Entertainment & Humor

A safety trial of high dose glyceryl triacetate for Canavan disease

Description
A safety trial of high dose glyceryl triacetate for Canavan disease
Published
of 4
All materials on our website are shared by users. If you have any questions about copyright issues, please report us to resolve them. We are always happy to assist you.
Related Documents
Share
Transcript
  A safety trial of high dose glyceryl triacetate for Canavan disease Reeval Segel a,b,c, ⁎ , Yair Anikster d,e , Shoshana Zevin f  , Avraham Steinberg b,g , William A. Gahl h ,Drora Fisher c,i , Orna Staretz-Chacham  j , Ari Zimran c,k , Gheona Altarescu a,c a Medical Genetics Institute, Shaare Zedek Medical Center, Jerusalem, Israel b Department of Pediatrics, Shaare Zedek Medical Center, Jerusalem, Israel c Hebrew University Medical School, Jerusalem, Israel d Metabolic Disease Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Aviv, Israel e Sackler Medical School, Tel Aviv, Israel f  Department of Internal Medicine, Shaare Zedek Medical Center, Jerusalem, Israel g Medical Ethics Unit, Shaare Zedek Medical Center, Jerusalem, Israel h National Human Genome Research Institute, NIH, Bethesda, MD, USA i Pediatric Radiology Unit, Shaare Zedek Medical Center, Jerusalem, Israel  j Department of Neonatology, Soroka Medical Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel k Gaucher Unit, Shaare Zedek Medical Center, Jerusalem, Israel a b s t r a c ta r t i c l e i n f o  Article history: Received 10 February 2011Received in revised form 9 March 2011Accepted 9 March 2011Available online 15 March 2011 Keywords: Canavan diseaseAspartoacylase de fi ciencyASPAGlyceryltriacetateGTASafety Canavan disease (CD MIM#271900) is a rare autosomal recessive neurodegenerative disorder presenting inearly infancy.Thecourse ofthediseaseisvariable, butitisalwaysfatal. CDiscaused bymutationsintheASPAgene, which codes for the enzyme aspartoacylase (ASPA), which breaks down N-acetylaspartate (NAA) toacetate and aspartic acid. The lack of NAA-degrading enzyme activity leads to excess accumulation of NAA inthe brain and de fi ciency of acetate, which is necessary for myelin lipid synthesis.Glyceryltriacetate (GTA) is a short-chain triglyceride with three acetate moieties on a glycerol backbone andhas proven an effective acetate precursor. Intragastric administration of GTA to tremor mice results in greatlyincreased brain acetate levels, and improved motor functions. GTA given to infants with CD at a low dose (upto 0.25 g/kg/d) resulted in no improvement in their clinical status, but also no detectable toxicity. We presentfor the  fi rst time the safety pro fi le of high dose GTA (4.5 g/kg/d) in 2 patients with CD. We treated 2 infantswithCDatages8 monthsand1 yearwithhighdoseGTA,for4.5and6 monthsrespectively.Nosigni fi cantsideeffects and no toxicity were observed. Although the treatment resulted in no motor improvement, it was welltolerated. The lack of clinical improvement might be explained mainly by the late onset of treatment, whensigni fi cant brain damage was already present. Further larger studies of CD patients below age 3 months arerequired in order to test the long-term ef  fi cacy of this drug.© 2011 Elsevier Inc. All rights reserved. 1. Introduction Canavan disease (CD MIM#271900) is a rare autosomal recessiveneurodegenerativedisorder,presentinginearlyinfancywithpoorheadcontrol, macrocephaly, marked developmental delay, hypotonia, opticatrophy,andseizures[1].Althoughthecourseofthediseaseisvariable,CDisinvariablyfatal, and death usually occurs in childhood,duringthe fi rstorseconddecadeoflife[2,3].CDiscausedbymutationsintheASPAgene atlocus 17pter-p13codingfor theenzyme aspartoacylase (ASPA)that normally breaks down N-acetylaspartate (NAA) [4]. The disease ismost common among Ashkenazi Jews (AJ), with a carrier rate of 1:40[5,6]. Two foundermutations(p.Glu285Alaand p.Tyr231X) account formore than 98% of affected AJ individuals while two other mutationsarepresentinasmallproportionofAJpatients(p.Ala305Gluandc.433-2A N G) [4,5].Themutatedenzymehasgreatlyreducedorevenabsentcapacitytohydrolyze the brain metabolite N-acetylaspartate (NAA) into acetateandaspartate.ThislackofNAA-degradingenzymeactivity,termedASPAde fi ciency (ASPAD), leads to accumulation of excess NAA in the brain,and high levels of excretion in the urine [7].NAA is synthesized and distributed primarily in neurons, whileASPA is distributed almost exclusively in oligodendrocytes. To bedegraded, NAA must be transferred transaxonally to oligodendro-cytes within the white matter of the brain. There it is hydrolyzed byASPA to acetate and aspartic acid. The free acetate is converted toacetyl CoA, which is necessary for myelin lipid synthesis. The failureof ASPA to produceacetatemayexplain thehypomyelinationseen inCD patients [8]. Molecular Genetics and Metabolism 103 (2011) 203 – 206 ⁎  Corresponding author at: Medical Genetics Institute, Shaare Zedek Medical Center,POB 3235, Jerusalem, 91031, Israel. Fax: +972 2 6666935. E-mail address:  Reevals@szmc.org.il (R. Segel).1096-7192/$  –  see front matter © 2011 Elsevier Inc. All rights reserved.doi:10.1016/j.ymgme.2011.03.012 Contents lists available at ScienceDirect Molecular Genetics and Metabolism  journal homepage: www.elsevier.com/locate/ymgme  In humans, myelination starts before birth, but the majority of brain myelination occurs postnatally [9]. Thus, the symptoms of CDare fully expressed only at the time myelinization is supposed tonormally take place.InthemousemodelofASPAD,acetatelevelsinthebrainarereducedby nearly 80% during the period of peak postnatal myelination [10].Moreover, cerebrosides and sulfatides were reduced in postmortembrain samples from a human patient with CD [10]. These data providestrong evidence for the concept that NAA-derived acetate is essentialduring postnatal myelination to supply substrate for part of the lipidsthat make up myelin sheaths in the developing brain.Glyceryltriacetate (GTA) is a short-chain triglyceride with threeacetatemoieties ona glycerolbackboneandis aproveneffectiveacetateprecursor[11].Ithasbeenstudiedasapotentialnutrientindogs[12]and rats[13];noadverseortoxiceffectsofGTAadministrationwereobserved.Intragastric administration of GTA to normal mice results ingreatly increased brain acetate levels [11]. Therefore, correcting brain acetate concentrations in pre-symptomatic infants with CD couldtheoretically allow myelination to proceed.Madhavarao et al. [14] gave GTA to infants with CD at a low dose(25 mg/kg body weight/d up to 250 mg/kg/d), with no detectabletoxicity. Although patients showed no deterioration in clinical status,no improvement was noted. It is theoretically possible that the doseused in the latter study was insuf  fi cient. Madhavarao et al. [14] usedhighdoseGTA(upto5.8 g/kg)inwildtypeandtremorratpups,whichisanaturalmutantstrainwithdeletionoftheentireASPAgene[15].Atthe end of the trial (~90 to 120 days) sera and tissues from rats wereanalyzed for changes in blood chemistry and histopathology. Therewere no signi fi cant differences in the mean blood chemistry valuesbetween treated and untreated groups, and no lesions indicatingtoxicityweredetectableinthetissuesexamined.Arunetal.[16]latelypublished a study which found that GTA is effective in signi fi cantlyreducing the severe phenotypic sequelae of ASPA de fi ciency in thetremor rat model of CD.Based on the growing body of evidence that GTA is a safe dietarynutrient, it has been approved by the FDA as a food additive and has “ generally regarded as safe ”  (GRAS) status. Thus, we suggested that atrialofhigher,effectivedosesofGTAisjusti fi edinhumanCDpatients.This suggestion is based upon the lack of GTA toxicity in the two CDpatients in low dose phase I trials and the lack of GTA toxicity in highdose animal studies.In this study, we present for the fi rst time the safety pro fi le of highdose GTA in 2 patients with CD. 2. Materials and methods High doses GTA (from 1% to 4.5% (~4.5 g/kg/d)) were given to twoinfants diagnosed with CD, who started treatment at ages 8 and12months,respectively.AllproceduresreportedwereapprovedbytheInstitutionalReviewBoardatShaareZedekMedicalCenter(SZMC),andthe trial was conducted in SZMC (Clinical-Trials.gov identi fi er:NCT00724802). The parents of the two patients with CD consented toenroll their children in the trial in order to test the tolerability of highdoseGTAsupplementationininfantformula.BecauseofastronglybittertasteofGTA,thedrugwasgiventhroughanasogastrictube(insertedforthis purpose) to the infants for 4.5 and 6 months respectively. Westarted at 0.5 g/kg body weight daily, doubling the dose every 3 daysuntil a maximum of 4.5 g/kg body weight/d was reached.Patient 1 (Pt1), of Ashkenazi-Jewish ancestry, was diagnosed withCDatage1 month.ShehadthreeprevioussiblingswithCD,andthreehealthy siblings. She was homozygous for the p.Glu285Ala mutation.Patient 2 (Pt2) was diagnosed with CD at 6 months of age. His fatherwasAJ,andhismotherwasanonJewishCaucasian.Hewasdiagnosedby elevated levels of NAA and is presumably a compound heterozy-gote for the p.Glu285Ala and a second unknown mutation.Thefollowingoutcomecriteriawereevaluatedpriortotheinitiationof treatment and reviewed at 4.5 months of treatment: neurologicalstatus,brainMRImaging(MRI)andMRSpectroscopy(MRS),urineNAAlevels and ophthalmoscopic examination. Adverse effects werescreened clinically and by blood work-up of complete blood count(CBC),kidneyfunction,electrolytes,liverfunctionandvenousbloodgasmeasurements (VBG). Urine analysis of NAA was performed using Gaschromatography – massspectrometry(GC – MS)analysisoforganicacidsin the urine [17].MRI and MRS were performed under sedation before and after4 months of treatment.GTA was administered four times daily mixed with infant formulastartingwithadoseof0.5 g/kgbodyweightinthe fi rst3 days,doublingevery 3 days up to a maximum dose of 4.5 g/kg body weight. Thepatients were admitted to the Pediatric Ward at SZMC in order toincreasethedosegradually,andwerecloselymonitoredclinically.Bloodgasses were drawn 1.5 h after each dose increase in order to check pH.Although our initial intent was to increase the drug to 5 g/kg bodyweight/d, we stopped at 4.5 g/kg body weight/d due to the parents'report of discomfort of both patients on 5 g/kg body weight/d. GastricpH was not measured, but the patients were treated empirically withomeprazole,andnofurtherdiscomfortwasreported.The4.5 g/kgbodyweight/ddosewascontinueduntiltheendofthetrial(4.5 monthsinPt1 and 6 months in Pt 2). The trial ended at different time points for thetwo patients at the parents' request. Patient 2 left the country 2 weeksaftercommencingthetreatment.Follow-upthereafterwasthroughtheprimarycarephysician — bloodtestswerenotperformedattheparent'srequest, and Pt 2 was not examined by a neurologist since leaving thecountry. 3. Results Tables 1 and 2 present the clinical and laboratory data of the twopatients. GTA at a dose of 4.5 gr/kg in infant formula was welltolerated,anddid notcauseanynoticeableadversereactionsin eitherpatient. GTA treatment at a dose of 4.5 gr/kg caused no changes inblood chemistry or CBC results. There were no large changes in theurine NAA levels.No changes were noted in the clinical status of the patientsbefore and after the GTA treatment. Before commencing treatmentPatient 1 smiled, made brief eye contact, and turned her head to theleft, but did not react to vocal stimuli. She had severe head lag, limbmuscle tone was increased and axial muscle tone was reduced. Deeptendonre fl exes were reduced, without gross cerebellarabnormality.Response to pain appeared normal. After 4.5 months of treatmentshe was more alert, smiled more readily, and made vocal sounds.Eye contact was improved. Severe head lag was still present, butaxial and limb muscle tone were improved. Deep tendon re fl exeswere still reduced. The MRI (Fig. 1) and MRS results of patient 1indicated that there was minimal radiological deterioration duringthe course of the clinical trial, which is what we expected. MRI and  Table 1 Clinical details.Patient 1 Patient 2Age at treatment start 8 months 12 monthsDuration of treatment 4.5 months 6 monthsDosage Start dosage — 0.5 g/kg,increase to 4.5 g/kgStart dosage — 0.5 g/kg,increase to 4.5 g/kgPace of escalation Every 3 days Every 3 daysAdverse events None NoneN-acetylaspartic acidmmol/mol creatinineNT Level at start :1500Level at end :1368Mutation p.Glu285Ala/p.Glu285Ala p.Glu285Ala/UnknownRoute of delivery Gastric tube Gastric tube204  R. Segel et al. / Molecular Genetics and Metabolism 103 (2011) 203 –  206   MRS data also do not show noticeable changes in the NAA peakbetween the beginning and the end of the trial period for eitherpatient, corroborating the urinalysis results for NAA.Patient 2 was followed carefully in the hospital for 2 weeks as thedose of GTA was up-titrated (Table 2). Shortly after reaching themaximal dose the patient was well. The patient and family left the  Table 2 Blood chemistries and CBC during treatment.Patient 1 Patient 2Baseline Day 2 Day 5 Day 8 Day 13 Day 16 Day 21 2 months 3 months Baseline Day 2 Day 5 Day 8 Day 10 Day 12 Blood chemistry Urea [9 – 20 mg/dl] 12 10 12 12 11 13 8 9 11 10 9 9 7 7 10Creatinine [0.80 – 1.20 mg/dl] 0.28 0.25 0.32 0.29 0.27 0.34 0.35 0.37 0.36 0.37 0.35 0.43 0.42 0.39 0.43Glucose [70 – 110 mg/dl] 78 76 85 82 81 97 82 82 71 102 93 91 89 110 105Potassium [3.5 – 5.2 meq/I] 5 5.2 4.4 4.7 5.1 5 4.8 4.7 4.6 4.6 5.3 5.4 3.9 4.2 5.2Sodium [139 – 142 meq/I] 142 141 141 140 139 137 142 138 140 141 139 142 139 141 142Chloride [98 – 110 meq/I] 105 106 107 105 105 106 106 116 108 108Calcium, total [7.2 – 10.0 mg/dl] 10.6 10 10.6 10.8 10.3 10.6Phosphorus [4.7 – 8.0 mg/dl] 5.9 5.1 5.7 6.2Bilirubin, total [0.1 – 1.1 mg/dl] 0.2 0.2 0.3 0.1 0.2 0.2  b 0.1SGOT(AST) [ b 3 – 100 IU/I] 60 46 46 40 41 45 44 50SGPT(ALT) [7 – 45 IU/I] 37 33 29 26 14 27 26 27LDH [100 – 260 IU/I] 740 720 729 612 763 757 726 716Alkaline Phosphatase[145 – 320 IU/I]196 220 278 226 275 200 207 200Protein, total [5.9 – 7.0 g/dl] 6.4 7Albumin [3.4 – 4.2 g/dl] 4.1 4.4Cholesterol,total [44 – 180 mg/dl]181 212 195 220 111 148 CBC  WBC [5.00 – 19.50 K/microL] 11.9 7.2 10.3 8.7 8.8 8.5 9.8 19.3 15.6 16.6RBC [3.00 – 5.40 M/microL] 5.27 5.36 4.8 4.88 4.45 5.24 5.35 5 4.77 4.75HGB [10.00 – 18.00 g/dl] 12.5 10.3 11.2 11.3 10.8 12.5 13.3 12 11.4 11.5HCT [31.00 – 55.00%] 36.8 37.3 33.7 34.6 31.7 38.5 39.7 37 35.5 35.4MCV [85.00 – 123.00 fL] 70 69.5 70 70.9 71.3 73.6 74.2 74 74.4 74.5MCH [28.0 – 40.0 pg] 23.6 19.1 23.3 23.1 24.2 24 24.8 24 23.9 24.2PLT [130 – 440 K/microL] 370 209 335 307 245 261 296 592 581 510NEUTRO% [20.0 – 46.0%] 25.7 34.5 34.5 34.9 61.9 28.4 35.8 16.1 23.5 26.5LYMPHO% [54.0 – 80.0%] 61.4 55.8 55.7 55.5 30.2 57.9 50.9 71.3 67.6 64.1MONO% [3.9 – 9.0%] 8.2 6.7 7.3 6.3 7.6 9.1 10.8 8.3 6.1 6.3 Venous gas pH 7.36 7.46 7.36 7.38 7.35 7.39 7.32 7.4 7.4 7.35 7.38 7.42 7.40 7.39 7.40Venous bicarbonate 22.4 23 20.9 22.2 21.9 22.7 18.9 23.5 35.7 19.9 23.3 23.7 18.3 20.9 20.7PCO2 [38 – 52 mm Hg] 42.2 29.7 38.3 38.2 41.6 39.1 38.3 38 38.6 35 40.6 35.6 25.3 32.1 30.5All blood tests were taken 1.5 h after dose change. Fig. 1.  Brain MRI images of Patient 1 before and after treatment. A: before start of treatment; B: after 4.5 months of treatment. Axial T2 weighted Spin echo images showing diffuseprolongation of the white matter with involvement of the internal and external capsules and the subcortical U  fi bers. Minimal deterioration can be detected in the brain MRI after4.5 months, as can be expected in Canavan disease.205 R. Segel et al. / Molecular Genetics and Metabolism 103 (2011) 203 –  206   country, thus further follow-up of Patient 2 was indirect. The parentsreported that he continued to receive GTA for 6 months without anyobserved adverse effects. 4. Discussion We present for the  fi rst time the tolerability and safety of a highdose potent acetate precursor, GTA, as a potential treatment for CD, adevastating degenerative disease of the brain.Madhavarao et al. [14] treated two infants aged 8 and 13 months,with low dose GTA (maximum dose was 0.5 mg/kg/d), with nodetectablesideeffects.Frompreviousstudies[11,14]itwascleartousthat only high dose GTA might allow myelinization and prevent thedevelopment of symptoms. In the current study, we tested thetolerability of higher doses of GTA, by treating two patients withCanavan disease with high dose GTA (4.5 gr/kg) for 4.5 – 6 months. Nosigni fi cant side effects were observed except for possible increasedgastricacidityatthehighestdoseof4.5 g/kgbodyweight/d,forwhichomeprazole was administrated. Since GTA is reported to causemetabolic acidosis, each dose increase was monitored by blood gasanalysis. No signi fi cant decrease in pH (Table 2) was observed at anydose given.Although the treatment unfortunately resulted in no motorimprovement, it was well tolerated. The lack of neurological improve-ment might be explained by the late initiation of treatment, whensigni fi cant brain damage was already present.We hope that better results may be achieved if therapeuticintervention starts at an earlier stage of CNS development, prior to3 months of age and before severe symptoms are already present andindicative of irreversible brain damage. It might even be possible toincrease acetate delivery to fetuses and newborn infants byadministering high levels of GTA to pregnant and nursing mothers.Because esterase activity is high in the gut and liver, one couldincrease acetate delivery to the brain by combining GTA with mildesterase inhibitors, such as the  fl avenoids found in grapefruit juice[18]. Therapeutic ef  fi cacy might also be improved by parenteral GTAadministration. A negative aspect of using GTA as a dietary acetatesupplement was its strongly bitter taste. In this study, we elected toadminister the medication by nasogastric tube, but it is possible thatappropriate sweeteners may help deal with this problem.Theaimofthecurrentstudywastodeterminetolerabilityandsafetyfor high-dose oral GTA administration in ASPAD infants. We concludethat acetate supplementation (by NG GTA) is a safe treatment strategyfor Canavan disease. The drug is inexpensive and easy to administer.GTA-based acetate supplementationis a unique method for addressingdysmyelination in Canavan disease in particular, and possibly otherdisorders of myelination, or brain injury [16]. Further larger studies of CD patients below age 3 months are required in order to test the long-term ef  fi cacy of this drug.  Acknowledgments The authors thank the families who participated in this study fortheir participation, and the NIH pharmacy for supplementing the drug. References [1] E.C. Traeger, I. Rapin, The clinical course of Canavan disease, Pediatr. Neurol. 18(3) (Mar 1998) 207 – 212.[2] J.Brismar,G.Brismar,G.Gascon,P.Ozand,Canavandisease:CTandMRimagingof the brain, AJNR Am. J. Neuroradiol. 11 (4) (Jul – Aug 1990) 805 – 810.[3] R.Matalon,K.Michals-Matalon,RecentadvancesinCanavandisease,Adv.Pediatr.46 (1999) 493 – 506 8  Review.[4] R. Kaul, G.P. Gao, M. Aloya, K. Balamurugan, A. Petrosky, K. Michals, R. Matalon,Canavan disease: mutations among Jewish and non-Jewish patients, Am. J. Hum.Genet. 55 (1) (Jul 1994) 34 – 41.[5] D. Kronn, C. Oddoux, J. Phillips, H. Ostrer, Prevalence of Canavan diseaseheterozygotes in the New York metropolitan Ashkenazi Jewish population, Am. J. Hum. Genet. 57 (5) (Nov 1995) 1250 – 1252 8  No abstract available.[6] R. Matalon, K. Michals, R. Kaul, Canavan disease: from spongy degeneration tomolecular analysis, J. Pediatr. 127 (4) (Oct 1995) 511 – 517 8  Review.[7] L. Hagenfeldt, I. Bollgren, N. Venizelos, N-acetylaspartic aciduria due toaspartoacylase de fi ciency — a new aetiology of childhood leukodystrophy, J. Inherit. Metab. Dis. 10 (2) (1987) 135 – 141.[8] V. Mehta, M.A. Namboodiri, N-acetylaspartate as an acetyl source in the nervoussystem, Brain Res. Mol. Brain Res. 31 (1 – 2) (Jul 1995) 151 – 157.[9] J.R.Moffett,B.Ross,P.Arun,C.N.Madhavarao,A.M.Namboodiri,N-Acetylaspartatein the CNS: from neurodiagnostics to neurobiology, Prog. Neurobiol. 81 (2) (Feb2007) 89 – 131 8  (Epub 2007 Jan 5).[10] C.N.Madhavarao,P.Arun,J.R.Moffett,S.Szucs,S.Surendran,R.Matalon,J.Garbern,D. Hristova, A. Johnson, W. Jiang, M.A. Namboodiri, Defective N-acetylaspartatecatabolism reduces brain acetate levels and myelin lipid synthesis in Canavan'sdisease, Proc. Natl Acad. Sci. U. S. A. 102 (14) (Apr 5 2005) 5221 – 5226.[11] R. Mathew, P. Arun, C.N. Madhavarao, J.R. Moffett, M.A. Namboodiri, Progresstoward acetate supplementation therapy for Canavan disease: glyceryl triacetateadministration increases acetate, but not N-acetylaspartate, levels in brain, J. Pharmacol. Exp. Ther. 315 (1) (Oct 2005) 297 – 303 8  (Epub 2005 Jul 7).[12] J.W. Bailey, J.M. Miles, M.W. Haymond, Effect of parenteral administration of short-chain triglycerides on leucine metabolism, Am. J. Clin. Nutr. 58 (6) (Dec1993) 912 – 916.[13] J.W. Lynch, J.W. Bailey, Dietary intake of the short-chain triglyceride triacetin vs.long-chain triglycerides decreases adipocyte diameter and fat deposition in rats, J. Nutr. 125 (5) (May 1995) 1267 – 1273.[14] C.N. Madhavarao, P. Arun, Y. Anikster, S.R. Mog, O. Staretz-Chacham, J.R. Moffett,N.E. Grunberg, W.A. Gahl, A.M. Namboodiri, Glyceryl triacetate for Canavandisease: a low-dose trial in infants and evaluation of a higher dose for toxicity inthe tremor rat model, J. Inherit. Metab. Dis. 32 (5) (Oct 2009) 640 – 650 8  (Epub2009 Aug 15).[15] K.Kitada,T.Akimitsu,Y.Shigematsu,A.Kondo,T.Maihara,N.Yokoi,T.Kuramoto,M.Sasa,T.Serikawa,AccumulationofN-acetyl-L-aspartateinthebrainofthetremorrat,amutantexhibitingabsence-likeseizureandspongiformdegenerationinthecentralnervous system, J. Neurochem. 74 (6) (Jun 2000) 2512 – 2519.[16] P.Arun,C.N.Madhavarao,J.R.Moffett,K.Hamilton,N.E.Grunberg,P.S.Ariyannur,W.A.Gahl,Y.Anikster,S.Mog,W.C.Hallows,J.M.Denu,A.M.Namboodiri,Metabolicacetatetherapy improves phenotype in the tremor rat model of Canavan disease, J. Inherit.Metab. Dis. 33 (3) (Jun 2010) 195 – 210 8  (Epub 2010 May 13).[17] Lawrence Sweetman, Organic acid analysis, in: Frits A.Hommes (Ed.), Techniquesin Diagnostic Human Biochemical Genetics, a Laboratory Manual, Wiley-Less Inc,1991, pp. 143 – 176.[18] P. Li, P.S. Callery, L.S. Gan, S.K. Balani, Esterase inhibition by grapefruit juice fl avonoids leading to a new drug interaction, Drug Metab. Dispos. 35 (7) (Jul2007) 1203 – 1208 8  (Epub 2007 Apr 23).206  R. Segel et al. / Molecular Genetics and Metabolism 103 (2011) 203 –  206 
Search
Similar documents
View more...
Related Search
We Need Your Support
Thank you for visiting our website and your interest in our free products and services. We are nonprofit website to share and download documents. To the running of this website, we need your help to support us.

Thanks to everyone for your continued support.

No, Thanks