Acute Body Weight Loss Research Articles

Impact of acute fat mobilisation on the pharmacokinetics of the highly fat distributed compound TAK-357, investigated by physiologically based pharmacokinetic (PBPK) modeling and simulation.

In a dog toxicokinetic study, an unusual plasma concentration increase of the highly lipophilic compound TAK-357 was observed 2weeks after termination of a 2-week repeated dosing in one dog with acute body weight loss. The present study investigates the cause of this increase. A physiologically based pharmacokinetic (PBPK) model was constructed using the rat and dog pharmacokinetic data. Using the constructed model, the TAK-357 concentration profile in the case of body weight change was simulated. The PBPK model-derived simulation suggested that redistribution from adipose tissues to plasma due to a loss of body fat caused the observed concentration increase of TAK-357 in dog plasma. The analysis demonstrates that the disposition of a highly lipophilic and fat-distributed compound can be affected by acute changes in adipose tissue mass. PBPK modeling and simulation proved to be efficient tools for the quantitative hypothesis testing of apparently atypical PK phenomena resulting from acute physiological changes.

Abstract 495: Mouse Model of Mesenteric Ischemia Secondary to Vascular Calcification and Atherosclerosis

Objective: Atherosclerosis is a leading cause of chronic mesenteric ischemia (CMI), defined as intestinal hypoperfusion resulting from stenosis of mesenteric arteries. Symptoms of CMI range from non-specific abdominal pain and weight loss to aversion of food resulting in cachexia. In this study we aim to define intestinal ischemia and its effects on gastrointestinal structure and function in an in vivo model of atherosclerosis. Hypothesis: Overexpression of tissue-nonspecific alkaline phosphatase (TNAP) under conditions of hypercholesterolemia in a mouse model will lead to atherosclerosis causing intestinal ischemia. Methods and Results: We have previously established that endothelial TNAP overexpression (eTNAP) results in calcification of medium-sized arteries including mesenteric. In this study eTNAP was combined with a point mutation in the low-density lipoprotein receptor ( ldlr ^WHC). When fed an atherogenic diet (Paigen’s diet, starting at 8 weeks of age), WHC-eTNAP mice developed acute body weight loss (>15% from baseline), whereas WHC mice continued to gain weight. Examination of the mesenteries of WHC-eTNAP demonstrated eccentric vascular remodeling and stiffening, as well as calcification of atherosclerotic plaques (n=4). Mesenteric arteries of WHC were not affected (n=3). WHC-eTNAP (n=2) mice developed extensive atherosclerosis of submucosal arterioles in the colon where most vessels were narrowed or occluded. Examination of the small intestine in WHC-eTNAP mice showed structurally distressed villi accompanied with an increase in goblet cells and fragmentation of the epithelial layer possibly reflecting cell death. The colon demonstrated loss of goblet cells and signs of denuding of the epithelium. Conclusion: Atherosclerosis induced by overexpression of TNAP causes occlusion of mesenteric arteries as well as structural pathology in the small and large intestine

Abstract T P223: Post-stroke Body Weight Loss Predicts Acute Stroke Outcome In Mice

Background and Purpose: Longitudinal imaging studies in stroke demonstrated that infarct development is a dynamic process and it matures over several days, even weeks depending on the severity of stroke. However, due to high cost and multiple exposure of anesthesia associated with repeated imaging, infarct volume has been typically measured at a fixed time point in preclinical studies, which prevent further assessment of behaviors during stroke recovery. In identifying a non-invasive physiological parameter that predicts the extent of stroke-induced brain injury, the study investigated whether acute body weight loss predicts the extent of brain injury and swelling. Methods: C57 male mice (10-12 wk old, 25-30 gr) were subjected to the proximal middle cerebral artery (MCA) occlusion for 30 min. Body weight was recorded daily. Infarct volume corrected with swelling (IVInd) and percent hemispheric swelling (%SW) were determined at 1, 3 and 7d after MCAO. In a retrospective study, we analyzed correlations between 3d %body weight reduction (%BWred) and stroke outcomes (IVInd & %SW) in C57 male animals that were subjected to MCAO by 3 different individuals over 8 years (n=91-96). Results: Stroke induced acute BW loss (%BWred; 1d, 88.9±3.3; 3d, 84.5±8.6; 5d, 86.8±10.6; 7d, 88.9±8.9). Correlation analyses in the post-ischemic time points showed IVind and %SW were significantly correlated with only at 3d BW reduction, but not 1d and 7d (Fig.1). A retrospective analysis in C57 mice also showed a significant correlation between 3d %BWred and IVInd & %SW (Fig.2). Conclusions: The study showed that acute post-stroke BWred is a simple and suitable index to predict the extent of stroke injury in C57 mice. Whether the prediction can be generalized across different strains and in comorbid conditions warrant further investigation.

A case report of Löfgren's syndrome (a variant of sarcoidosis) with atypical manifestations in a Taiwan Chinese man

A 28-year-old Chinese man presented with refractory ocular redness in the bilateral eyes. His symptoms co-existed with dysphasia and acute body weight loss. Excisional biopsy of the conjunctiva and hilar lymph nodes was performed and Löfgren's syndrome was confirmed. The patient was treated with systemic steroid and symptoms gradually subsided over the 2-year follow-up period. Ocular redness and dysphagia with acute body weight loss are atypical symptoms of Löfgren's syndrome. Careful survey and prompt treatment is necessary.

Urine specific gravity as a diagnostic tool for dehydration in children

Background Using clinical judgment to diagnose dehydration can be highly subjective. To diagnose dehydration, it would be ideal to have an accurate, inexpensive, objective and easy-to-perform diagnostic tool. In cases of dehydration, plasma osmolality rises, causing an increase in antidiuretic hormone (ADH) secretion. The increased ADH reduces urine production and increases urine osmolality. Previous studies have show that urine osmolality correlates well to urine specific gravity. We investigated if urine specific gravity can be a reliable and objective detennination of dehydration status.Objective To assess the accuracy of using urine specific gravity as a diagnostic tool to determine dehydration status of children with diarrhea.Methods We conducted the study in the pediatric ward of Sardjito Hospital from September 2009 to December 2009. Using a refractometer we measured urine specific gravity from patients with diarrhea. This measurement was then compared to a standard of acute body weight loss, with dehydration defined as weight loss of 5% or more. The cut-off value for defining dehydration using specific gravity measurements was detennined by a receiver-operator curve (ROC).Results Out of 61 pediatric patients who were recruited in this study, 18 (30%) had dehydration as defined by a body weight loss of 5% or more. Based on the ROC, we determined the cut off value for urine specific gravity to be 1.022. Using this value, urine specific gravity was 72% sensitive (95% CI 52 to 93), and 84% specific (95% CI 73 to 95) in determining dehydration status.Conclusion Urine specific gravity is less accurate than clinical judgment in determining dehydration status in children with diarrhea.

A case showing an association between type 1 diabetes mellitus and Kabuki syndrome

The case of a 31-year-old female suffering from type 1 diabetes mellitus (DM) and Kabuki syndrome is presented. The patient was diagnosed as having impaired glucose tolerance (IGT) at age 18; secondary amenorrhea occurred at age 20, following acute body weight loss. Extensive examination revealed the patient to have a slowly progressive form of type 1 DM and, based on the physical findings, including her facial features, she was diagnosed as also having congenital Kabuki syndrome. Since then, this patient has experienced several episodes of diabetic ketoacidosis, all of which were brought about by prolonged bronchial infection. Although it is perhaps reasonable at present to consider this case to represent a chance association, further clinical investigations will be carried out to clarify whether or not Kabuki syndrome and type 1 DM have any common pathogenic features.

Interleukin-4 deficiency promotes gallstone formation

Feeding interleukin-4 (IL-4) deficient C57BL/6 LDL receptor (LDLr)−/− mice a modified diet to investigate the role of this cytokine in cholesterol metabolism led to an unexpected phenotype. IL-4−/−→ LDLr−/− mice had enlarged gallbladders and an increased mortality that was preceded by acute body weight loss. To determine if IL-4 deficiency accounted for these findings, C57BL/6 IL-4+/+ and IL-4−/− mice were fed either a normal or modified diet. IL-4 deficiency did not alter bile composition or cause liver toxicity in mice fed a fat-enriched diet. Following 8 weeks of feeding a fat-enriched diet, no gallstones were detected in IL-4+/+ mice, and only 20% had cholesterol crystals. In contrast, IL-4−/− mice had a 100% incidence of gallstones and cholesterol crystals. IL-4−/− deficiency also increased serum concentrations of bilirubin following feeding a fat-enriched diet. Therefore, these studies revealed an unexpected finding that IL-4 deficiency predisposes to gallstone formation.—King, V. L., S. J. Szilvassy, and A. Daugherty. Interleukin-4 deficiency promotes gallstone formation. J. Lipid Res. 2002. 43: 768–771.

Induction of ovarian cystic follicles in sheep

Cystic follicles are a significant cause of infertility in women, dairy cattle and sheep. Sheep were used as a model to identify factors that may elicit formation of cystic follicles. Insulin resistance and elevated LH activity were tested in overweight ewes because of associations among these factors and the formation of cystic follicles. Sheep were synchronized using a progesterone-releasing pessary and insulin resistance was induced during the synchronization period through administration of bovine somatotropin. Following removal of pessaries follicular growth was stimulated by treatment with eCG or eCG and hCG (PG-600). Follicular growth was monitored via daily transrectal ultrasonography and blood samples were collected for hormonal analyses. Six of 18 ewes had a subnormal or absent preovulatory gonadotropin surge and developed cystic follicles. Neither insulin resistance nor elevated LH activity were associated with formation of cystic follicles. Ewes that developed cystic follicles were heavier (93 ± 4 kg) than ewes that ovulated (81 ± 3 kg; P = 0.02). Furthermore, following pessary removal and initiation of daily ultrasonography, ewes that developed cystic follicles lost body weight (−3 ± 1%), while ovulatory ewes continued to gain body weight (1 ± 1%; P = 0.005). It is speculated that in heavy ewes metabolic factors associated with acute body weight loss inhibit the positive feedback of estradiol and thereby suppress the preovulatory gonadotropin surge leading to formation of cystic follicles.

Suppression of the drug-induced morphine withdrawal syndrome by cyproheptadine.

In rats treated with gradually increasing amounts of morphine hydrochloride until they tolerated fatal doses, levallorphan precipitated acute body weight loss and elicited a variety of other typical withdrawal symptoms. Cyproheptadine markedly reduced this b.w. loss and abolished the drug-induced withdrawal syndrome. Fenfluramine also suppressed the major signs of the levallorphan-induced morphine withdrawal; however the combination of the three drugs proved to be very toxic. Since both agents interfere with different hypothalamic feeding mechanisms these results are accordant with the hypothesis of Kerr and Pozuelo (1971) that morphine dependence and tolerance are due to a functional disorganization of the hypothalamic centers concerned wit the regulation of food intake.