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Quantitative prediction of pharmacokinetic properties of drugs in humans: Recent advance in in vitro models to predict the impact of efflux transporters in the small intestine and blood-brain barrier.
Hashimoto, Y, Michiba, K, Maeda, K, Kusuhara, H
Journal of pharmacological sciences. 2022;(1):142-151
Abstract
Efflux transport systems are essential to suppress the absorption of xenobiotics from the intestinal lumen and protect the critical tissues at the blood-tissue barriers, such as the blood-brain barrier. The function of drug efflux transport is dominated by various transporters. Accumulated clinical evidences have revealed that genetic variations of the transporters, together with coadministered drugs, affect the expression and/or function of transporters and subsequently the pharmacokinetics of substrate drugs. Thus, in the preclinical stage of drug development, quantitative prediction of the impact of efflux transporters as well as that of uptake transporters and metabolic enzymes on the pharmacokinetics of drugs in humans has been performed using various in vitro experimental tools. Various kinds of human-derived cell systems can be applied to the precise prediction of drug transport in humans. Mathematical modeling consisting of each intrinsic metabolic or transport process enables us to understand the disposition of drugs both at the organ level and at the level of the whole body by integrating a variety of experimental results into model parameters. This review focuses on the role of efflux transporters in the intestinal absorption and brain distribution of drugs, in addition to recent advances in predictive tools and methodologies.
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2.
Metabolic liver disease - what's in a name?
Herman, MA
Nature reviews. Endocrinology. 2021;(2):79-80
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3.
Small and Large Intestine (II): Inflammatory Bowel Disease, Short Bowel Syndrome, and Malignant Tumors of the Digestive Tract.
Ber, Y, García-Lopez, S, Gargallo-Puyuelo, CJ, Gomollón, F
Nutrients. 2021;(7)
Abstract
The small intestine is key in the digestion and absorption of macro and micronutrients. The large intestine is essential for the absorption of water, to allow adequate defecation, and to harbor intestinal microbiota, for which their nutritional role is as important as it is unknown. This article will describe the causes and consequences of malnutrition in patients with inflammatory bowel diseases, the importance of screening and replacement of micronutrient deficits, and the main indications for enteral and parenteral nutrition in these patients. We will also discuss the causes of short bowel syndrome, a complex entity due to anatomical or functional loss of part of the small bowel, which can cause insufficient absorption of liquid, electrolytes, and nutrients and lead to complex management. Finally, we will review the causes, consequences, and management of malnutrition in patients with malignant and benign digestive tumors, including neuroendocrine tumors (present not only in the intestine but also in the pancreas).
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4.
Small Intestinal Bacterial Overgrowth as Potential Therapeutic Target in Parkinson's Disease.
Dănău, A, Dumitrescu, L, Lefter, A, Tulbă, D, Popescu, BO
International journal of molecular sciences. 2021;(21)
Abstract
Increasing evidence suggests that the gut microbiota and the brain are closely connected via the so-called gut-brain axis. Small intestinal bacterial overgrowth (SIBO) is a gut dysbiosis in which the small intestine is abundantly colonized by bacteria that are typically found in the colon. Though not a disease, it may result in intestinal symptoms caused by the accumulation of microbial gases in the intestine. Intestinal inflammation, malabsorption and vitamin imbalances may also develop. SIBO can be eradicated by one or several courses of antibiotics but reappears if the predisposing condition persists. Parkinson's disease (PD) is a common neurodegenerative proteinopathy for which disease modifying interventions are not available. Sporadic forms may start in the gut years before the development of clinical features. Increased gastrointestinal transit time is present in most people with PD early during the course of the disease, predisposing to gut dysbiosis, including SIBO. The role that gut dysbiosis may play in the etiopathogenesis of PD is not fully understood yet. Here, we discuss the possibility that SIBO could contribute to the progression of PD, by promoting or preventing neurodegeneration, thus being a potential target for treatments aiming at slowing down the progression of PD. The direct symptomatic impact of SIBO and its impact on symptomatic medication are also briefly discussed.
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5.
Small Intestinal Bacterial Overgrowth: How to Diagnose and Treat (and Then Treat Again).
Ginnebaugh, B, Chey, WD, Saad, R
Gastroenterology clinics of North America. 2020;(3):571-587
Abstract
Small intestinal bacterial overgrowth (SIBO) is a condition with presentation that can vary from asymptomatic to steatorrhea and malnutrition. Small bowel aspiration and culture is the current gold standard of diagnosis; however, this is invasive and is not without risk to the patient. Breath testing is a noninvasive and less expensive alternative method; however, it lacks diagnostic sensitivity and specificity. Novel diagnostic methods being studied include gas-sensing capsules. The mainstay of treatment is antibiotics; alternative therapies include herbal medications, dietary modifications, and prokinetic agents. Further investigation into less invasive and less harmful diagnostic methods and treatment options is warranted.
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6.
A Guide to Human Zinc Absorption: General Overview and Recent Advances of In Vitro Intestinal Models.
Maares, M, Haase, H
Nutrients. 2020;(3)
Abstract
Zinc absorption in the small intestine is one of the main mechanisms regulating the systemic homeostasis of this essential trace element. This review summarizes the key aspects of human zinc homeostasis and distribution. In particular, current knowledge on human intestinal zinc absorption and the influence of diet-derived factors on bioaccessibility and bioavailability as well as intrinsic luminal and basolateral factors with an impact on zinc uptake are discussed. Their investigation is increasingly performed using in vitro cellular intestinal models, which are continually being refined and keep gaining importance for studying zinc uptake and transport via the human intestinal epithelium. The vast majority of these models is based on the human intestinal cell line Caco-2 in combination with other relevant components of the intestinal epithelium, such as mucin-secreting goblet cells and in vitro digestion models, and applying improved compositions of apical and basolateral media to mimic the in vivo situation as closely as possible. Particular emphasis is placed on summarizing previous applications as well as key results of these models, comparing their results to data obtained in humans, and discussing their advantages and limitations.
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7.
Radiation enteritis: Diagnostic and therapeutic issues.
Loge, L, Florescu, C, Alves, A, Menahem, B
Journal of visceral surgery. 2020;(6):475-485
Abstract
Abdominal pelvic radiation therapy can induce acute or chronic lesions in the small bowel wall, called radiation enteritis. Treatment of acute radiation enteritis is essentially symptomatic; symptoms regress when radiation is discontinued. Conversely, late toxicity can occur up to 30 years after discontinuation of radiation therapy, posing diagnostic problems. Approximately one out of five patients treated by radiation therapy will present clinical signs of radiation enteritis, including obstruction, malabsorption, malnutrition and/or other complications. Management should be multidisciplinary, centered mainly on correction of malnutrition. Surgery is indicated in case of complications (i.e., abscess, perforation, fistula) and/or resistance to medical treatment; intestinal resection should be preferred over internal bypass. The main risk in case of iterative resections is the short bowel syndrome and the need for definitive nutritional assistance.
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8.
Small bowel transplant: state-of-the-art vascular and nonvascular imaging.
Panick, CEP, Partovi, S, Liu, PS, Kapoor, BS
Abdominal radiology (New York). 2020;(3):601-614
Abstract
BACKGROUND Small bowel transplant (SBT) is a surgical procedure that may be used in patients with pathology resulting in severe intestinal failure resistant to conventional forms of surgical and nonsurgical treatment. Intestinal failure is defined as the failure of enterocytes to absorb sufficient macronutrients, water, and/or electrolytes to sustain homeostasis and/or promote growth. With the advancement of surgical techniques and advancements in perioperative transplant management, SBT has become an increasingly common treatment for intestinal failure, with survival rates for SBT comparable to those for other solid organ transplants. MATERIALS AND METHODS This review provides background on SBT, its variations, and the associated preoperative and postoperative imaging studies with regard to surgical planning and anticipated complications. RESULTS AND CONCLUSIONS With the increasing use of SBT, radiologists will be expected to be familiar with the diagnostic studies and available endovascular interventions associated with this procedure.
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9.
Management of Small Bowel Villous Atrophy in Patients Seronegative for Celiac Disease.
Jansson-Knodell, CL, Murray, JA, Rubio-Tapia, A
The American journal of gastroenterology. 2020;(4):492-497
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10.
Small Bowel Dysmotility, Pseudoobstruction, and Functional Correlation with Histopathology: Lessons Learned.
Gonzalez, Z, McCallum, R
Current gastroenterology reports. 2020;(3):14
Abstract
PURPOSE OF REVIEW Small bowel dysmotility is a broad heterogeneous term that encompasses a wide range of gastrointestinal disorders resulting from abnormal gut motility. Chronic intestinal pseudo-obstruction (CIPO) is a severe, rare, and complex small bowel motility disorder at the extreme end of this spectrum. It is characterized by failure of the intestinal tract to propel contents, which results in signs and symptoms of bowel obstruction albeit in the absence of any obstructive lesion(s). In this article, we discuss up-to-date diagnostic techniques, management options, and histopathological findings in CIPO. RECENT FINDINGS We will emphasize the latest diagnostic methodologies and therapeutic options as well as enteric histopathologic abnormalities in patients with CIPO. CIPO continues to be a clinical challenge. Several novel pharmacological agents hold promise including gastrointestinal hormone agonists and prokinetics. Furthermore, histopathologic findings may help guide therapy and provide further prognostic significance. At present, nutritional support, symptom management, and avoidance of long-term complications are the mainstay of treatment in CIPO.