sirolimus and Weight-Gain

Weight gain is a known complication of corticosteroid maintenance therapy. The purpose of the present study was to compare patterns of weight gain under chronic corticosteroid therapy (CCST) with that observed under early (i.e., within 7 days posttransplant) corticosteroid withdrawal (CSWD) in renal-transplant recipients.. Renal-transplant recipients who underwent early CSWD under four prospective, institutional review board-approved clinical trials were compared with a historic control group of patients receiving maintenance CCST.. One hundred sixty-nine patients with early CSWD were compared with 132 patients who received CCST. Mean population weight gain was significantly higher in CCST patients at 3, 6, and 12 months posttransplant. Race influenced weight gain because white CSWD patients demonstrated greater reductions in weight gain compared with African-American patients. Sex also influenced weight gain: women demonstrated a greater benefit from CSWD than did men. Corticosteroid rejection therapy in CSWD patients completely restored weight gain because these patients showed weight gains similar to the CCST group. Finally, pretransplant body mass index (BMI) also influenced weight gain because patients who were overweight (BMI 25-30) or obese (BMI>30) demonstrated a greater reduction in weight gain with CSWD than did patients of normal weight (BMI<25).. Early CSWD minimizes weight gain in renal-transplant recipients. Women, whites, and patients with high pretransplant BMI had greater reductions in weight gain with early CSWD.

Topics: Adrenal Cortex Hormones; Body Mass Index; Body Weight; Drug Administration Schedule; Drug Therapy, Combination; Follow-Up Studies; Graft Rejection; Histocompatibility Testing; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Sirolimus; Time Factors; Weight Gain

Given the increasing prevalence of and severity of complications associated with obesity, there is great need for treatments resulting in prolonged weight loss. Long-term maintenance of weight loss requires sustained changes in food-intake and energy-expenditure strategies, which are unfortunately often taxing, resulting in a return to predieting weight. Therefore, drug therapies may facilitate greater adherence to a restricted diet and prolong weight loss. One such drug is rapamycin (RAP), a mechanistic target of rapamycin (mTOR) inhibitor. Here, we show that a single injection of RAP dampens the hyperphagic response in calorically restricted rats when they are returned to free feed immediately or 10 days after injection. Moreover, we demonstrate that a single injection of RAP given to calorically restricted rats prevents body-weight regain when animals are returned to free feed either immediately or 10 days after injection. Furthermore, we extend our previous findings that RAP does not produce malaise or illness and show that RAP does not produce any behavioral deficits that may inhibit an animal from eating. Thus, we suggest that mTOR may be a useful target in obesity research, given that its inhibition may decrease the hyperphagic response following caloric restriction. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Topics: Affect; Animals; Caloric Restriction; Eating; Hyperphagia; Male; Rats, Sprague-Dawley; Sirolimus; Weight Gain

Identifying regulatory mechanisms that influence inflammation in metabolic tissues is critical for developing novel metabolic disease treatments. Here, we investigated the role of microRNA-146a (miR-146a) during diet-induced obesity in mice. miR-146a is reduced in obese and type 2 diabetic patients and our results reveal that miR-146a-/- mice fed a high-fat diet (HFD) have exaggerated weight gain, increased adiposity, hepatosteatosis, and dysregulated blood glucose levels compared to wild-type controls. Pro-inflammatory genes and NF-κB activation increase in miR-146a-/- mice, indicating a role for this miRNA in regulating inflammatory pathways. RNA-sequencing of adipose tissue macrophages demonstrated a role for miR-146a in regulating both inflammation and cellular metabolism, including the mTOR pathway, during obesity. Further, we demonstrate that miR-146a regulates inflammation, cellular respiration and glycolysis in macrophages through a mechanism involving its direct target Traf6. Finally, we found that administration of rapamycin, an inhibitor of mTOR, was able to rescue the obesity phenotype in miR-146a-/- mice. Altogether, our study provides evidence that miR-146a represses inflammation and diet-induced obesity and regulates metabolic processes at the cellular and organismal levels, demonstrating how the combination of diet and miRNA genetics influences obesity and diabetic phenotypes.

Topics: Animals; Blood Glucose; Diet, High-Fat; Disease Models, Animal; Female; Gene Expression; Humans; Hyperglycemia; Inflammation; Insulin; Intra-Abdominal Fat; Macrophages; Male; Metabolic Diseases; Mice; Mice, Inbred C57BL; Mice, Knockout; MicroRNAs; NF-kappa B; Obesity; Proto-Oncogene Proteins c-akt; Sirolimus; TOR Serine-Threonine Kinases; Weight Gain

Topics: Animals; Blood Glucose; Body Composition; Body Weight; Cardiomyopathies; Cardiotonic Agents; Diabetes Mellitus, Type 2; Diet; Disease Models, Animal; Echocardiography; Female; Insulin; Insulin Resistance; Longevity; Male; Mice; Mice, Inbred C57BL; Sirolimus; Weight Gain

Topics: Adaptor Proteins, Signal Transducing; Adolescent; Adult; Child; Chronic Disease; Diarrhea; Female; Genetic Predisposition to Disease; Humans; Immunologic Deficiency Syndromes; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Phenotype; Recurrence; Sirolimus; Treatment Outcome; Weight Gain; Young Adult

Growing evidence implicates the dentate gyrus in temporal lobe epilepsy (TLE). Dentate granule cells limit the amount of excitatory signaling through the hippocampus and exhibit striking neuroplastic changes that may impair this function during epileptogenesis. Furthermore, aberrant integration of newly-generated granule cells underlies the majority of dentate restructuring. Recently, attention has focused on the mammalian target of rapamycin (mTOR) signaling pathway as a potential mediator of epileptogenic change. Systemic administration of the mTOR inhibitor rapamycin has promising therapeutic potential, as it has been shown to reduce seizure frequency and seizure severity in rodent models. Here, we tested whether mTOR signaling facilitates abnormal development of granule cells during epileptogenesis. We also examined dentate inflammation and mossy cell death in the dentate hilus. To determine if mTOR activation is necessary for abnormal granule cell development, transgenic mice that harbored fluorescently-labeled adult-born granule cells were treated with rapamycin following pilocarpine-induced status epilepticus. Systemic rapamycin effectively blocked phosphorylation of S6 protein (a readout of mTOR activity) and reduced granule cell mossy fiber axon sprouting. However, the accumulation of ectopic granule cells and granule cells with aberrant basal dendrites was not significantly reduced. Mossy cell death and reactive astrocytosis were also unaffected. These data suggest that anti-epileptogenic effects of mTOR inhibition may be mediated by mechanisms other than inhibition of these common dentate pathologies. Consistent with this conclusion, rapamycin prevented pathological weight gain in epileptic mice, suggesting that rapamycin might act on central circuits or even peripheral tissues controlling weight gain in epilepsy.

Topics: Animals; Carrier Proteins; Cation Transport Proteins; Cell Movement; Disease Models, Animal; Gene Expression Regulation; Hippocampus; Immunosuppressive Agents; Membrane Proteins; Membrane Transport Proteins; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mossy Fibers, Hippocampal; Neurogenesis; Neurons; Pilocarpine; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction; Sirolimus; Status Epilepticus; Weight Gain; Zinc Finger Protein GLI1

Resistance to obesity is observed in rodents and humans treated with rapamycin (Rap) or nebivolol (Neb). Because cardiac miR-208a promotes obesity, this study tested whether the modes of actions of Rap and Neb involve inhibition of miR-208a.. Mouse cardiomyocyte HL-1 cells and Zucker obese (ZO) rats were used to investigate regulation of cardiac miR-208a.. Angiotensin II (Ang II) increased miR-208a expression in HL-1 cells. Pretreatment with an AT1 receptor (AT1R) antagonist, losartan (1 μM), antagonized this effect, whereas a phospholipase C inhibitor, U73122 (10 μM), and an NADPH oxidase inhibitor, apocynin (0.5 mM), did not. Ang II-induced increase in miR-208a was suppressed by Rap (10 nM), an inhibitor of nutrient sensor kinase mTORC1, and Neb (1 μM), a 3rd generation β-blocker that suppressed bioavailable AT1R binding of (125) I-Ang II. Thus, suppression of AT1R expression by Neb, inhibition of AT1R activation by losartan, and inhibition of AT1R-induced activation of mTORC1 by Rap attenuated the Ang II-induced increase in miR-208a. In ZO rats, Rap treatment (750 μg kg(-1)  day(-1) ; 12 weeks) reduced obesity despite similar food intake, suppressed cardiac miR-208a, and increased cardiac MED13, a suppresser of obesity.. Rap and Neb suppressed cardiac miR-208a. Suppression of miR-208a and increase in MED13 correlated with attenuated weight gain despite leptin resistance.

Topics: Angiotensin II; Animals; Cells, Cultured; Gene Expression Regulation; Male; Mediator Complex; Mice; MicroRNAs; Myocytes, Cardiac; Nebivolol; Obesity; Rats; Rats, Zucker; Signal Transduction; Sirolimus; Weight Gain

We report the identification of an FBXW7 mutation in a patient with adenocarcinoma of the lung, whose tumor had previously been shown to be EGFR and ALK wild type and who had previously progressed on multiple lines of systemic therapy. She experienced both clinical and radiographic benefit from treatment with the mTOR inhibitor temsirolimus.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Cell Cycle Proteins; Drug Resistance, Neoplasm; F-Box Proteins; F-Box-WD Repeat-Containing Protein 7; Female; Glutamates; Guanine; High-Throughput Nucleotide Sequencing; Humans; Lung Neoplasms; Middle Aged; Molecular Targeted Therapy; Motor Activity; Mutation; Neoplasm Metastasis; Pemetrexed; Recurrence; Remission Induction; Sirolimus; TOR Serine-Threonine Kinases; Ubiquitin-Protein Ligases; Weight Gain

At a wide range of doses, rapamycin extends life span in mice. It was shown that intraperitoneal injections (i.p.) of rapamycin prevent weight gain in mice on high-fat diet (HFD). We further investigated the effect of rapamycin on weight gain in female C57BL/6 mice on HFD started at the age of 7.5 months. By the age of 16 and 23 months, mice on HFD weighed significantly more (52 vs 33 g; p = 0.0001 and 70 vs 38 g; p < 0.0001, respectively) than mice on low fat diet (LFD). The i.p. administration of 1.5 mg/kg rapamycin, 3 times a week every other week, completely prevented weight gain, whereas administration of rapamycin by oral gavash did not. Rapamycin given in the drinking water slightly decreased weight gain by the age of 23 months. In addition, metabolic parameters were evaluated at the age of 16 and 23 months, 6 and 13 days after last rapamycin administration, respectively. Plasma leptin levels strongly correlated with body weight, (P < 0.0001, r=0.86), suggesting that the difference in weight was due to fat tissue mass. Levels of insulin, glucose, triglycerides and IGF1 were not statistically different in all groups, indicating that these courses of rapamycin treatment did not impair metabolic parameters at least after rapamycin discontinuation. Despite rapamycin discontinuation, cardiac levels of phospho-S6 and pAKT(S473) were low in the i.p.-treated group. This continuous effect of rapamycin can be explained by prevention of obesity in the i.p. group. We conclude that intermittent i.p. administration of rapamycin prevents weight gain without causing gross metabolic abnormalities. Intermittent gavash administration minimally affected weight gain. Potential clinical applications are discussed.

Topics: Animals; Blood Glucose; Diet, High-Fat; Female; Immunosuppressive Agents; Injections, Intraperitoneal; Insulin; Leptin; Mice; Mice, Inbred C57BL; Obesity; Phosphorylation; Proto-Oncogene Proteins c-akt; Ribosomal Protein S6 Kinases; Sirolimus; Triglycerides; Weight Gain

Immunosuppression after kidney transplantation has been associated with weight gain. The aim was to evaluate if sirolimus (SRL) had a different effect on weight gain than calcineurin inhibitor (CNI).. Data on body weight in different patient populations were analyzed at several time points: (a) SRL (CNI-free) versus cyclosporine A (CsA) treatment de novo, (b) CsA+SRL versus CsA (SRL-free) treatment de novo, (c) SRL+tacrolimus elimination at 3 months versus SRL+mycophenolate mofetil versus tacrolimus+mycophenolate mofetil de novo, and (d) conversion from CNI to SRL versus CNI in maintenance patients.. Patients were analyzed from de novo transplantation trials (n=1863) and from the conversion study (n=742). At baseline, weight in the SRL-containing and SRL-free treatment arms was not different, but weight gain was significantly less pronounced in SRL in de novo treatment (group 1: 2.8±4.6 vs. 6.2±6.6 kg every 2 years, P=0.020; group 2: 6.1±9.5 vs. 9.6±9.1 kg every 2 years, P<0.001; and group 3: 3.7±7.0 vs. 3.5±6.2 vs. 5.9±9.0 kg every 1 year, P=0.042). In the conversion study, patients lost weight in the SRL arm and gained weight in the CNI arm (-1.0±6.0 vs. +1.0±5.1 kg every 2 years; P<0.001).. SRL treatment is associated with less weight gain de novo as well as in late conversion.

Topics: Adult; Blood Glucose; Calcineurin Inhibitors; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Sirolimus; TOR Serine-Threonine Kinases; Weight Gain

High doses of rapamycin, an antiaging agent, can prevent obesity in mice on high fat diet (HFD). Obesity is usually associated with hyperinsulinemia. Here, we showed that rapamycin given orally, at doses that did not affect weight gain in male mice on HFD, tended to decrease fasting insulin levels. Addition of resveratrol, which alone did not affect insulin levels, potentiated the effect of rapamycin, so that the combination decreased obesity and prevented hyperinsulinemia. Neither rapamycin nor resveratrol, and their combination affected fasting levels of glucose (despite lowering insulin levels), implying that the combination might prevent insulin resistance. We and others previously reported that resveratrol at high doses inhibited the mTOR (Target of Rapamycin) pathway in cell culture. Yet, as we confirmed here, this effect was observed only at super-pharmacological concentrations. At pharmacological concentrations, resveratrol did not exert 'rapamycin-like effects' on cellular senescence and did not inhibit the mTOR pathway in vitro, indicating nonoverlapping therapeutic mechanisms of actions of rapamycin and resveratrol in vivo. Although, like rapamycin, resveratrol decreased insulin-induced HIF-1-dependent transcription in cell culture, resveratrol did not inhibit mTOR at the same concentrations. Given distinct mechanisms of action of rapamycin and resveratrol at clinically relevant doses, their combination warrants further investigation as a potential antiaging, antiobesity and antidiabetic modality.

Topics: Animals; Cell Line, Tumor; Cellular Senescence; Diet, High-Fat; Humans; Hyperinsulinism; Hypoxia-Inducible Factor 1, alpha Subunit; Insulin; Insulin Resistance; Male; Mice; Obesity; Resveratrol; Sirolimus; Stilbenes; TOR Serine-Threonine Kinases; Transcription, Genetic; Weight Gain

The nutrient-sensing TOR (target of rapamycin) pathway is involved in cellular and organismal aging. Rapamycin, an inhibitor of TOR, extends lifespan in yeast, fruit flies and genetically heterogeneous mice. Here, we demonstrate that lifelong administration of rapamycin extends lifespan in female 129/Sv mice characterized by normal mean lifespan of 2 y. Importantly, rapamycin was administrated intermittently (2 weeks per month) starting from the age of 2 mo. Rapamycin inhibited age-related weight gain, decreased aging rate, increased lifespan (especially in the last survivors) and delayed spontaneous cancer. 22.9% of rapamycin-treated mice survived the age of death of the last mouse in control group. Thus we demonstrated for the first time in normal inbred mice that lifespan can be extended by rapamycin. This opens an avenue to develop optimal doses and schedules of rapamycin as an anti-aging modality.

Topics: Aging; Animals; Body Temperature; Cell Transformation, Neoplastic; Estrus; Female; Longevity; Mice; Mice, 129 Strain; Sirolimus; Statistics, Nonparametric; Survival Analysis; Weight Gain

Ischemia reperfusion injury (IRI) has long-term sequelae on kidney allograft function. Early initiation of rapamycin can retard surgical wound healing and recovery from IRI. In contrast, rapamycin may paradoxically retard long-term fibrotic effects of kidney IRI. We, therefore, hypothesized that delayed initiation of rapamycin after kidney ischemia, started after the initial week of wound healing, would decrease the long-term inflammation and fibrosis caused by IRI. C57BL/6 male mice were subjected to either 45 or 60 minutes of unilateral kidney ischemia or a sham operation. Mice were given rapamycin (subcutaneous, 1.5 mg/kg/d) or vehicle starting at 1 week after IRI surgery for 3 weeks. Urine albumin excretion, kidney histology, and kidney cytokine proteins were examined at 4 weeks after surgery. The 3-week treatment course of rapamycin significantly reduced body weight gain in all 3 groups and reduced postischemic kidney weight in both the 45- and 60-minute ischemia groups, but unexpectedly increased urine albumin excretion in all rapamycin-treated sham or IRI mice compared with vehicle-treated mice. Rapamycin treatment showed minimal effects on postischemic kidney fibrosis with variable effects on various cytokine/chemokine protein expressions, namely, decreasing interleukin (IL)-1alpha, IL-6, tumor necrosis factor (TNF)-alpha, and regulated on activation normal T cell expressed and secreted (RANTES) while increasing IL-4, keratinocyte-derived chemokine (KC), macrophage inflammatory protein (MIP-1alpha), and IL-10 in the ischemic kidney. These data demonstrated that rapamycin reduced mouse body weight and ischemic kidney weight, while increasing urinary albumin excretion. Delayed initiation of rapamycin after IRI had a minimal effect on renal fibrosis and mixed effects on proinflammatory mediator production. These data do not support delayed initiation of rapamycin after IRI to attenuate IRI-induced progressive fibrosis and inflammation, and They raise further caution regarding rapamycin and albuminuria.

Topics: Albuminuria; Animals; Body Weight; Cytokines; Fibrosis; Immunosuppressive Agents; Injections, Subcutaneous; Kidney; Kidney Diseases; Male; Mice; Mice, Inbred C57BL; Organ Size; Reperfusion Injury; Sirolimus; Weight Gain

Clinical studies have shown enhancement of cyclosporine toxicity when co-administered with the immunosuppressant sirolimus. We evaluated the biochemical mechanisms underlying the sirolimus/cyclosporine interaction on rat brain metabolism using magnetic resonance spectroscopy (MRS) and compared the effects of sirolimus with those of the structurally related RAD. Two-week-old rats (25 g) were allocated to the following treatment groups (all n=6): I. control, II. cyclosporine (10 mg kg(-1) d(-1)), III. sirolimus (3 mg kg(-1) d(-1)), IV. RAD (3 mg kg(-1) d(-1)), V. cyclosporine+sirolimus and VI. cyclosporine+RAD. Drugs were administered by oral gavage for 6 days. Twelve hours after the last dose, metabolic changes were assessed in brain tissue extracts using multinuclear MRS. Cyclosporine significantly inhibited mitochondrial glucose metabolism (glutamate: 78+/-6% of control; GABA: 67+/-12%; NAD(+): 76+/-3%; P<0.05), but increased lactate production. Sirolimus and RAD inhibited cytosolic glucose metabolism via lactate production (sirolimus: 81+/-3% of control, RAD: 69+/-2%; P<0.02). Sirolimus enhanced cyclosporine-induced inhibition of mitochondrial glucose metabolism (glutamate: 60+/-4%; GABA: 59+/-8%; NAD(+): 45+/-5%; P<0.02 versus cyclosporine alone). Lactate production was significantly reduced. In contrast, RAD antagonized the effects of cyclosporine (glutamate, GABA, and NAD(+), not significantly different from controls). The results can partially be explained by pharmacokinetic interactions: co-administration increased the distribution of cyclosporine and sirolimus into brain tissue, while co-administration with RAD decreased cyclosporine brain tissue concentrations. In addition RAD, but not sirolimus, distributed into brain mitochondria. The combination of cyclosporine/RAD compares favourably to cyclosporine/sirolimus in regards to their effects on brain high-energy metabolism and tissue distribution in the rat.

Topics: Animals; Aspartic Acid; Body Weight; Brain; Cyclosporine; Drug Synergism; Everolimus; gamma-Aminobutyric Acid; Glutamic Acid; Glutamine; Immunosuppressive Agents; Magnetic Resonance Spectroscopy; Mitochondria; Oxaloacetic Acid; Phosphates; Rats; Rats, Wistar; Sirolimus; Weight Gain

Transplantation of the small intestine would be an attractive therapeutic option for treatment of short bowel syndrome if effective, nontoxic immunosuppressive agents could be developed. This study examines the effect of three newly developed immuno-suppressive agents: rapamycin, deoxyspergualin, and mycophenolate mofetil, on the nutritional status and intestinal function of normal juvenile rats.. Rapamycin (2 mg/kg every second day), deoxyspergualin (2 mg/kg every second day) and mycophenolate mofetil (MM) (25 mg/kg every second day) were injected subcutaneously for six weeks.. Rapamycin and deoxyspergualin caused significant reductions in weight gain without impairing feed intake. Both drugs caused small decreases in fat absorption; treatment with DSG induced an increase in permeability to 99Tc-DTPA. However, the permeability to other markers, such as mannitol and lactulose, was decreased in the rapamycin and mycophenolate mofetil-treated animals. Intestinal function in vitro was quantified using glucose flux (absorption). In the rapamycin group, there was a significant decrease in ileal uptake of glucose, with the net flux (absorption) being zero; there was an associated loss of villous size histologically. In the deoxyspergualin-treated groups, there was a decrease in the jejunal glucose flux. In the mycophenolate mofetil-treated animals, there was a decrease in jejunal with a compensatory increase in ileal glucose absorption. There were minor variations in intestinal morphology, but these were not consistent.. Rapamycin and deoxyspergualin in these doses cause a significant reduction in weight gain in healthy juvenile animals, and all the drugs caused changes in the active transport characteristics of the intestine. Accordingly, the use of these drugs for intestinal transplantation should be evaluated carefully for their nutritional impact.

Topics: Animals; Eating; Gastrointestinal Motility; Guanidines; Immunosuppressive Agents; Intestine, Small; Lactulose; Male; Mannitol; Mycophenolic Acid; Permeability; Polyenes; Rats; Rats, Inbred Lew; Sirolimus; Weight Gain

The effect on intestinal nutrient transport of the immunosuppressive drugs cyclosporin A (CsA), cyclosporin G (CsG), and rapamycin (RAP) was determined in New Zealand white rabbits. Rabbits received oral doses of CsA (20 mg/kg/day), CsG (10 mg/kg/day), or RAP (1 mg/kg/day) for 10 days. Animals receiving RAP had decreased food intake and weight gain compared with controls. This correlated with a decrease in both total ileal weight and corresponding mucosal weight. CsA and CsG administration had no effect on food intake, total weight gain, or intestinal weight. Villus surface area was significantly decreased in all groups as compared with controls. Jejunal uptake of D-glucose as well as 1 medium and 4 long chain fatty acids was not affected by drug administration, while both mucosal-to-serosal and net 3-0-methylglucose fluxes were increased (P < 0.05) in the jejunum by all 3 drugs. In the ileum, the rates of uptake of D-glucose as well as stearic and linoleic acids were increased in animals treated with RAP compared with controls. There was an increase in the ileal values of the maximal transport rate (Vmax) and apparent Michaelis constant (Km*) in RAP, and a fall in the Vmax and Km* in CsG. CsG administration resulted in a decreased cholesterol uptake in both jejunum and ileum, and a decreased D-glucose uptake in the ileum compared with controls. These differences in glucose uptake among groups could not be attributed to variations in body, intestinal, or mucosal weights. It is unlikely that the changes observed in CsA- and CsG-treated animals would have nutritional importance, as these animals gained weight normally. In addition, in these animals the changes mainly occurred in the ileum, not in the jejunum, where most glucose is absorbed, and the associated alterations in the values of the Vmax and Km* would lead to reciprocal changes in the rates of uptake of varying luminal concentrations of glucose. In contrast, these changes are likely to be of more importance in RAP-treated animals, since they failed to gain weight normally. The significance of these findings needs to be established in chronically treated animals.

Topics: Administration, Oral; Animals; Cholesterol; Cyclosporine; Cyclosporins; Fatty Acids; Glucose; Ileum; Immunosuppressive Agents; Intestinal Mucosa; Jejunum; Male; Polyenes; Rabbits; Sirolimus; Weight Gain

The effects of rapamycin (RAPA) on kidney function and histology were investigated in the Sprague-Dawley rat and compared with cyclosporine. Drugs were administered orally in a Cremophor-ethanol formulation for 14 days in two separate studies. RAPA, at 1 mg/kg, had no effect either functionally or histologically on the kidney. At 10 mg/kg, RAPA depressed the gain in body weight by 20% in the rat but had only minor functional disturbances on urine output, plasma creatinine, and creatinine clearance in the kidney. It did not induce any histomorphologic abnormalities. CsA, at 25 mg/kg, produced functional alterations in the kidney including elevated plasma creatinine and depressed clearance of creatinine as well as depressed body weight gain (17%). Histologically, CsA induced proximal tubule damage. These results demonstrate that RAPA (10 mg/kg) does not produce nephrotoxicity in the Sprague-Dawley rat at doses three times higher than its effective immunosuppressive doses established in the rat.

Topics: Animals; Creatinine; Cyclosporine; Immunosuppressive Agents; Kidney; Male; Organ Size; Osmolar Concentration; Polyenes; Rats; Rats, Inbred Strains; Sirolimus; Urine; Weight Gain