Safety and potential efficacy of gemfibrozil as a supportive treatment for children with late infantile neuronal ceroid lipofuscinosis and other lipid storage disorders.

Existing Reviews

Please note, new claims can take a short while to show up.

No claims yet.

Annotation Summary

Term Occurence Count Dictionary
metabolic syndrome 1 endocrinologydiseases
neuronal ceroid lipofuscinosis 1 endocrinologydiseases
pioglitazone 1 endocrinologydiseasesdrugs
ezetimibe 1 endocrinologydiseasesdrugs
hyperlipidemia 4 endocrinologydiseases
rosuvastatin 1 endocrinologydiseasesdrugs
pravastatin 1 endocrinologydiseasesdrugs
rosiglitazone 1 endocrinologydiseasesdrugs
lysosomal storage disease 1 endocrinologydiseases
obesity 1 endocrinologydiseases
gemfibrozil 69 endocrinologydiseasesdrugs
lipid storage disease 2 endocrinologydiseases
atorvastatin 1 endocrinologydiseasesdrugs
glyburide 1 endocrinologydiseasesdrugs

Graph of close proximity drug and disease terms (within 200 characters).

Note: If this graph is empty, then there are no terms that meet the proximity constraint.

Review

Having read the paper, please pick a pair of statements from the paper to indicate that a drug and disease are related.

Select Drug Character Offset Drug Term Instance
atorvastatin 26604 rosiglitazone) may be required to reduceOATP1B1 substratessubstrates of OATP1B1 (e.g., atrasentan, atorvastatin , bosentan, ezetimibe, fluvastatin, glyburide, SN-38 [active metabolite of irinotecan], rosuvastatin,
ezetimibe 26628 required to reduceOATP1B1 substratessubstrates of OATP1B1 (e.g., atrasentan, atorvastatin, bosentan, ezetimibe , fluvastatin, glyburide, SN-38 [active metabolite of irinotecan], rosuvastatin, pitavastatin, pravastatin,
gemfibrozil 73 Title: Orphanet Journal of Rare DiseasesSafety and potential efficacy of gemfibrozil as a supportive treatment for children with late infantile neuronal ceroid lipofuscinosis and other
gemfibrozil 1233 disease/conditions other than NCL for the non-invasive use, safety, and tolerability of a lipid-lowering drug, gemfibrozil , as a potential treatment for NCLs. Gemfibrozil has shown efficacy in an animal model of NCL known as
gemfibrozil 1536 in children. Among the 200 non-NCL children found in the published literature who were treated with gemfibrozil for NCL-related problems, only 3 experienced adverse events, including 2 with muscle pain and 1 with
gemfibrozil 1707 events, including 2 with muscle pain and 1 with localized linear IgA bullous dermatitis. We conclude that gemfibrozil is safe for long-term use in children, causes minimal adverse events, is well tolerated, and may delay
gemfibrozil 12272 treatments can deter the families from opting to try them. Recently, a simple and safe lipid lowering drug, gemfibrozil , has shown efficacy in cells and in an animal model and may offer the patients a non-invasive option
gemfibrozil 13343 is taken orally as a 600 mg tablet twice a day before meals and has minimal side effects. In fact, gemfibrozil has been found to have many additional effects on reducing inflammation, regulating oxidative stress,
gemfibrozil 13693 other disease pathologies (www.clinicaltrials.gov).Fig. 1Scheme showing the dual mechanism of action of gemfibrozil The mechanism of action of Gemfibrozil on lowering lipidsFatty acids are metabolized in mitochondria
gemfibrozil 14342 and thiolase) via PPAR-α (Fig. 1) [[39], [41]]. Since VLCFAs are major components of LDL and VLDL, a gemfibrozil -mediated decrease in bad cholesterol (VLDL and LDL) is directly correlated to increased catabolism of
gemfibrozil 14487 cholesterol (VLDL and LDL) is directly correlated to increased catabolism of VLCFAs in peroxisomes.How does gemfibrozil modulate TPP1?Gemfibrozil acts in two ways to increase TPP1 in cells (Fig. 1). Gemfibrozil activates
gemfibrozil 15066 genes. All-trans retinoic acid has similar activity. The combination of all-trans retinoic acid with gemfibrozil also enhances TFEB production within 12 h, and lower doses of both compounds provided maximal activity
gemfibrozil 15568 Increased TPP1 activity has been observed in a variety of neuronal cells and fibroblasts treated with gemfibrozil but not in iPSC cells (Table 1) [[38], [47]]. Based on these dual activities, gemfibrozil has potential
gemfibrozil 15658 treated with gemfibrozil but not in iPSC cells (Table 1) [[38], [47]]. Based on these dual activities, gemfibrozil has potential for therapeutic applications in the NCLs.Table 1Effect of gemfibrozil on cells and on
gemfibrozil 15742 dual activities, gemfibrozil has potential for therapeutic applications in the NCLs.Table 1Effect of gemfibrozil on cells and on animalsTreatmentEffectReferenceCells in vitro Mouse & human primary astrocytesgemfibrozi
gemfibrozil 15954 astrocytesgemfibrozi 25 μm↑CLN2 mRNA ↑TPP1 protein38, 39 Mouse neurons from cortex, striatum & hippocampus gemfibrozil 25 μm↑TPP1 protein38 Lymphoblastic cells from CLN3 patientsgemfibrozil 25 μm↑viability ↑autophagy
gemfibrozil 16031 striatum & hippocampusgemfibrozil 25 μm↑TPP1 protein38 Lymphoblastic cells from CLN3 patients gemfibrozil 25 μm↑viability ↑autophagy recovery ↑autophagy genes48 Human IPS models CLN2 and CLN3 mutationsgemfibrozil
gemfibrozil 16149 25 μm↑viability ↑autophagy recovery ↑autophagy genes48 Human IPS models CLN2 and CLN3 mutations gemfibrozil 25 µmNo effect on TPP147Animals Mouseoral gemfibrozil 7.5 mg/kg for 21 d↑TTP1 in astrocytes,
gemfibrozil 16212 genes48 Human IPS models CLN2 and CLN3 mutationsgemfibrozil 25 µmNo effect on TPP147Animals Mouseoral gemfibrozil 7.5 mg/kg for 21 d↑TTP1 in astrocytes, cortical neurons, & non neural cells of dentate gyrus & CAI
gemfibrozil 16364 astrocytes, cortical neurons, & non neural cells of dentate gyrus & CAI of hippocampus38 Mouse KO LINCLoral gemfibrozil 7.5 mg/kg for 21 d↑longevity, ↑motor retention, ↓apoptosis, ↑anti-inflammatory molecules49d = daysStudies
gemfibrozil 16515 ↑motor retention, ↓apoptosis, ↑anti-inflammatory molecules49d = daysStudies on cells treated with gemfibrozil Various cells in culture have been treated with gemfibrozil (38,47,48) (Table 1). The effect of gemfibrozil
gemfibrozil 16574 molecules49d = daysStudies on cells treated with gemfibrozilVarious cells in culture have been treated with gemfibrozil (38,47,48) (Table 1). The effect of gemfibrozil on Cln2 mRNA, protein expression, and TPP1 activity
gemfibrozil 16622 gemfibrozilVarious cells in culture have been treated with gemfibrozil (38,47,48) (Table 1). The effect of gemfibrozil on Cln2 mRNA, protein expression, and TPP1 activity has been studied in primary mouse neurons and in
gemfibrozil 17086 [39]]. Interestingly the mRNA for other lysosomal genes, such as Cln1 and Cln3, were also increased by gemfibrozil . Increased TPP1 protein was observed inside the cells as well. Neuronal cells and human astrocytes also
gemfibrozil 17377 validated by either western blot, immunofluorescence, and/or by a TPP1 activity assay [[38]]. The effect of gemfibrozil on TPP1 mRNA was evaluated in wild type, PPARα deficient, and PPARβ deficient astrocytes isolated
gemfibrozil 17568 astrocytes isolated from cells from wild type and genetically modified mice [[39]]. Interestingly, gemfibrozil did not increase Cln2 mRNA levels in the cells from the PPARα knock out (KO) mice whereas the increase
gemfibrozil 17711 levels in the cells from the PPARα knock out (KO) mice whereas the increase in Cln2 mRNA was seen with gemfibrozil treatment of cells from both wild type and PPARβ KO mice. Immunofluorescence, western blot, and an
gemfibrozil 17894 Immunofluorescence, western blot, and an enzyme activity assay confirmed the lack of Cln2 mRNA up-regulation by gemfibrozil in the cells isolated from the PPARα KO mice [[38]]. Similar studies were done with siRNA-treated cells
gemfibrozil 18052 [[38]]. Similar studies were done with siRNA-treated cells where there was no increase in TPP1 with gemfibrozil , and this study further demonstrated the role of RXRα in regulating the expression of TPP1 mRNA. These
gemfibrozil 18223 regulating the expression of TPP1 mRNA. These studies confirm the involvement of PPARα/RXRα in the gemfibrozil -mediated increase in both Cln2 mRNA and TPP1 protein [[38]]. It was concluded that gemfibrozil and retinoic
gemfibrozil 18318 the gemfibrozil-mediated increase in both Cln2 mRNA and TPP1 protein [[38]]. It was concluded that gemfibrozil and retinoic acid recruit both PPARα and RXRα to the RXR-binding site of the Cln2 gene promoter.Some
gemfibrozil 18614 [[48], [49]]. Lymphoblasts isolated from control and NCL patients were investigated for the effect of gemfibrozil on apoptosis, depolarization of the mitochondrial membrane, and defective autophagy [[49]]. NCL (CLN3)
gemfibrozil 18789 defective autophagy [[49]]. NCL (CLN3) lymphoblast cell viability to normal levels was restored by gemfibrozil in NCL patient-derived lymphoblasts via decreased apoptosis. Furthermore, the high level of membrane
gemfibrozil 18996 membrane potential depolarization of NCL patient-derived lymphoblasts was restored to normal levels by gemfibrozil , and defective autophagy was normalized by gemfibrozil. These findings suggest that gemfibrozil may
gemfibrozil 19051 lymphoblasts was restored to normal levels by gemfibrozil, and defective autophagy was normalized by gemfibrozil . These findings suggest that gemfibrozil may have a therapeutic effect by multiple mechanisms for NCL
gemfibrozil 19092 by gemfibrozil, and defective autophagy was normalized by gemfibrozil. These findings suggest that gemfibrozil may have a therapeutic effect by multiple mechanisms for NCL patients [[39], [40]].Studies on animals
gemfibrozil 19219 therapeutic effect by multiple mechanisms for NCL patients [[39], [40]].Studies on animals treated with gemfibrozil The effect of gemfibrozil has been evaluated in a newly created mouse model of CLN2/TPP1 of NCL (Figure
gemfibrozil 19244 multiple mechanisms for NCL patients [[39], [40]].Studies on animals treated with gemfibrozilThe effect of gemfibrozil has been evaluated in a newly created mouse model of CLN2/TPP1 of NCL (Figure 2) [[49]]. This model
gemfibrozil 19507 mice develop progressive motor dysfunction and die prematurely. A dose of 7.5 mg/kg body weight of gemfibrozil increased survival by several weeks to 172 days over that observed with vehicle alone, 123 days. Furthermore,
gemfibrozil 20010 assay. Finally, a decrease in storage materials in the motor cortex of the brain was observed in the gemfibrozil -treated cln2 knock out mice as compared with the untreated knock out mice [[49]]. Interestingly, since
gemfibrozil 20177 untreated knock out mice [[49]]. Interestingly, since these genetically-modified mice lack the cln2 gene, gemfibrozil is likely not working by increasing TPP1 expression but rather via lysosome biogenesis and other activities.
gemfibrozil 20324 TPP1 expression but rather via lysosome biogenesis and other activities. The findings suggest that gemfibrozil can delay the progression of neurodegenerative decline in an animal model by multiple mechanisms. Clearly
gemfibrozil 20586 may further improve the outcome with the animals. The data also suggest that the neuroprotection by gemfibrozil may be applicable to treating children with CLN2/TPP1 NCL and possible other genetic variants of the
gemfibrozil 20749 CLN2/TPP1 NCL and possible other genetic variants of the NCLs [[48], [49]].Fig. 2Summary of the effects of gemfibrozil on the CLN2 knock out mouseWhen wild type and PPARα and PPARβ KO mice were analyzed for the effect
gemfibrozil 20865 the CLN2 knock out mouseWhen wild type and PPARα and PPARβ KO mice were analyzed for the effect of gemfibrozil on TPP1 expression, gemfibrozil markedly increased TTP1 protein expression in the cells of the brains
gemfibrozil 20897 type and PPARα and PPARβ KO mice were analyzed for the effect of gemfibrozil on TPP1 expression, gemfibrozil markedly increased TTP1 protein expression in the cells of the brains of the wild type and PPARβ KO
gemfibrozil 21125 the PPARα KO mice [[38], [39]]. These findings again demonstrate the involvement of PPARα in the gemfibrozil -mediated increase in TTP1 (38). Furthermore, the Cln2 gene contains an RXR-binding site, and all-trans
gemfibrozil 21340 retinoic alone can increase TTP1 expression. The studies further confirm the mechanism of action of gemfibrozil in vivo and demonstrate the role of the PPARα/RXRα heterodimer in its activity.Safety of gemfibrozil:
gemfibrozil 21443 gemfibrozil in vivo and demonstrate the role of the PPARα/RXRα heterodimer in its activity.Safety of gemfibrozil : Studies with children treated with gemfibrozilHaving been approved for human use in 1976, gemfibrozil
gemfibrozil 21491 PPARα/RXRα heterodimer in its activity.Safety of gemfibrozil: Studies with children treated with gemfibrozil Having been approved for human use in 1976, gemfibrozil has a long history of safety and tolerability
gemfibrozil 21546 gemfibrozil: Studies with children treated with gemfibrozilHaving been approved for human use in 1976, gemfibrozil has a long history of safety and tolerability in adults as a lipid-lowering agent. It has also been
gemfibrozil 21824 study with 12 children aged 5–17 years who had hyperlipidemia with persistent nephrotic syndrome, gemfibrozil given for 4 months to 7 of the patients (5 were controls) was found to be effective in improving the
gemfibrozil 22010 effective in improving the lipoprotein profile of the nephrotic children [[50]]. Besides efficacy, gemfibrozil had no side effects, and renal function and urine protein excretion in this fragile population were
gemfibrozil 22394 non-hemolytic jaundice. While there was no change in the need and duration of phototherapy with the gemfibrozil , it was noted that there were no side effects in the preterm and term neonates [[51]]. In another pilot
gemfibrozil 22589 [[51]]. In another pilot study on 47 pediatric patients with metabolic syndrome, a dose of 1200 mg/day gemfibrozil for 8 months significantly lowered the triglyceride levels and raised the HDL levels [[52]]. Two of
gemfibrozil 23170 (oldest child age 7 in the study) and at 6 months of age (younger child age 4 in the study) with 300 mg gemfibrozil twice per day [[54]]. At 7 and 3.5 years respectively, there were no side effects from the gemfibrozil,
gemfibrozil 23274 gemfibrozil twice per day [[54]]. At 7 and 3.5 years respectively, there were no side effects from the gemfibrozil , and the risk of acute pancreatitis, a complication of hyperlipidemia, was significantly reduced. There
gemfibrozil 23514 an age 13 female patient who developed linear IgA bullous dermatitis on her areola after 3 weeks on gemfibrozil , which resolved with drug withdrawal and steroid treatment [[55]]. Although side effects have been reported
gemfibrozil 23651 withdrawal and steroid treatment [[55]]. Although side effects have been reported in adults taking gemfibrozil (Table 3), these are generally uncommon and rarely severe.Table 2Safety of gemfibrozil in childrenAgeDose
gemfibrozil 23738 adults taking gemfibrozil (Table 3), these are generally uncommon and rarely severe.Table 2Safety of gemfibrozil in childrenAgeDose (duration)PurposeEffectSide effects (reference)Children with metabolic Syndrome,
gemfibrozil 24468 lipids↓cholesterol ↓triglyceridesnone (50)Age 13 female n = 13 weeksreduce lipidsNALABD (55)*Siblings started gemfibrozil at birth and at 6 months, respectivelyLABD, linear IgA bullous dermatitisTable 3Events related to treatment
gemfibrozil 24594 at 6 months, respectivelyLABD, linear IgA bullous dermatitisTable 3Events related to treatment with gemfibrozil Causal relationshipCausal relationshipProbableNot establishedGeneral:weight lossCardiacextrasystolesGastrointestinalcholestatic
gemfibrozil 25639 Characteristics) of LOPID® (Gemfibrozil Tablets, USP) by Pfizer, Revised March 2016These studies demonstrate that gemfibrozil was well tolerated and was safe for use in children even with ongoing disease processes. Based on the
gemfibrozil 25780 safe for use in children even with ongoing disease processes. Based on the known drug interactions of gemfibrozil (Table 4), children with NCL should not be expected to experience problems. However, with gemfibrozil
gemfibrozil 25882 gemfibrozil (Table 4), children with NCL should not be expected to experience problems. However, with gemfibrozil treatment there may be a potential reduction in the effectiveness of the anti-convulsive therapies that
gemfibrozil 26040 in the effectiveness of the anti-convulsive therapies that should be monitored. The off label use of gemfibrozil in ill children over a range of ages, doses, and durations suggests that gemfibrozil can be expected
gemfibrozil 26125 off label use of gemfibrozil in ill children over a range of ages, doses, and durations suggests that gemfibrozil can be expected to be safe for use in children with lipid storage diseases.Table 4Drug interactions
gemfibrozil 26242 be expected to be safe for use in children with lipid storage diseases.Table 4Drug interactions with gemfibrozil Concomitant medicationCautionsHMG-CoA Reductase Inhibitorsrisk of myopathy and rhabdomyolysisAnticoagulantswarfarin
gemfibrozil 27090 colchicineSPC of LOPID issued March.2016Summary and conclusionsThere are several advantages for use of gemfibrozil in children with lysosomal storage diseases, NCLs, and in particular late infantile batten disease CLN2/TPP1.
gemfibrozil 27808 apoptosis, oxidative stress, and inflammation. Finally, using knock out animal models of CLN2/TPP1, gemfibrozil was found to prolong the lifespan of the animals, decrease lipid accumulation in the motor cortex, delay
gemfibrozil 28167 combined with the potential increases in TPP1 enzyme levels and in biogenesis of lysosomes suggest that gemfibrozil will have some benefit in treating early stage children with CLN2/TPP1 and possibly with other genetic
glyburide 26652 substratessubstrates of OATP1B1 (e.g., atrasentan, atorvastatin, bosentan, ezetimibe, fluvastatin, glyburide , SN-38 [active metabolite of irinotecan], rosuvastatin, pitavastatin, pravastatin, rifampin, valsartan,
pioglitazone 26491 reducedCYP2C8 Substratesdrugs metabolized CYP2C8 (e.g., dabrafenib, loperamide, montelukast, paclitaxel, pioglitazone , rosiglitazone) may be required to reduceOATP1B1 substratessubstrates of OATP1B1 (e.g., atrasentan,
pravastatin 26732 ezetimibe, fluvastatin, glyburide, SN-38 [active metabolite of irinotecan], rosuvastatin, pitavastatin, pravastatin , rifampin, valsartan, olmesartan) may be required to reduceBile Acid-Binding Resinsresin-granule drugs
rosiglitazone 26505 Substratesdrugs metabolized CYP2C8 (e.g., dabrafenib, loperamide, montelukast, paclitaxel, pioglitazone, rosiglitazone ) may be required to reduceOATP1B1 substratessubstrates of OATP1B1 (e.g., atrasentan, atorvastatin, bosentan,
rosuvastatin 26704 atorvastatin, bosentan, ezetimibe, fluvastatin, glyburide, SN-38 [active metabolite of irinotecan], rosuvastatin , pitavastatin, pravastatin, rifampin, valsartan, olmesartan) may be required to reduceBile Acid-Binding
Select Disease Character Offset Disease Term Instance
hyperlipidemia 21773 children for various indications (Table 2). In a small study with 12 children aged 5–17 years who had hyperlipidemia with persistent nephrotic syndrome, gemfibrozil given for 4 months to 7 of the patients (5 were controls)
hyperlipidemia 22964 Further, it has been suggested that fibrates should be considered for children with obesity-related hyperlipidemia s [[53]]. Two siblings with familial chylomicronemia syndrome were treated from birth (oldest child age
hyperlipidemia 23341 there were no side effects from the gemfibrozil, and the risk of acute pancreatitis, a complication of hyperlipidemia , was significantly reduced. There was one case report of an age 13 female patient who developed linear
hyperlipidemia 24251 Syndrome, n = 2300 mg 2 x /day (3, 7 years)improve jaundice↓pancreatitisnone (54)Children with hyperlipidemia & nephrotic syndrome, n=12 (7 active, 5 placebo)150 mg 2 x/day (4 months)reduce lipids↓cholesterol
lipid storage disease 3699 these genes and for the different mutations within each gene [[2]]. Thus, a complex family of related lipid storage disease s with different genetic etiologies forms the NCL family. Such diversity in the genes and in the gene
lipid storage disease 26189 doses, and durations suggests that gemfibrozil can be expected to be safe for use in children with lipid storage disease s.Table 4Drug interactions with gemfibrozilConcomitant medicationCautionsHMG-CoA Reductase Inhibitorsrisk
lysosomal storage disease 27119 March.2016Summary and conclusionsThere are several advantages for use of gemfibrozil in children with lysosomal storage disease s, NCLs, and in particular late infantile batten disease CLN2/TPP1. Gemfibrozil is an oral drug that
metabolic syndrome 22546 effects in the preterm and term neonates [[51]]. In another pilot study on 47 pediatric patients with metabolic syndrome , a dose of 1200 mg/day gemfibrozil for 8 months significantly lowered the triglyceride levels and
neuronal ceroid lipofuscinosis 144 DiseasesSafety and potential efficacy of gemfibrozil as a supportive treatment for children with late infantile neuronal ceroid lipofuscinosis and other lipid storage disordersKyeongsoon KimHynda K. KleinmanHahn-Jun LeeKalipada PahanPublication
obesity 22948 event in adults. Further, it has been suggested that fibrates should be considered for children with obesity -related hyperlipidemias [[53]]. Two siblings with familial chylomicronemia syndrome were treated from

You must be authorized to submit a review.