) and evaluated the safety and tolerability of this intravenous (i.v.) iron preparation. Two doses of iron as FCM were given as i.v. infusion over 15 min, 500 mg iron given once weekly for up to 4 weeks (Cohort 1) or 1000 mg iron weekly for 2 weeks (Cohort 2), in patients with a total requirement > or = 1000 mg iron (total cumulative maximum dose < or = 2000 mg iron). Adults with moderate to severe, stable iron-deficiency anaemia (IDA) (haemoglobin [Hb] < or = 11.0 g/dl, serum ferritin < 100 microg/l, transferrin saturation [TSAT] < 16%) due to a gastrointestinal (GI) disorder were included. Pharmacodynamics variables: proportion of patients achieving values within the reference range for Hb (men: 14.0-18.0 g/dl, women: 12.0-16.0 g/dl), serum ferritin (20-500 microg/l), TSAT (16-45%) and proportion of patients with an increase in Hb of at least 2.0 g/dl. Pharmacokinetics variables: total serum iron levels at time of maximum serum iron concentration during the fast elimination phase and at trough time-points. Safety assessments: the incidence of adverse events (AEs) and changes in vital signs, physical examinations, and clinical laboratory parameters. In Cohorts 1 and 2, 14/20 (70%) versus 19/26 (73%) of patients completed the study. Individual calculated iron deficits were 1000-2100 mg. The mean cumulative dose of FCM in Cohorts 1 and 2 was 1800 mg and 1563 mg iron, respectively. At baseline, patients in both cohorts had similar Hb levels (mean 8.7 g/dl in both cohorts). More than 97% of patients demonstrated a clinically meaningful increase in Hb levels (> or = 1.0 g/dl) during the study. By the week 4 follow-up visit, an increase of at least 2.0 g/dl was achieved by 15/20 (75%) and by 19/26 (73.1%) patients in Cohorts 1 and 2, respectively, and the mean increase in Hb was 3.2 g/dl in Cohort 1 and 3.3 g/dl in Cohort 2. By day 28, 3/6 (50%) patients in Cohort 1 had achieved normal Hb levels, and by the 4-week post-treatment followup visit 7/19 patients (37%) in Cohort 1 and 12/25 (48%) in Cohort 2 had reached Hb levels within the reference range. Serum ferritin levels increased rapidly at the start of treatment and remained in the reference range throughout the study; increases were greater in Cohort 2. Mean baseline TSAT values were similar in both cohorts (24.2% in Cohort 1, 20.7% in Cohort 2), and were within the reference range at the week 4 follow-up visit for 41.0 and 39.1% of the patients in Cohorts 1 and 2, respectively. The incidence of AEs occurring after the first administration of FCM (treatment-emergent AEs, TEAE) was generally low and similar in Cohorts 1 (11/20 [55.0%]) and 2 (13/26 [50.0%]). Most TEAEs were mild; only 2/ 20 patients (10.0%) in Cohort 1 and 3/26 (11.5%) in Cohort 2 had TEAEs of moderate intensity. There were no AEs of severe intensity, serious AEs, or deaths. Most AEs were considered by the investigator to be unrelated or unlikely to be related to the study medication. Since accumulation of serum iron was not observed, a dosing interval of 3-4 days (500 mg iron) or 1 week (1000 mg iron) was demonstrated to be adequate. The increase in serum ferritin and TSAT at the 4-week follow-up visit is indicative of a repletion of the iron stores. The results suggest that doses up to 1000 mg i.v. iron administered as FCM over 15 min arewell tolerated and effective in the treatment of patients with IDA due to a GI disorder.
Assuntos
Anemia Ferropriva/tratamento farmacológico , Anemia Ferropriva/etiologia , Compostos Férricos/farmacocinética , Compostos Férricos/uso terapêutico , Gastroenteropatias/complicações , Maltose/análogos & derivados , Adolescente , Adulto , Anemia Ferropriva/sangue , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Compostos Férricos/toxicidade , Ferritinas/sangue , Hemoglobinas/efeitos dos fármacos , Hemoglobinas/metabolismo , Humanos , Masculino , Maltose/farmacocinética , Maltose/uso terapêutico , Maltose/toxicidade , Pessoa de Meia-Idade , Seleção de Pacientes , Transferrina/metabolismoRESUMO
UNLABELLED: Cancer-related anemia is common and multifactorial in origin. Functional iron deficiency (FID) is now recognized as a cause of iron-restricted erythropoiesis and may be one of the major reasons for lack of response to treatment with Erythropoietic Stimulating Agents (ESAs). Numerous studies have shown that intravenous (IV), but not oral, iron therapy effectively provides sufficient iron for optimal erythropoiesis in anemic patients with chronic renal disease receiving ESA therapy. The use of IV iron has also been suggested in the cancer setting. Six recent studies have tested this assumption and are summarized in this review. Four formulations of IV iron are available in Europe, with different pharmacokinetics, iron bioavailability, and risk of acute adverse drug reactions. CONCLUSION: Limited iron stores and FID are common causes of response failure during ESA treatment in cancer patients and should be diagnosed. There is now substantial scientific support for the use of IV iron supplementation to improve response and this has been acknowledged in international and national guidelines. Prospective long-term data on the safety of IV iron in this setting are still awaited. Recommendations concerning the optimal formulation, doses, and schedule of iron supplementation to ESA treatment in cancer-related anemia are provisional awaiting data from prospective, randomized trials.
Assuntos
Anemia Ferropriva , Hematínicos/administração & dosagem , Compostos de Ferro/administração & dosagem , Neoplasias/complicações , Administração Oral , Anemia Ferropriva/tratamento farmacológico , Anemia Ferropriva/etiologia , Esquema de Medicação , Eritropoese/efeitos dos fármacos , Compostos Férricos/administração & dosagem , Compostos Férricos/efeitos adversos , Compostos Férricos/farmacocinética , Óxido de Ferro Sacarado , Compostos Ferrosos/administração & dosagem , Compostos Ferrosos/efeitos adversos , Compostos Ferrosos/farmacocinética , Ácido Glucárico , Hematínicos/efeitos adversos , Hematínicos/farmacocinética , Humanos , Infusões Intravenosas , Compostos de Ferro/efeitos adversos , Compostos de Ferro/farmacocinética , Ferro da Dieta/administração & dosagem , Ferro da Dieta/efeitos adversos , Ferro da Dieta/farmacocinética , Complexo Ferro-Dextran/administração & dosagem , Complexo Ferro-Dextran/efeitos adversos , Complexo Ferro-Dextran/farmacocinética , Maltose/administração & dosagem , Maltose/efeitos adversos , Maltose/análogos & derivados , Maltose/farmacocinética , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Maltose, a disaccharide composed of two glucose molecules, is used in a number of biological preparations as a stabilizing agent or osmolality regulator. Icodextrin, which is converted to maltose, is present in a peritoneal dialysis solution. Galactose and xylose are found in some foods, herbs, and dietary supplements; they are also used in diagnostic tests. When some blood glucose monitoring systems are used--specifically, those that use test strips containing the enzymes glucose dehydrogenase-pyrroloquinolinequinone or glucose dye oxidoreductase--in patients receiving maltose, icodextrin, galactose, or xylose, interference of blood glucose levels can occur. Maltose, icodextrin, galactose, and xylose are misinterpreted as glucose, which can result in erroneously elevated serum glucose levels. This interference can result in the administration of insulin, which may lead to hypoglycemia. In severe cases of hypoglycemia, deaths have occurred. If patients are receiving maltose, icodextrin, galactose, or xylose, clinicians must review the package inserts of all test strips to determine the type of glucose monitoring system being used and to use only those systems whose tests strips contain glucose oxidase, glucose dehydrogenase-nicotinamide adenine dinucleotide, or glucose dehydrogenase-flavin adenine dinucleotide.
Assuntos
Automonitorização da Glicemia , Glicemia/análise , Maltose/análise , Fitas Reagentes , Diabetes Mellitus , Soluções para Diálise/efeitos adversos , Rotulagem de Medicamentos , Galactose/análise , Glucanos/análise , Glucose/análise , Humanos , Icodextrina , Maltose/farmacocinética , Maltose/farmacologia , Reprodutibilidade dos Testes , Xilose/análiseRESUMO
The transport of carbohydrates by Streptococcus mutans is accomplished by the phosphoenolpyruvate-phosphotransferase system (PTS) and ATP-binding cassette (ABC) transporters. To undertake a global transcriptional analysis of all S. mutans sugar transporters simultaneously, we used a whole-genome expression microarray. Global transcription profiles of S. mutans UA159 were determined for several monosaccharides (glucose, fructose, galactose, and mannose), disaccharides (sucrose, lactose, maltose, and trehalose), a beta-glucoside (cellobiose), oligosaccharides (raffinose, stachyose, and maltotriose), and a sugar alcohol (mannitol). The results revealed that PTSs were responsible for transport of monosaccharides, disaccharides, beta-glucosides, and sugar alcohol. Six PTSs were transcribed only if a specific sugar was present in the growth medium; thus, they were regulated at the transcriptional level. These included transporters for fructose, lactose, cellobiose, and trehalose and two transporters for mannitol. Three PTSs were repressed under all conditions tested. Interestingly, five PTSs were always highly expressed regardless of the sugar source used, presumably suggesting their availability for immediate uptake of most common dietary sugars (glucose, fructose, maltose, and sucrose). The ABC transporters were found to be specific for oligosaccharides, raffinose, stachyose, and isomaltosaccharides. Compared to the PTSs, the ABC transporters showed higher transcription under several tested conditions, suggesting that they might be transporting multiple substrates.
Assuntos
Perfilação da Expressão Gênica , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Sistema Fosfotransferase de Açúcar do Fosfoenolpiruvato/genética , Streptococcus mutans/genética , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Transportadores de Cassetes de Ligação de ATP/fisiologia , Transporte Biológico/genética , Carboidratos/farmacocinética , Celobiose/metabolismo , Celobiose/farmacocinética , Frutose/metabolismo , Frutose/farmacocinética , Galactose/metabolismo , Galactose/farmacocinética , Regulação Bacteriana da Expressão Gênica , Glucose/metabolismo , Glucose/farmacocinética , Lactose/metabolismo , Lactose/farmacocinética , Maltose/metabolismo , Maltose/farmacocinética , Manose/metabolismo , Manose/farmacocinética , Oligossacarídeos/metabolismo , Oligossacarídeos/farmacocinética , Sistema Fosfotransferase de Açúcar do Fosfoenolpiruvato/metabolismo , Sistema Fosfotransferase de Açúcar do Fosfoenolpiruvato/fisiologia , Rafinose/metabolismo , Rafinose/farmacocinética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Streptococcus mutans/metabolismo , Sacarose/metabolismo , Sacarose/farmacocinética , Transcrição Gênica , Trissacarídeos/metabolismo , Trissacarídeos/farmacocinéticaRESUMO
The hyperthermophilic archaeon Sulfolobus solfataricus contains an unusual large number of sugar binding proteins that are synthesized as precursors with a class III signal peptide. Such signal peptides are commonly used to direct archaeal flagellin subunits or bacterial (pseudo)pilins into extracellular macromolecular surface appendages. Likewise, S. solfataricus binding proteins have been suggested to assemble in higher ordered surface structures as well, tentatively termed the bindosome. Here we show that S. solfataricus contains a specific system that is needed for the functional surface localization of sugar binding proteins. This system, encoded by the bas (bindosome assembly system) operon, is composed of five proteins: basABC, three homologues of so-called bacterial (pseudo)pilins; BasE, a cytoplasmic ATPase; and BasF, an integral membrane protein. Deletion of either the three (pseudo)pilin genes or the basEF genes resulted in a severe defect of the cells to grow on substrates which are transported by sugar binding proteins containing class III signal peptides, while growth on glucose and maltose was restored when the corresponding genes were reintroduced in these cells. Concomitantly, DeltabasABC and DeltabasEF cells were severely impaired in glucose uptake even though the sugar binding proteins were normally secreted across the cytoplasmic membrane. These data underline the hypothesis that the bas operon is involved in the functional localization of sugar binding proteins at the cell surface of S. solfataricus. In contrast to surface structure assembly systems of Gram-negative bacteria, the bas operon seems to resemble an ancestral simplified form of these machineries.
Assuntos
Proteínas de Transporte/metabolismo , Sinais Direcionadores de Proteínas , Sulfolobus solfataricus/metabolismo , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Transportadores de Cassetes de Ligação de ATP/fisiologia , Arabinose/metabolismo , Arabinose/farmacocinética , Southern Blotting , Western Blotting , Carboidratos/farmacocinética , Radioisótopos de Carbono , Proteínas de Transporte/genética , Proteínas de Transporte/fisiologia , Eletroforese em Gel de Poliacrilamida , Deleção de Genes , Teste de Complementação Genética , Glucose/metabolismo , Glucose/farmacocinética , Maltose/metabolismo , Maltose/farmacocinética , Modelos Biológicos , Mutação , Óperon/genética , Ligação Proteica , Sulfolobus solfataricus/genéticaRESUMO
Tetradecylmaltoside (TDM) was evaluated as a potential gastrointestinal absorption enhancer for low molecular weight heparin (LMWH), enoxaparin. The in vitro efficacy of TDM (0.0625, 0.125 and 0.25% w/v) in enhancing transport of 3H-enoxaparin or 14C-mannitol was investigated in human colonic epithelial cells (C2BBel). Metabolic stability of the drug was determined in C2BBel cell extracts. Transepithelial electrical resistance (TEER) was measured before and after exposure of the cells to TDM. Enoxaparin was further administered to anesthetized Sprague-Dawley rats in oral formulations in the absence or presence of increasing concentrations of TDM and drug absorption was monitored by measuring anti-factor Xa activity in rat blood. In vitro permeability study shows that apparent permeability (Papp) of 3H-enoxaparin across C2BBe1 cells was increased by 8-fold in the presence of 0.0625% TDM compared to untreated cells. The movement of 14C-mannitol across the cell monolayer followed a similar pattern in the presence of increasing concentrations of TDM. No degradation or depolymerization of enoxaparin was observed when the drug was incubated in C2BBel cell extract. TEER was reversible after 60 min exposure of the cells to 0.0625% (w/v) TDM. Oral formulations of enoxaparin containing TDM administered to anesthetized rats significantly and rapidly increased gastrointestinal absorption as compared to those animals which received enoxaparin plus saline (p < 0.05). In the presence of 0.125% TDM in the formulation, enoxaparin oral bioavailability was increased by 2.5-fold compared to the saline control group. Overall, the data on the effect of TDM on the in vitro and in vivo intestinal permeation of enoxaparin suggest that TDM may represent a promising excipient for use in oral LMWH formulations.