RESUMEN
A high volume of fluid can strongly reduce a drug's concentration in urine. Therefore, to detect diluted samples, the concentration of creatinine in urine is determined during testing drugs of abuse. If the concentration is below 20 mg creatinine/dl urine, the urine sample is usually rejected for drug testing. It should be examined whether creatine or creatinine ingestion can mask urine dilution by increasing the creatinine concentration. A total of 18 subjects drank 1.3 L of water and 0.2 L of orange juice on each of the three testing days: (1) without creatine, (2) with 20 g of creatine, and (3) with 20 g of creatine following incubation for 4 days in orange juice at room temperature; an acidic environment should promote conversion of creatine to creatinine. The lowest creatinine concentrations in urine were observed on average 2 h after fluid intake. At that time, ingestion of fluid without creatine, with creatine, and with creatine(ine)-orange juice mixture resulted in mean values of 11.6, 22.5, and 28.3 mg creatinine/dl urine, respectively. It can be concluded that ingestion of creatine or creatinine can increase the concentration of creatinine in urine and thus mask dilution of a sample. The conversion of creatine in orange juice further increases availability of creatinine as it is obvious from urine creatinine concentration. Therefore, creatine ingestion during drug testing will give rise to negative results due to matrix adulteration. In a case of suspected creatine supplementation, the creatine content of the sample should be determined in addition to creatinine.
Asunto(s)
Creatina/administración & dosificación , Creatinina/orina , Jugos de Frutas y Vegetales , Detección de Abuso de Sustancias/métodos , Adulto , Citrus sinensis , Creatina/análisis , Creatinina/administración & dosificación , Creatinina/análisis , Femenino , Humanos , Masculino , Persona de Mediana Edad , Agua/administración & dosificación , Adulto JovenRESUMEN
Abstract The aim of present study was to explore protective and curative effects of Malve neglecta on kidneys. In silco study with network pharmacology was performed to find out potential target organs, genes and cellular cell lines which confirmed kidneys as target organ of phyto-constituents present in Malva neglecta extract. Gentamicin (40 mg/kg, i.p) was given to induce renal toxicity. Prophylactic study was performed with 300-, 600- and 900 mg/kg doses to find out nephro-protective and -curative effects and curative potential was evaluated at 900 mg/kg dose. Renal function biomarkers, blood urea, BUN, serum creatinine and uric acid, and oxidative stress measuring biomarkers, SOD, CAT, GSH and MDA levels in kidney homogenate were quantified at the end of study. Treatment groups showed decrease in blood urea, BUN, serum creatinine and uric acid levels dose dependently and curative group also showed decline in these biomarkers. SOD, CAT, GSH levels were increased and MDA level decreased in treatment groups significantly as compared to toxic control which revealed the role of oxidative stress in renal damage and anti-oxidant power of MN. Data suggested that use of MN along with drugs causing renal toxicity may prove beneficial due to its nephro- protective and curative effects.
Asunto(s)
Animales , Masculino , Ratas , Preparaciones Farmacéuticas , Malva/metabolismo , Neglecta , Terapéutica/instrumentación , Gentamicinas , Malvaceae/clasificación , Creatinina/administración & dosificación , Dosificación/métodos , Antioxidantes/efectos adversosRESUMEN
Cyclocreatine (LUM-001) was evaluated for chronic toxicity (23 weeks) in beagle dogs to support clinical development in patients with creatine transporter deficiency (CTD) disorder. Deionized water (vehicle control) or cyclocreatine was administered by oral gavage twice daily (12 ± 1 h apart) at 20, 40 and 75 mg/kg/dose followed by a recovery period. Due to severe toxicity, the study was terminated earlier than the planned 39 weeks of dosing. Animals in the 20, 40 and 75 mg/kg/dose groups completed 160, 106, and 55 days of dosing, respectively, followed by 30, 55 and 106 days of a recovery period, respectively. Three (25%), 7 (58%), and 7 (58%) animals were euthanized and/or found dead in the 40, 80, and 150 mg/kg/day dose groups, respectively. Clinical signs observed were inappetence, frequent emesis, stool abnormalities, weight loss, lethargy and respiratory distress. Histopathological evaluation revealed congestion, edema, cellular infiltration, fibrin, and/or hemorrhage in the lungs of all dose groups. Additionally, animals in all cyclocreatine treatment groups had perinuclear cytoplasmic vacuoles in the heart, kidneys, skeletal and smooth muscles. After the recovery period, the vacuoles were still observed in the cardiac and renal tissues. Cyclocreatine was absorbed rapidly with mean Tmax within 1 to 2 h and half-life ranged between 2.17 and 2.79 h on Day 1, however, on the final day of dosing, it ranged between 5.80 and 8.77 h (males) and 10.3 to 13.1 h (females). To conclude, in this study the lungs, kidneys, heart, skeletal and smooth muscles were identified as the target organs of cyclocreatine toxicity in beagle dogs.
Asunto(s)
Creatinina/análogos & derivados , Pruebas de Toxicidad Crónica , Administración Oral , Animales , Creatinina/administración & dosificación , Creatinina/farmacocinética , Creatinina/toxicidad , Perros , Relación Dosis-Respuesta a Droga , Femenino , Semivida , Riñón/efectos de los fármacos , Riñón/patología , Pulmón/efectos de los fármacos , Pulmón/patología , Pulmón/fisiopatología , Enfermedades Pulmonares/inducido químicamente , Enfermedades Pulmonares/patología , Enfermedades Pulmonares/fisiopatología , Masculino , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/patología , Músculo Liso/efectos de los fármacos , Músculo Liso/patología , Miocardio/patología , Nivel sin Efectos Adversos Observados , Medición de Riesgo , Factores de Tiempo , Toxicocinética , Vacuolas/efectos de los fármacos , Vacuolas/patologíaRESUMEN
ABSTRACT Introduction: Currently there is a lack of clarity around the use of Fourier transform infrared (FT-IR) spectroscopy to analyze the effect of creatine (Cr) supplementation on the secondary structures of skeletal muscle tissue protein subjected to exercise. Objective: The objective of this study was to evaluate the spectral characteristics of the tibialis anterior muscle in rats subjected to exercise in a pool and to Cr supplementation. Methods: Experiment 1. First, an experiment was conducted to ensure that FT-IR would be able to detect change in the secondary structures of skeletal muscle tissue protein in the group of sedentary rats (SED) and in the group of rats that received creatine supplementation (CRE). Experiment 2. Next, the effect of physical exercise on the spectral characteristics of muscle tissue, especially when compared to the groups without exercise practice, was examined. Results: It was possible to verify that the peaks centered on 1658 cm-1 (amide I) and 1546 cm-1 (amide II) are characteristic spectra and indicated as markers of protein content. Conclusion: Thus, FT-IR spectroscopy proved to be able to monitor changes in secondary structures of skeletal muscle protein in both animals that received supplements and in those subjected to exercise and both cases reconciled. Furthermore, the FT-IR technique proved to be a viable method for the nondestructive evaluation of skeletal muscle protein structures. Level of evidence II, Investigation of treatment results.
RESUMEN Introducción: Actualmente, no hay claridad en lo que se refiere al uso de la técnica de espectroscopia de Infrarrojo con transformada de Fourier (FT-IR) para análisis del efecto de la suplementación de creatina (Cr) sobre las estructuras secundarias de la proteína del tejido muscular esquelético sometido a ejercicio. Objetivo: El objetivo de este estudio fue evaluar las características espectrales del músculo tibial anterior de ratones sometidos a ejercicio en piscina y a la suplementación con Cr. Métodos: Experimento 1. En primer lugar, fue realizada una experiencia para asegurar que la FT-IR sería capaz de detectar la variación en las estructuras secundarias de la proteína del tejido muscular esquelético en el grupo de ratones sedentarios (SED) y el grupo de ratones que sólo recibieron suplemento de creatina (CRE). Experimento 2. A continuación, fue examinado el efecto del ejercicio físico sobre las características espectrales del tejido muscular, especialmente cuando comparado con los grupos sin práctica de ejercicio. Resultados: Fue posible verificar que los picos centrados en 1658 cm−1 (amida I) y 1546 cm−1 (amida II) son espectros característicos e indicados como marcadores del tenor proteico. Conclusión: Siendo así, la técnica de espectroscopia de FT-IR mostró ser capaz de monitorizar las variaciones en las estructuras secundarias de la proteína del tejido muscular esquelético, tanto en animales que recibieron suplementos, como en los que fueron sometidos a ejercicio y ambos casos conciliados. Además, la técnica FT-IR probó ser un método viable para la evaluación no destructiva de las estructuras proteicas en el músculo esquelético. Nivel de evidencia II, Investigación de los resultados del tratamiento.
RESUMO Introdução: Atualmente, não há clareza no que diz respeito ao uso da técnica de espectroscopia de infravermelho com transformada de Fourier (FT-IR) para análise do efeito da suplementação de creatina (Cr) sobre as estruturas secundárias da proteína do tecido muscular esquelético submetido a exercício. Objetivo: O objetivo deste estudo foi avaliar as características espectrais do músculo tibial anterior de ratos submetidos a exercício em piscina e à suplementação com Cr. Métodos: Experimento 1. Em primeiro lugar, foi realizada uma experiência para assegurar que a FT-IR seria capaz de detectar a variação nas estruturas secundárias da proteína do tecido muscular esquelético no grupo de ratos sedentários (SED) e no grupo de ratos que só receberam suplemento de creatina (CRE). Experimento 2. Em seguida, foi examinado o efeito do exercício físico sobre as características espectrais do tecido muscular, especialmente quando comparado com os grupos sem prática de exercício. Resultados: Foi possível verificar que os picos centrados em 1658 cm−1(amida I) e 1546 cm−1(amida II) são espectros característicos e indicados como marcadores do teor proteico. Conclusão: Assim sendo, a técnica de espectroscopia de FT-IR mostrou ser capaz de monitorar as variações nas estruturas secundárias da proteína do tecido muscular esquelético tanto em animais que receberam suplementos, quanto nos que foram submetidos a exercício e ambos os casos conciliados. Além disso, a técnica FT-IR provou ser um método viável para a avaliação não destrutiva de estruturas proteicas no músculo esquelético. Nível de evidência II, Investigação dos resultados do tratamento.
Asunto(s)
Animales , Masculino , Ratas , Suplementos Dietéticos , Creatinina/administración & dosificación , Músculos , Músculos/efectos de los fármacos , Músculos/química , Condicionamiento Físico Animal , Natación , Ratas Wistar , Espectroscopía Infrarroja por Transformada de FourierRESUMEN
Cross-species studies have identified an evolutionarily conserved role for serotonin in flexible behavior including reversal learning. The aim of the current study was to investigate the contribution of serotonin within the orbitofrontal cortex (OFC) and medial prefrontal cortex (mPFC) to visual discrimination and reversal learning. Male Lister Hooded rats were trained to discriminate between a rewarded (A+) and a nonrewarded (B-) visual stimulus to receive sucrose rewards in touchscreen operant chambers. Serotonin was depleted using surgical infusions of 5,7-dihydroxytryptamine (5,7-DHT), either globally by intracebroventricular (i.c.v.) infusions or locally by microinfusions into the OFC or mPFC. Rats that received i.c.v. infusions of 5,7-DHT before initial training were significantly impaired during both visual discrimination and subsequent reversal learning during which the stimulus-reward contingencies were changed (A- vs. B+). Local serotonin depletion from the OFC impaired reversal learning without affecting initial discrimination. After mPFC depletion, rats were unimpaired during reversal learning but slower to respond at the stimuli during all the stages; the mPFC group was also slower to learn during discrimination than the OFC group. These findings extend our understanding of serotonin in cognitive flexibility by revealing differential effects within two subregions of the prefrontal cortex in visual discrimination and reversal learning.
Asunto(s)
Aprendizaje Discriminativo/fisiología , Corteza Prefrontal/metabolismo , Aprendizaje Inverso/fisiología , Neuronas Serotoninérgicas/metabolismo , Serotonina/metabolismo , Percepción Visual/fisiología , 5,6-Dihidroxitriptamina/administración & dosificación , 5,6-Dihidroxitriptamina/análogos & derivados , 5,6-Dihidroxitriptamina/toxicidad , Animales , Creatinina/administración & dosificación , Creatinina/análogos & derivados , Creatinina/toxicidad , Aprendizaje Discriminativo/efectos de los fármacos , Infusiones Intraventriculares , Masculino , Estimulación Luminosa/métodos , Corteza Prefrontal/efectos de los fármacos , Ratas , Aprendizaje Inverso/efectos de los fármacos , Neuronas Serotoninérgicas/efectos de los fármacos , Percepción Visual/efectos de los fármacosRESUMEN
Cyclocreatine (LUM-001), a creatine analog, was evaluated for its nonclinical toxicity in Sprague Dawley (SD) rats. Deionized water as a vehicle control article or cyclocreatine was administered by oral gavage twice daily (approximately 12 ± 1 h apart) at 30, 100 and 300 mg/kg/dose levels in rats up to 26 weeks followed by a 28-day recovery period. Due to an increased incidence of seizures, the 600 mg/kg/day dose group males were dosed only for 16-weeks followed by a 14-week recovery period. Thirteen males and four females from 600 mg/kg/day dose group were sacrificed at interim on Day 113 to study plausible brain lesions and not due to moribundity. There was a dose dependent increase in the number of seizure incidences in ≥60 mg/kg/day males and 600 mg/kg/day females. Microscopically, higher incidences of vacuoles in the brain at 600 mg/kg/day in both sexes, thyroid follicular atrophy and follicular cell hypertrophy at ≥200 mg/kg/day in males and 600 mg/kg/day in females, and seminiferous tubular degeneration and/or interstitial edema in testes at ≥200 mg/kg/day were observed. Mean plasma half-life of cyclocreatine was between 3.5 and 6.5 h. In conclusion, chronic administration of cyclocreatine by oral gavage in Sprague Dawley rats induced the seizures and microscopic lesions in the brain, testes and thyroid. Based on the results of this study the highest tested dose of 600 mg/kg/day (mean Cmax of 151.5 µg/mL; AUC0-24 of 1970 h*µg/mL) was considered the maximum tolerated dose (MTD) in SD rats.
Asunto(s)
Encéfalo/efectos de los fármacos , Creatinina/análogos & derivados , Pruebas de Toxicidad Crónica/métodos , Administración Oral , Animales , Encéfalo/metabolismo , Encéfalo/patología , Creatina/análogos & derivados , Creatina/sangre , Creatina/toxicidad , Creatinina/administración & dosificación , Creatinina/sangre , Creatinina/toxicidad , Femenino , Masculino , Tamaño de los Órganos/efectos de los fármacos , Tamaño de los Órganos/fisiología , Ratas , Ratas Sprague-Dawley , Testículo/efectos de los fármacos , Testículo/metabolismo , Testículo/patología , Glándula Tiroides/efectos de los fármacos , Glándula Tiroides/metabolismo , Glándula Tiroides/patología , Factores de TiempoRESUMEN
Early diagnosis of kidney diseases in avian species is limited. Endogenous markers currently used in avian practice are not sensitive enough to identify early kidney failure. Consequently, alternative markers should be evaluated. To be able to evaluate these alternative markers, an accurate marker to estimate the GFR should be validated. This study determined the GFR, measured as clearance of exogenous creatinine and exo-iohexol, in six different bird species, i.e. broiler chickens, laying chickens, turkeys, Muscovy ducks, pigeons and African grey parrots (4â/4â). To be able to compare the six bird species, normalization to bodyweight (BW) of the GFR was performed, after a good correlation between BW and kidney weight was demonstrated (R² = 0.9836). Clearance of exo-iohexol normalized to BW (mL/min/kg) was determined in all bird species, i.e. 3.09 in broiler chickens; 2.57 in laying chickens; 1.94 in turkeys; 1.29 in pigeons; 2.60 in ducks and 1.11 in parrots. However, these results differed significantly with the clearance of exogenous creatinine: 8.41 in broiler chickens; 9.33 in laying chickens; 5.62 in turkeys; 14.97 in pigeons; 17.59 in ducks and 25.56 in parrots 25.56. Iohexol is preferred to measure the GFR, since it is not prone to tubular reabsorption nor secretion.
Asunto(s)
Aves/fisiología , Creatinina/sangre , Tasa de Filtración Glomerular/fisiología , Pruebas de Función Renal/veterinaria , Animales , Biomarcadores/sangre , Enfermedades de las Aves/sangre , Enfermedades de las Aves/diagnóstico , Enfermedades de las Aves/fisiopatología , Aves/sangre , Pollos , Columbidae , Creatinina/administración & dosificación , Creatinina/farmacocinética , Patos , Diagnóstico Precoz , Femenino , Yohexol/administración & dosificación , Yohexol/farmacocinética , Enfermedades Renales/diagnóstico , Enfermedades Renales/fisiopatología , Enfermedades Renales/veterinaria , Pruebas de Función Renal/métodos , Masculino , Loros , Especificidad de la Especie , PavosRESUMEN
BACKGROUND: Kidney function reduces with age, increasing the risk of harm from increased blood levels of many medicines. Although estimated glomerular filtration rate (eGFR) is reported for prescribing decisions in those aged ≥65 years, creatinine clearance (Cockcroft-Gault) gives a more accurate estimate of kidney function. AIM: To explore the extent of prescribing outside recommendations for people aged ≥65 years with reduced kidney function in primary care and to assess the impact of using eGFR instead of creatinine clearance to calculate kidney function. DESIGN AND SETTING: A cross-sectional survey of anonymised prescribing data in people aged ≥65 years from all 80 general practices (70 900 patients) in a north of England former primary care trust. METHOD: The prevalence of prescribing outside recommendations was analysed for eight exemplar drugs. Data were collected for age, sex, actual weight, serum creatinine, and eGFR. Kidney function as creatinine clearance (Cockcroft-Gault) was calculated using actual body weight and estimated ideal body weight. RESULTS: Kidney function was too low for recommended prescribing in 4-40% of people aged ≥65 years, and in 24-80% of people aged ≥85 years despite more than 90% of patients having recent recorded kidney function results. Using eGFR overestimated kidney function for 3-28% of those aged ≥65 years, and for 13-58% of those aged ≥85 years. Increased age predicted higher odds of having a kidney function estimate too low for recommended prescribing of the study drugs. CONCLUSION: Prescribing recommendations when kidney function is reduced are not applied for many people aged ≥65 years in primary care. Using eGFR considerably overestimates kidney function for prescribing and, therefore, creatinine clearance (Cockcroft-Gault) should be assessed when prescribing for these people. Interventions are needed to aid prescribers when kidney function is reduced.
Asunto(s)
Creatinina/administración & dosificación , Medicina General , Pautas de la Práctica en Medicina , Insuficiencia Renal/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Creatinina/sangre , Estudios Transversales , Inglaterra , Femenino , Tasa de Filtración Glomerular , Humanos , Pruebas de Función Renal , Masculino , Pautas de la Práctica en Medicina/normas , Pautas de la Práctica en Medicina/estadística & datos numéricos , Insuficiencia Renal/sangre , Insuficiencia Renal/fisiopatologíaRESUMEN
The CK/PCr-system, with creatine (Cr) as an energy precursor, plays a crucial role in cellular physiology. In the kidney, as in other organs and cells with high and fluctuating energy requirements, energy-charged phospho-creatine (PCr) acts as an immediate high-energy source and energy buffer, and as an intracellular energy transport vehicle. A maximally filled total Cr (Cr plus PCr) pool is a prerequisite for optimal functioning of the body and its organs, and health. Skeletal- and cardiac muscles of dialysis patients with chronic kidney disease (CKD) are depleted of Cr in parallel with the duration of dialysis. The accompanying accumulation of cellular damage seen in CKD patients lead to a deterioration of musculo-skeletal and neurological functioning and poor quality of life (QOL). Therefore, to counteract Cr depletion, it is proposed to supplement CKD patients with Cr. The anticipated benefits include previously documented improvements in the musculo-skeletal system, brain and peripheral nervous system, as well as improvements in the common comorbidities of CKD patients (see below). Thus, with a relatively simple, safe and inexpensive Cr supplementation marked improvements in quality of life (QOL) and life span are likely reached. To avoid Cr and fluid overload by oral Cr administration, we propose intradialytic Cr supplementation, whereby a relatively small amount of Cr is added to the large volume of dialysis solution to a final concentration of 1-10mM. From there, Cr enters the patient's circulation by back diffusion during dialysis. Because of the high affinity of the Cr transporter (CRT) for Cr affinity for Cr (Vmax of CRT for Cr=20-40µM Cr), Cr is actively transported from the blood stream into the target cells and organs, including skeletal and cardiac muscle, brain, proximal tubules of kidney epithelial cells, neurons, and leukocytes and erythrocytes, which all express CRT and depend on the CK/PCr system. By this intradialytic strategy, only as much Cr is taken up by the body as is needed to fill the tissue Cr pools and no excess Cr has to be excreted, as is the case with oral Cr. Because aqueous solutions of Cr are not very stable, Cr must be added immediately before dialysis either as solid Cr powder or from a frozen Cr stock solution to the dialysate, or alternatively, Cr could become an additional component of a novel dry dialysate mixture in a cartridge device.
Asunto(s)
Creatinina/administración & dosificación , Diálisis Renal/métodos , Insuficiencia Renal/terapia , Administración Oral , Animales , Apoptosis , Densidad Ósea , Creatina , Creatinina/metabolismo , Citosol/metabolismo , Femenino , Tasa de Filtración Glomerular , Humanos , Mucosa Intestinal/metabolismo , Isquemia , Riñón/metabolismo , Trasplante de Riñón , Masculino , Proteínas de Transporte de Membrana/metabolismo , Mitocondrias/metabolismo , Estrés Oxidativo , Calidad de Vida , Insuficiencia Renal/psicologíaRESUMEN
Creatine plays an important role in muscle energy metabolism. Postactivation potentiation (PAP) is a phenomenon that can acutely increase muscle power, but it is an individualized process that is influenced by muscle fatigue. This study examined the effects of creatine supplementation on explosive performance and the optimal individual PAP time during a set of complex training bouts. Thirty explosive athletes performed tests of back squat for one repetition maximum (1RM) strength and complex training bouts for determining the individual optimal timing of PAP, height and peak power of a counter movement jump before and after the supplementation. Subjects were assigned to a creatine or placebo group and then consumed 20 g of creatine or carboxymethyl cellulose per day for six days. After the supplementation, the 1RM strength in the creatine group significantly increased (p < 0.05). The optimal individual PAP time in the creatine group was also significant earlier than the pre-supplementation and post-supplementation of the placebo group (p < 0.05). There was no significant difference in jump performance between the groups. This study demonstrates that creatine supplementation improves maximal muscle strength and the optimal individual PAP time of complex training but has no effect on explosive performance.
Asunto(s)
Creatinina/administración & dosificación , Suplementos Dietéticos , Metabolismo Energético/efectos de los fármacos , Tolerancia al Ejercicio/efectos de los fármacos , Contracción Muscular/efectos de los fármacos , Músculo Esquelético/efectos de los fármacos , Sustancias para Mejorar el Rendimiento/administración & dosificación , Creatinina/metabolismo , Método Doble Ciego , Humanos , Masculino , Fatiga Muscular/efectos de los fármacos , Fuerza Muscular/efectos de los fármacos , Músculo Esquelético/metabolismo , Sustancias para Mejorar el Rendimiento/metabolismo , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
Major depressive disorder (MDD) often begins during adolescence and is projected to become the leading cause of global disease burden by the year 2030. Yet, approximately 40 % of depressed adolescents fail to respond to standard antidepressant treatment with a selective serotonin reuptake inhibitor (SSRI). Converging evidence suggests that depression is related to brain mitochondrial dysfunction. Our previous studies of MDD in adult and adolescent females suggest that augmentation of SSRI pharmacotherapy with creatine monohydrate (CM) may improve MDD outcomes. Neuroimaging with phosphorus-31 magnetic resonance spectroscopy ((31)P-MRS) can measure the high-energy phosphorus metabolites in vivo that reflect mitochondrial function. These include phosphocreatine (PCr), a substrate for the creatine kinase reaction that produces adenosine triphosphate. As part of the National Institute of Mental Health's experimental medicine initiative, we conducted a placebo-controlled dose-ranging study of adjunctive CM for adolescent females with SSRI-resistant MDD. Participants were randomized to receive placebo or CM 2, 4 or 10 g daily for 8 weeks. Pre- and post-treatment (31)P-MRS scans were used to measure frontal lobe PCr, to assess CM's target engagement with cerebral energy metabolism. Mean frontal lobe PCr increased by 4.6, 4.1 and 9.1 % in the 2, 4 and 10 g groups, respectively; in the placebo group, PCr fell by 0.7 %. There was no group difference in adverse events, weight gain or serum creatinine. Regression analysis of PCr and depression scores across the entire sample showed that frontal lobe PCr was inversely correlated with depression scores (p = 0.02). These results suggest that CM achieves target engagement with brain bioenergetics and that the target is correlated with a clinical signal. Further study of CM as a treatment for adolescent females with SSRI-resistant MDD is warranted.
Asunto(s)
Encéfalo/metabolismo , Creatinina/administración & dosificación , Trastorno Depresivo Mayor/tratamiento farmacológico , Resistencia a Medicamentos/efectos de los fármacos , Adolescente , Adulto , Encéfalo/diagnóstico por imagen , Trastorno Depresivo Mayor/diagnóstico por imagen , Trastorno Depresivo Mayor/metabolismo , Metabolismo Energético/efectos de los fármacos , Femenino , Humanos , Neuroimagen , Inhibidores Selectivos de la Recaptación de Serotonina/administración & dosificaciónRESUMEN
Hepatocyte transplantation has been explored as a therapeutic alternative to liver transplantation, but a means to monitor the success of the procedure is lacking. Published findings support the use of in vivo (31)P MRSI of creatine kinase (CK)-expressing hepatocytes to monitor proliferation of implanted hepatocytes. Phosphocreatine tissue level depends upon creatine (Cr) input to the CK enzyme reaction, but Cr measurement by (1)H MRS suffers from low signal-to-noise ratio (SNR). We examine the possibility of using the Cr analog cyclocreatine (CCr, a substrate for CK), which is quickly phosphorylated to phosphocyclocreatine (PCCr), as a higher SNR alternative to Cr. (1)H MRS and (31)P MRSI were employed to measure the effect of incremental supplementation of CCr upon PCCr, γ-ATP, pH and Pi /ATP in the liver of transgenic mice expressing the BB isoform of CK (CKBB) in hepatocytes. Water supplementation with 0.1% CCr led to a peak total PCCr level of 17.15 ± 1.07 mmol/kg wet weight by 6 weeks, while adding 1.0% CCr led to a stable PCCr liver level of 18.12 ± 3.91 mmol/kg by the fourth day of feeding. PCCr was positively correlated with CCr, and ATP concentration and pH declined with increasing PCCr. Feeding with 1% CCr in water induced an apparent saturated level of PCCr, suggesting that CCr quantization may not be necessary for quantifying expression of CK in mice. These findings support the possibility of using (31)P MRS to noninvasively monitor hepatocyte transplant success with CK-expressing hepatocytes.
Asunto(s)
Adenosina Trifosfato/metabolismo , Creatina Quinasa/metabolismo , Creatinina/análogos & derivados , Hígado/efectos de los fármacos , Hígado/metabolismo , Espectroscopía de Protones por Resonancia Magnética/métodos , Administración Oral , Animales , Creatina Quinasa/genética , Creatinina/administración & dosificación , Estudios de Factibilidad , Hepatocitos/metabolismo , Ratones , Ratones Transgénicos , Isótopos de Fósforo/farmacocinéticaRESUMEN
Serum creatinine is routinely used to monitor renal function in transplant recipients. External factors including diet, exercise and hydration status can also influence serum creatinine concentration on a day-to-day basis. We describe a case of a patient whose serum creatinine increased from 128 to 171 µmol/L after ingestion of creatinine-rich (3098 µmol/L) soup. A renal biopsy was performed but revealed no cause for the rise in creatinine and by the next day, serum creatinine had returned to baseline. We conducted two experiments to examine the effect of soup ingestion by healthy volunteers. We measured the creatinine concentration of various store-bought stock preparations and found creatinine concentrations less than one-quarter of that contained in our patient's homemade soup. A creatinine-rich soup (4334 µmol/L) was ingested by six healthy volunteers age 33 (± 6.5) years with baseline normal serum creatinine 68 (± 14) µmol/L. Mean (standard deviation) serum creatinine increased to 77 (± 11) µmol/L 4 hours after soup ingestion (P = 0.0015, paired t-test). Mean (standard deviation) creatinine clearance, extrapolated from the 4 hour urine collection following soup ingestion, was high (267 ± 198 mL/min) exhibiting a supra-normal creatinine clearance. The rate of serum creatinine rise was lower in volunteers compared with the transplant patient, consistent with the concept of renal functional reserve. Our case highlights the importance of taking dietary changes into account when interpreting serum creatinine as a measure of allograft function.
Asunto(s)
Creatinina/administración & dosificación , Creatinina/sangre , Dieta/efectos adversos , Trasplante de Riñón , Adulto , Aloinjertos , Animales , Biomarcadores/sangre , Biomarcadores/orina , Huesos , Pollos , Culinaria , Creatinina/orina , Femenino , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Carne Roja , Reproducibilidad de los Resultados , Resultado del Tratamiento , Regulación hacia ArribaRESUMEN
The diagnostic evaluation of the glomerular filtration rate by urinary clearance has significant practical limitations in birds because urine is excreted together with feces. Thus, pharmacokinetic modeling of an exogenous plasma creatinine clearance could be useful for assessing renal creatinine excretion in birds. For this study, creatinine (50 mg/kg) was administered to 2 groups of 15 pigeons (Columba livia) each; in one group by the intravenous (IV) route and in the second by the intramuscular (IM) route. The time series of the plasma creatinine concentrations were analyzed by pharmacokinetic models. Body mass-specific creatinine excretion was determined for IV and IM administration to be between 6.30 and 6.44 mL/min per kg, respectively. Body surface area-specific creatinine clearance, which is related to the metabolic rate, was calculated between 0.506 and 0.523 mL/min per dm2, respectively. The results showed that IV as well as IM administration can be used for assessing renal creatinine excretion in pigeons. For practical reasons, IM administration is recommended, with the use of the Bateman function to calculate creatinine elimination.
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Columbidae/sangre , Creatinina/farmacocinética , Riñón/fisiología , Animales , Área Bajo la Curva , Creatinina/administración & dosificación , Creatinina/sangre , Inyecciones Intramusculares , Inyecciones IntravenosasRESUMEN
BACKGROUND/OBJECTIVES: Elevated plasma homocysteine has been linked to reduced mobility and muscle functioning in the elderly. The relation of methylenetetrahydrofolate reductase (MTHFR) 677C-->T polymorphism with these associations has not yet been studied. This study aimed to investigate (1) the association of plasma homocysteine and the MTHFR 677C-->T polymorphism with muscle mass, handgrip strength, physical performance and postural sway; (2) the interaction between plasma homocysteine and the MTHFR 677C-->T polymorphism. SUBJECTS/METHODS: Baseline data from the B-PROOF study (n=2919, mean age=74.1±6.5) were used. Muscle mass was measured using dual X-ray absorptiometry, handgrip strength with a handheld dynamometer, and physical performance with walking-, chair stand- and balance tests. Postural sway was assessed on a force platform. The data were analyzed using regression analyses with plasma homocysteine levels in quartiles. RESULTS: There was a significant inverse association between plasma homocysteine and handgrip strength (quartile 4: regression coefficient B=-1.14, 95% confidence interval (CI)=-1.96; -0.32) and physical performance score (quartile 3: B=-0.53, 95% CI=-0.95; -0.10 and quartile 4: -0.94; 95% CI=-1.40; -0.48) in women only, independent of serum vitamin B12 and folic acid. No association was observed between the MTHFR 677C-->T polymorphism and the outcomes. High plasma homocysteine in the 677CC and 677CT genotypes, but not in the 677TT genotype, was associated with lower physical performance. CONCLUSIONS: Elevated plasma homocysteine concentrations are associated with reduced physical performance and muscle strength in older women. There is an urgent need for randomized controlled trials to examine whether lowering homocysteine levels might delay physical decline.
Asunto(s)
Homocisteína/sangre , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Actividad Motora , Músculo Esquelético/fisiología , Equilibrio Postural , Absorciometría de Fotón , Anciano , Anciano de 80 o más Años , Composición Corporal , Creatinina/administración & dosificación , Creatinina/sangre , Suplementos Dietéticos , Método Doble Ciego , Femenino , Ácido Fólico/sangre , Genotipo , Fuerza de la Mano , Humanos , Modelos Lineales , Masculino , Metilenotetrahidrofolato Reductasa (NADPH2)/metabolismo , Polimorfismo de Nucleótido Simple , Resultado del Tratamiento , Vitamina B 12/administración & dosificación , Vitamina B 12/sangreRESUMEN
We have previously reported that maternal creatine supplementation protects the neonate from hypoxic injury. Here, we investigated whether maternal creatine supplementation altered expression of the creatine synthesis enzymes (arginine:glycine amidinotransferase [AGAT], guanidinoaceteate methyltransferase [GAMT]) and the creatine transporter (solute carrier family 6 [neurotransmitter transporter, creatine] member 8: SLC6A8) in the term offspring. Pregnant spiny mice were fed a 5% creatine monohydrate diet from midgestation (day 20) to term (39 days). Placentas and neonatal kidney, liver, heart, and brain collected at 24 hours of age underwent quantitative polymerase chain reaction and Western blot analysis. Maternal creatine had no effect on the expression of AGAT and GAMT in neonatal kidney and liver, but mRNA expression of AGAT in brain tissues was significantly decreased in both male and female neonates born to mothers who were fed the creatine diet. SLC6A8 expression was not affected by maternal dietary creatine loading in any tissues. Maternal dietary creatine supplementation from midgestation in the spiny mouse did not alter the capacity for creatine synthesis or transport.
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Fenómenos Fisiológicos Nutricionales de los Animales , Creatinina/administración & dosificación , Creatinina/metabolismo , Suplementos Dietéticos , Fenómenos Fisiologicos de la Nutrición Prenatal , Amidinotransferasas/genética , Amidinotransferasas/metabolismo , Animales , Animales Recién Nacidos , Encéfalo/metabolismo , Femenino , Edad Gestacional , Guanidinoacetato N-Metiltransferasa/genética , Guanidinoacetato N-Metiltransferasa/metabolismo , Riñón/metabolismo , Hígado/metabolismo , Masculino , Proteínas de Transporte de Membrana/genética , Proteínas de Transporte de Membrana/metabolismo , Murinae , Miocardio/metabolismo , Placenta/metabolismo , Embarazo , ARN Mensajero/metabolismoRESUMEN
To elucidate the role of serotonin in the onset of puberty, the effects of both systemic and in-ovarian bursa administration of serotonin on the neuroendocrine mechanism that modulates the onset of puberty, follicular development and first ovulation were evaluated. Two experiments were carried out. For the first, 25 or 37.5 mg kg⻹ of bodyweight of serotonin creatinine sulfate was administered by a subcutaneous route to 30-day-old female rats. In the second experiment, serotonin creatinine sulfate was administered directly into the ovarian bursa of 34-day-old female rats. Systemic administration of 25 or 37.5 mg kg⻹ of serotonin creatinine sulfate induced a delay in the ages of vaginal opening and first vaginal oestrus, a decrease in the number of ovulating animals, and serum concentrations of FSH, LH, oestradiol and progesterone. An increase in the number of Class 3 (>500 µm) and atretic follicles was observed in the ovaries of these animals. The administration of serotonin creatinine sulfate in the ovarian bursa did not modify the onset of puberty and ovulation, but a reduced serum concentration of oestradiol was observed. Our results suggest that serotonin acts on the components of the hypothalamus-hypophysis-ovary axis by modulating follicular development, ovarian functions and the onset of puberty.
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Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Oogénesis/efectos de los fármacos , Folículo Ovárico/metabolismo , Ovulación/efectos de los fármacos , Agonistas de Receptores de Serotonina/administración & dosificación , Serotonina/administración & dosificación , Maduración Sexual/efectos de los fármacos , Animales , Creatinina/administración & dosificación , Relación Dosis-Respuesta a Droga , Combinación de Medicamentos , Estradiol/sangre , Estradiol/metabolismo , Femenino , Hormona Folículo Estimulante/sangre , Hormona Folículo Estimulante/metabolismo , Sistema Hipotálamo-Hipofisario/crecimiento & desarrollo , Sistema Hipotálamo-Hipofisario/metabolismo , Inyecciones Subcutáneas , Hormona Luteinizante/sangre , Hormona Luteinizante/metabolismo , Sistemas Neurosecretores/efectos de los fármacos , Folículo Ovárico/citología , Folículo Ovárico/crecimiento & desarrollo , Progesterona/sangre , Progesterona/metabolismo , Ratas , Ratas Endogámicas , Serotonina/farmacología , Agonistas de Receptores de Serotonina/farmacología , Vagina/efectos de los fármacos , Vagina/crecimiento & desarrolloRESUMEN
SCOPE: Aim of this study was to investigate urinary excretion and metabolism of procyanidins a group of secondary plant metabolites with many beneficial health effects described in literature. METHODS AND RESULTS: To investigate the metabolism of procyanidins in the absence of flavan-3-ols, centrifugal partition chromatography was used for their reduction in a grape seed extract to a level of almost zero. After administration of the monomer reduced grape seed extract (mredGSE) containing procyanidins B1, B2, B3, B4, C1 to pigs flavan-3-ols, their methyl derivatives, dimeric and trimeric procyanidins were determined in urine by high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS). Maximal concentrations of procyanidins 6 h after administration vary from 5 to 30 ng/mg creatinine. Total excretion of flavan-3-ols and their methyl derivatives indicates an increasing trend for pigs given mredGSE in comparison to pigs of the control group. Flavan-3-ols were conjugated and methylated to a great extent in comparison to dimeric and trimeric procyanidins. In the case of low molecular weight metabolites, an increasing trend was observed for hippuric acid, not for phenolic acids. CONCLUSIONS: Ratios of total excretion of procyanidins to administrated amounts between 0.004% (C1) and 0.019% (B4) suggest a poor urinary excretion by pigs. A transfer of these results to humans is possible due to their similar gastrointestinal tract.
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Extracto de Semillas de Uva/farmacocinética , Extracto de Semillas de Uva/orina , Proantocianidinas/farmacocinética , Proantocianidinas/orina , Porcinos/metabolismo , Animales , Cromatografía Líquida de Alta Presión , Cromatografía Liquida , Creatinina/administración & dosificación , Flavonoides/farmacología , Espectrometría de Masas en TándemRESUMEN
Significant differences in homocysteine levels in the urine of autistic children are observed. We hypothesized that vitamin supplementation might reduce the level of urinary homocysteine. To rationalize such a hypothesis, analyses were performed using the gas chromatography/mass spectrometry method. The homocysteine level in the urine of autistic children was measured twice: (1) before vitamin supplementation (group C, 30 autistic children) and (2) after supplementation, with either folic acid and vitamins B(6) and B(12) (group A1, 24 autistic children) or vitamins B(6) and B(12) alone (group A2, 6 autistic children). The homocysteine level in the urine of autistic children before vitamin supplementation was 2.41 ± 1.10 mmol/mol creatinine (mean ± SD difference). After treatment, the homocysteine level was reduced to 1.13 ± 0.44 and 1.33 ± 0.39 mmol/mol creatinine for A1 and A2 groups, respectively. The intake of vitamins B(6) and B(12), together with folic acid, was found to be more effective in lowering the levels of urinary homocysteine than the intake of vitamins B(6) and B(12) alone. Our findings may lead to the recommendation of including vitamins B(6) and B(12) together with folic acid supplementation in the diets of children with autism.
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Trastorno Autístico/dietoterapia , Suplementos Dietéticos , Ácido Fólico/administración & dosificación , Homocisteína/orina , Vitamina B 12/administración & dosificación , Vitamina B 6/administración & dosificación , Niño , Preescolar , Creatinina/administración & dosificación , Femenino , Cromatografía de Gases y Espectrometría de Masas , Humanos , MasculinoRESUMEN
OBJECTIVES: This study aims to evaluate the sorption by montmorillonite of creatinine and the accelerating effect of montmorillonite on creatinine excretion from the intestine. METHODS: The sorption of montmorillonite was observed in vitro. Also, rat intestinal tract and blood vessels were perfused circularly with perfusate with or without creatinine, respectively, to study the promotion of creatinine diffusion from the blood vessel to the intestine and the inhibition of creatinine absorption in the intestinal tract. The effect of decreasing the serum concentration of creatinine was studied in an acute hypercreatininaemia mouse model. The concentration of creatinine was determined by the basic picric acid method. KEY FINDINGS: Montmorillonite adsorbed creatinine markedly in the simulated intestinal solution in a concentration-dependent manner. The sorption-time curve of montmorillonite with creatinine showed that the sorption was fast. The adsorption rate reached a maximum in 10 min. The pH of the solution influenced the sorption, the rate of which was higher at a low pH than at a high pH. Creatinine could diffuse from the blood vessel to the intestine and was reabsorbed in the intestine. Montmorillonite promoted the diffusion and inhibited the absorption. Montmorillonite decreased the serum creatinine level of hypercreatininaemia mice prepared by injecting creatinine intraperitoneally. CONCLUSIONS: Montmorillonite adsorbs creatinine and accelerates its excretion from the intestine.