7 X 11.5 Long Title.P65

Cambridge University Press 978-0-521-51781-2 - Small Molecule Therapy for Genetic Disease Edited by Jess G. Thoene Index More information

Index

Abderhalden, Emil, 101 long-term therapy results, 147–149 absolute oral bioavailability, 37 side effects, 147 acquired copper deficiency, 202–203 antagonists, 46 active tubular secretion, 43 apomorphine, 12 acute hereditary tyrosinemia, 115 apoptosis, in cysteamine treatment, for adenosine triphosphate (ATP) nephropathic cystinosis, 103 ATP7A, 203 apparent first-order kinetics, 40–41 distal hereditary motor neuropathy, apparent volume of distribution, 39 206–207 argininosuccinate lyase (AL) deficiency, Menkes disease, 203 135 OHS, 206 argininosuccinate synthetase (AS) nephropathic cystinosis, 103 deficiency, 135 agonists, 46 AS deficiency. See argininosuccinate AKU. See alkaptonuria synthetase deficiency AL deficiency. See argininosuccinate lyase ATP. See adenosine triphosphate deficiency ATP7A, 203 ALA. See aminolevulinic acid distal hereditary motor neuropathy, alkaptonuria (AKU), 114, 118–121 206–207 cardiac involvement, 119–120 Menkes disease, 203 clinical presentation, 119 OHS, 206 arthritis as, 119 diagnosis, 121 basal ganglion diseases, 60 dietary therapies, 120 biotin therapy, 66 genetic factors, 121 inheritance factors, 63 HGA, 118–119 Bench-To-Bedside Research Program, HPPD inhibition, 124 25 incidence rates, 118–119 betaine, in homocystinuria treatment, nitisinone therapy, 125 176–179 future developments, 130 clinical evidence of, 176–177 side effects, 127 development, 176–177 tyrosine levels, 129–130 dosage, 177–178 pathophysiology, 121 FDA status, 179 renal transplants, 120 future developments, 179 vitamin therapy, 120 for remethylation disorders, 177 Alpha-1 Foundation, 21 cblC disorder, 177 ambrisentan, 11 MTHFR, 177 amino acylation products, 142–144 side effects, 178–179 aminolevulinic acid (ALA), 117–118 case studies, 178–179 Ammonul, 144–145 Bickel, Horst, 76 alternative therapy uses, 149 bioavailability, of drugs, 37–38 dosage, 146 absolute oral, 37 overdosage, 147 bioequivalence and, 38 FDA status, 147 relative, 37 HIP, 144–145 studies, 37

213

© in this web service Cambridge University Press www.cambridge.org Cambridge University Press 978-0-521-51781-2 - Small Molecule Therapy for Genetic Disease Edited by Jess G. Thoene Index More information

214 Index

bioequivalence, 38 primary, 88–92 FDA guidelines for, 38 case reports, 89–90 biomarkers, in drug development, 49–50 definition, 88 Biopten. See sapropterin dihydrochloride incidence rate, 88–89 biotin, 64–66 L-carnitine therapy for, 90–92 biosynthetic pathways, 64 in muscles, 89 cGMP activity enhancement and, 62 from OCTN2 deficiency, 89–90 dosing, 65 secondary, 88, 92–96 FDA recommendations, 65–66 clinical presentation, 92–94 gene transcription regulation, 61–62 clinical study history, 95 metabolism of, responsive disorders and, L-carnitine therapy for, 94–96 58–59 pathophysiology, 92 preparation for, 64–65 screening, 95 side effects, 65 symptoms, 92 structure, 64 Carnitor, 94 UV light and, 64 cblC disorder, 175 biotin therapy, 66 betaine therapy, 177 basal ganglion diseases, 66 CCO. See cytochrome c oxidase biotinidase deficiency, 66 CDME. See cystine dimethyl ester HCS deficiency, 66 CETT. See Collaboration, Education and biotinidase deficiency, 60 Test Translation program biotin therapy, 66 cGMP. See cyclic guanosine inheritance factors, 63 monophosphate biotin-responsive disorders, 57–64 chemical chaperones, 156, 168 basal ganglion diseases, 60 Fabry disease, 168 inheritance factors, 63 Gaucher disease, 167–168 biotin metabolism, 58–59 children. See also neonates, Menkes disease biotin therapy, 66 and biotinidase deficiency, 60 biotin-responsive disorders, 60–61 inheritance factors, 63 pharmacokinetic variables in, 51–52 in children, 60–61 Wilson disease in, zinc therapy for, 195 clinical presentation, 59–60 chitotriosidase, 165 COA deficiency, 57 chronic hereditary tyrosinemia, 115–116 HCS deficiency, 57 chronic hyperammonemia, 138–139 clinical presentation, 59 clearance, of drugs, 39–40 inheritance factors, 62–63 elimination, 39–40 hearing loss from, 61 hepatic, mechanisms and determinants immunological abnormalities, 61 of, 40 inheritance factors, 62–64 blood flow and, 40 MCD, 57 protein binding and, 40 pathophysiology, 60–62 intercompartmental, 39 in brain tissue, 61 renal, mechanisms and determinants of, causative factors, 60 40 PCC deficiency, 57 Fick principle, 40 screening programs, 62 GFR and, 40 symptoms, 59 Clinical and Translational Science Award bone marrow transplantation, for (CTSA), 25 lysosomal storage disorders, 156 COA. See ␤-methylcrotonyl-coenzyme A bosentan, 11 CoA. See coenzyme A Buphenyl. See sodium phenylbutyrate cobalamin, 72–73 coenzymes, 69 carbamoyl phosphate synthetase (CPS) deficiency, 72 deficiency, 135 mechanism of action, 73 cardiomyopathy, HT and, 129 metabolism, 69 carnitine deficiency disorders as MMA treatment therapy, 70, 73 L-carnitine therapy, 86–87 clinical effects, 73 mortality rates, 94–95 dosage, 73 for primary carnitine deficiency, 90–92 future developments, 74 for secondary carnitine deficiency, natural forms, 69 94–96 pharmaceutical formulations, 72–73

Index 215

processing defects, 71–72 mutation inheritance, 104 Cb1A, 71 renal failure from, 109 Cb1B, 71 results, 109–110 Cb1C, 71–72 side effects, 108 Cb1D, 72 Stevens-Johnson syndrome from, 108 Cb1F, 72 vomiting, 108 Cockroft-Gault equation, 50 Cystic Fibrosis Foundation, 20–21 coenzyme A (CoA), 86–87 cystine dimethyl ester (CDME), 103 Collaboration, Education and Test cystinosis. See nephropathic cystinosis Translation (CETT) program, 22–23 cystinuria, 101 genetic mutation information collection, cytochrome c oxidase (CCO), 205 23 goals, 22 distal hereditary motor neuropathy, copper, as trace element, 202 206–207 copper chloride, 208 distribution, of drugs, 38–39 copper deficiency syndromes, 202–211 VD, 38–39 acquired, 202–203 apparent, 39 distal hereditary motor neuropathy, drug absorption, 37 206–207 drug development, 47–50. See also inherited, 203–207 pharmacodynamics; Menkes disease, 202–205 pharmacokinetics animal models, 207 biomarkers, 49–50 ATP7A, 203 dose-escalation schemes, 48–49 brain pathology, 205 Fibonacci, 48 CCO activity, 205 PGDE, 48–49 clinical features, 204–205 exploratory trials, with clinical presentation, 203–204 nonpharmacological doses, 49 diagnosis, 204 FIH dosing estimates, 48 during neonatal period, 205 drug metabolism, 40–41 PAM deficiency, 204–205 clinical approaches to, 51 phenotypes, 204 enzymes for, 42 X-linked, 203 CYP, 41–42 OHS, 206 kinetics, 40–41 molecular basis, 206 apparent first-order, 40–41 small copper complexes, in treatment saturable of Michaelis-Menten type, therapies, 207–209 41 transport mechanisms to central nervous reactions, 41 system, 209–210 hepatic cells, 41 copper gluconate, 207–209 Phase I, 41 copper histidine, 208 transport, 41–42 copper sulfate, 208 CYP enzymes, 41–42 CPS deficiency. See carbamoyl phosphate genomics, 41–42 synthetase deficiency drug-dosing, pharmacokinetic principles, CTSA. See Clinical and Translational 43–45 Science Award continuous infusion, 44 cyclic guanosine monophosphate (cGMP), design criteria, 45 62 multiple regimens, 44–45 CYP enzymes, 41–42 plateau principle, 43–44 racial distribution, 42 single regimens, 44 Cystagon. See cysteamine drug-receptor interactions, 46 cysteamine, 104–106 agonists, 46 cystine storage, 105 antagonists, 46 hygroscopic nature, 104 dose-response relationship, 46–47 structure, 104 drug efficacy, 46 as treatment, for nephropathic cystinosis, 101–106, 111 elimination clearance, 39–40 apoptosis, 103 EMEA. See European Medicines Agency dosage, 107–108 enzyme replacement therapy, for lysosomal FDA status, 109 storage disorders, 155–156, 168 future applications, 110–111 epoprostenol, 12

216 Index

European Medicines Agency (EMEA), 6 for neglected diseases, 30 OTT, 30 FAA. See fumarylacetoacetate Gallin, John, 24 Fabry disease, 155 GARD. See Gaining Access to Research chemical chaperones, 168 Discoveries combination therapy for, 168 Gaucher disease, 155 enzyme replacement therapy, 155–156, alternative small molecular entities, 168 165–168 synthesis inhibition therapy, 156–157 chemical chaperones, 167–168 Fanconi syndrome, 101, 109 miglustat, 165–167 MAA as factor, 117 chitotriosidase as biomarker, 165 Faucett, Andrew, 23 combination therapy for, 168 FDA. See Food and Drug Administration enzyme replacement therapy, 155–156, FDAAA. See Food and Drug Administration 168 Amendments Act Genz-112638 in treatment therapy, 166 FDCA. See Federal Food, Drug, and miglustat in treatment therapy, 166 Cosmetics Act Phase II studies, 164 Federal Food, Drug, and Cosmetics Act synthesis inhibition therapy, 156–157 (FDCA) (U.S.), 3 gene therapy, for lysosomal storage Fibonacci scheme, 48 disorders, 156, 168 Fick principle, 40 genetic disorders, orphan drugs for FIH dose. See first-in-human dose clinical development of, 14 first-in-human (FIH) dose, 48 nonbiological, FDA approval of, 9, 12–15 Folling, Asbjorn, 76 Genz-112638, 163–165 Food and Drug Administration (FDA) Gaucher disease therapy, 166 Ammonul status, 147 miglustat v., as treatment therapy, 167 betaine status, in homocystinuria GFR. See glomerular filtration rate treatment, 179 glomerular filtration rate (GFR), 40 bioequivalence guidelines, 38 drug elimination and, 43 biotin recommendations, 65–66 glucosylceramide synthase inhibition, cysteamine treatment, status under, 109 159–160 NDAs, 5, 12 glutamine hypothesis, 138 phases, 12 MAPK, 138 nitisinone status, 122 MPT, 138 nonbiological orphan drugs under glutathione (GSH), 103–104 clinical studies, 13–15 glycol phenylbutyrate, 150 for genetic disorders, 9, 12–15 Groft, Stephen, xii, 24 under Orphan Drug Act, 8–15 GSH. See glutathione Orphan Drug Act under, 3–4 marketing exclusivity, 4, 7–8 Haffner, Marlene, xii OOPD, 4 half-life, of drugs, 39 written recommendations for Hart, Suzanne, 23 investigation, 5 HCS. See holocarboxylase synthetase Prescription Drug User Free Act under, 5 deficiency NDAs, 5 hereditary tyrosinemia (HT), 114–118 sapropterin dihydrochloride approval, acute, 115 80 age of presentation as prognosis factor, TM therapy for Wilson disease, status of, 116 197 chronic, 115–116 Food and Drug Administration diagnosis, 116–117 Amendments Act (FDAAA), 5–6 newborn-screening programs, 117 Forman, Lisa, 23 genetic factors, 118 Friedreich Ataxia Research Association, 21 HPPD inhibition, 123–124 fumarylacetoacetate (FAA), 117 incidence rates, 115 nitisinone therapy, 124–125, 127–130 Gahl, William, 23–24 administration, 124–125 Gaining Access to Research Discoveries cardiomyopathy complications, 129 (GARD), 29–30 in children, 127 functions, 29 dosage, 124 Internet applications, 29 future developments, 130

Index 217

growth and development INOD. See In Need of Diagnosis complications, 129 intercompartmental clearance, 39 hepatic complications, 127–128 investigational new drug (IND) neurologic complications, 128 applications, 163. See also New Drug renal tubular dysfunction, 128 Applications side effects, 125–127 tyrosine levels, 129 kidneys pathophysiology, 117–118 drug clearance, mechanisms and ALA, 117–118 determinants of, 40 FAA, 117 Fick principle, 40 MAA, 117 GFR and, 40 SA, 117 drug elimination, 43 screening for, 116 active tubular secretion, 43 in diagnosis, in newborns, 117 GFR, 43 HGA. See homogentisic acid passive tubular secretion, 43 HIP nitrogen. See hippurate nitrogen HT and, nitisinone therapy for, 128 hippurate (HIP) nitrogen, 140 PTD, 128 Ammonul, 144–145 holocarboxylase synthetase (HCS) L-carnitine deficiency, 57 in carnitine deficiency disorders therapy, biotin therapy, 66 86–87 clinical presentation, 59 clinical study history, 95 inheritance factors, 62–63 mortality rates, 94–95 homocystinurias, 173–179 for primary carnitine deficiency, betaine treatment, 176–179 90–92 clinical evidence of, 176–177 for secondary carnitine deficiency, development, 176–177 94–96 dosage, 177–178 CoA, 86–87 FDA status, 179 primary sources, 87 future developments, 179 synthesis, 86 remethylation disorders, 177 liver for remethylation disorders, 177 drug clearance, mechanisms and side effects, 178–179 determinants of, 40 methionine metabolic pathways, 173 blood flow and, 40 pathogenesis, 174–175 protein binding and, 40 presymptomatic therapy, 175 Wilson disease, zinc therapy and, 195 remethylation disorders, 175–176 lysosomal storage disorders, 153–169 betaine therapy, 177 discovery of, 154–155 cblC disorder, 175 Fabry disease, 155 MTHFR deficiency, 176 chemical chaperones, 168 transsulfuration disorder, 174–175 combination therapy for, 168 homogentisic acid (HGA), 118–119 enzyme replacement therapy, HPPD. See hydroxyphenylpyruvate 155–156, 168 dioxygenase synthesis inhibition therapy, 156–157 HT. See hereditary tyrosinemia Gaucher disease, 155 hydroxyphenylpyruvate dioxygenase alternative small molecular entities, (HPPD), 123–124 165–168 AKU and, 124 chitotriosidase as biomarker, 165 HT and, 123–124 combination therapy for, 168 hyperammonemia, 136–137 enzyme replacement therapy, chronic, 138–139 155–156, 168 treatment therapies, 140 Genz-112638 in treatment therapy, hypothyroidism, 102, 109 166 miglustat in treatment therapy, 166 iloprost, 12 Phase II studies, 164 In Need of Diagnosis (INOD), 25 synthesis inhibition therapy, 156–157 IND applications. See investigational new IND applications, 163 drug applications nephropathic cystinosis, 103 infants, nephropathic cystinosis, cysteamine, as treatment, 101–106, development of, 101–102 111

218 Index

lysosomal storage disorders (cont.) cobalamin, 69 cystinuria, 101 secondary carnitine deficiency, inborn diagnosis, 102 errors, 93 hypothyroidism, 102, 109 metallothionein (MT) induction, 191 inheritance, 104 methionine metabolic pathways, 173 mortality rates, 102 ␤-methylcrotonyl-coenzyme A (COA), 57 natural history, 101–102 methylenetetrahydrofolate reductase pancreatitis, 102 (MTHFR) deficiency, 176 pathophysiology, 102–104 betaine therapy, 177 phenotypes, 102–104 methylmalonic acidemias (MMAs), 68–74. restrictive pulmonopathy, 102 See also cobalamin PDMP-based inhibitors, 157–163 cobalamin as treatment therapy, 70, 73 additional activities, 161 clinical effects, 73 as cationic amphiphilic drug, 160–161 dosage, 73 combination therapy with, 168 future developments, 74 functional groups, 158 cobalamin-processing defects, 71–72 glucosylceramide synthase inhibition, Cb1A, 71 159–160 Cb1B, 71 homologue development, clinical trials Cb1C, 71–72 for, 162–163 Cb1D, 72 Phase studies, 163–165 Cb1F, 72 Gaucher disease, 164 early clinical reports, 68–69 I, 163–164 mutase deficiency, 69–71 II, 164–165 diagnosis, 70 sphingolipids, 153–154 treatment, 70–71 synthesis inhibition therapy, 156–157 pathophysiology, 68 treatment strategies, 155–156 miglustat, 165–167 bone marrow transplantation, 156 Gaucher disease therapy, 166 chemical chaperones, 156, 168 Genz-112638 v., as treatment therapy, enzyme replacement, 155–156, 168 167 gene therapy, 156, 168 mitochondrial permeability transition (MPT), 138 MAA. See maleylacetoacetate mitogen-activated protein kinases (MAPK), maleylacetoacetate (MAA), 117 138 Fanconi syndrome, 117 MMAs. See methylmalonic acidemias MAPK. See mitogen-activated protein Modification in Diet in Renal Disease kinases (MDRD) equation, 50–51 MCD. See multiple carboxylase deficiency Molecular Libraries initiative, 31–32 MDRD equation. See Modification in Diet MPT. See mitochondrial permeability in Renal Disease equation transition medically plausible subsets, under Orphan MT induction. See metallothionein Drug Act, 7, 17 induction definition of, 7 MTHFR deficiency. See for Parkinson disease, 12 methylenetetrahydrofolate reductase therapeutic orphans, 7, 16 deficiency Menkes disease, 202–205 multiple carboxylase deficiency (MCD), animal models, 207 57 ATP7A, 203 Muscular Dystrophy Association, 21 brain pathology, 205 mutase deficiency, 69–71 CCO activity, 205 diagnosis, 70 clinical features, 204–205 treatment, 70–71 clinical presentation, 203–204 diagnosis, 204 N-acetylglutamate synthetase (NAGS) during neonatal period, 205 deficiency, 135 PAM deficiency, 204–205 NAGS deficiency. See N-acetylglutamate phenotypes, 204 synthetase deficiency X-linked, 203 National Center for Research Resources metabolism. See also drug metabolism (NCRR), 25 of biotin, responsive disorders and, National Commission on Orphan 58–59 Diseases, xii

Index 219

National Institutes of Health (NIH), 19–34. pancreatitis, 102 See also Office of Rare Diseases pathophysiology, 102–104 Research aberrant energy production, 103 ORDR, 19–34 ATP production, 103 CETT program, 22–23 CDME, 103 collaborative research efforts, 25 cystine content, 103 development of, 19–20 PKC, 103 function of, 20 phenotypes GARD, 29–30 aberrant energy production, 103 goals of, 20 development, 102–103 orphan drug development and, 20–21 GSH, 103–104 PAGs and, 29 lysosomal storage, 103 RDCRN, 26–28 restrictive pulmonopathy, 102 scientific conferences support, 21–22 New Drug Applications (NDAs), 5 PAGs as collaborators, 28–29, 34 definition criteria, 18 ORDR and, 29 lysosomal storage disorders, 163 research initiatives, 31, 34 phases, 12 Molecular Libraries, 31–32 substantial evidence of effectiveness as RAID program, 32 criteria, 13 TRND program, 32–33 well-controlled investigations, 13 Roadmap for Medical Research, 30–31 NGCC. See NIH Chemical Genomics Center UDP, 23–25 NIH Chemical Genomics Center (NGCC), National Library of Medicine/National 33 Center for Biotechnology nitisinone, 121–123 Information (NLM/NCBI), 23 for AKU, 125 National Organization for Rare Disorders future developments, 130 (NORD), 25 side effects, 127 natural history of disease studies, 24 tyrosine levels, 129–130 NCRR. See National Center for Research FDA status, 122 Resources half-life, 123 NDAs. See New Drug Applications HPPD, 123–124 neglected diseases, 30 AKU and, 124 neonates, Menkes disease and, 205 HT and, 123–124 nephropathic cystinosis for HT, 124–125, 127–130 cysteamine, as treatment, 101–106, 111 administration, 124–125 apoptosis, 103 cardiomyopathy complications, 129 cystine storage, 105 in children, 127 dosage, 107–108 dosage, 124 FDA status, 109 future developments, 130 future applications, 110–111 growth and development hygroscopic nature, 104 complications, 129 mechanism of action, 106–107 hepatic complications, 127–128 mutation inheritance, 104 HPPD, 123–124 renal failure from, 109 neurologic complications, 128 results, 109–110 renal tubular dysfunction, 128 side effects, 108 side effects, 125–127 Stevens-Johnson syndrome from, 108 tyrosine levels, 129 structure, 104 mechanism of action for, 123–124 vomiting, 108 pharmacokinetics of, 122–123 cystinuria, 101 side effects, 125–127 diagnosis, 102 toxicity, 125–127 hypothyroidism, 102, 109 NLM/NCBI. See National Library of inheritance, 104 Medicine/National Center for gene location, 104 Biotechnology Information mortality rates, 102 nonbiological orphan drugs, 8–15 natural history, 101–102 FDA approval, for genetic disorders, 9, Fanconi syndrome, 101, 109 12–15 infant development, 101–102 clinical studies, 13–15 late complications, 102 market exclusivity of, 11 urinary volume, 102 timeline, 10–11

220 Index

NORD. See National Organization for Rare incentives, 4–6, 15 Disorders marketing exclusivity, 4 open treatment protocols, 5 occipital horn syndrome (OHS), 206 product grants, 4–5 molecular basis, 206 tax credits, 5, 16 ochronosis, 119 waiver of use fees, 5–6 OCTN2 deficiency, 89–90 written recommendations for Office of Rare Diseases Research (ORDR), investigation, 5 19–34 marketing exclusivity under, 4 CETT program, 22–23 for clinical superiority of new drugs, 8, genetic mutation information 17 collection, 23 protections, 7–8 goals, 22 medically plausible subsets, 7, 17 collaborative research efforts, 25 definition, 7 Bench-To-Bedside Research Program, therapeutic orphans, 7, 16 25 orphan drugs development of, 19–20 clinical superiority of new drugs, 8 function of, 20 definition of, 4 GARD, 29–30 designation, 6–7 functions, 29 information criteria for, 6 Internet applications, 29 nonbiological, 8–9, 15 for neglected diseases, 30 revocation of designation, 7 OTT, 30 Orphan Products Development (OOPD), 4 goals of, 20 OTC deficiency. See ornithine orphan drug development and, 20–21 transcarbamylase deficiency PAGs and, 29 OTT. See Office of Technology Transfer RDCRN, 26–28 consortia of organizations, 26 PAGN nitrogen. See phenylacetylglutamine goals of, 26 nitrogen patient participation, 26–28 Pagon, Roberta, 23 researched diseases, 26 PAGs. See patient advocacy groups scientific conferences support, 21–22 PAH. See phenylalanine hydroxylase Office of Technology Transfer (OTT), 30 PAM deficiency. See peptidylglycine OHS. See occipital horn syndrome alpha-amidating monooxygenase OOPD. See Orphan Products Development deficiency ORDR. See Office of Rare Diseases Research pancreatitis, 102 ornithine transcarbamylase (OTC) Parent Project for Duchenne Muscular deficiency, 135 Dystrophy, 21 neonatal onset, 149 Parkinson disease, medically plausible orphan diseases, 3 subsets for, 12 orphan drug(s) passive tubular secretion, 43 clinical superiority of new drugs, 8 patient advocacy groups (PAGs), 20 definition of, 4 NIH collaboration, 28–29, 34 designation, 6–7 ORDR and, 29 for genetic disorders, clinical Patrick, A.D., 102 development of, 14 PCC. See propionyl-CoA carboxylase information criteria for, 6 PDMP. See nonbiological, 8–9, 15 1-phenyl-2-decanoylamino-3-morpholino- FDA approval, for genetic disorders, 9, propanol inhibitors 12–15 penicillamine, 189–190 market exclusivity of, 11 peptidylglycine alpha-amidating timeline, 10–11 monooxygenase (PAM) deficiency, ORDR coordination, 20–21 204–205 revocation of designation, 7 PET. See positron emission tomography Orphan Drug Act (U.S.), xi, 3–16 (PET), in drug development under FDA, 3–4 PGDE scheme. See pharmacologically OOPD, 4 guided dose escalation scheme orphan drug designation, 6–7 pharmacodynamics, 35–52 written recommendations for clinical approach, 50–52 investigation, 5 definition, 36

Index 221

drug development and, 47–50 PAH deficiency, 76 key abbreviations, 36 inheritance factors, 79 principles, 45–47 pathophysiology, 76 antagonism, 47 central nervous system dysfunction, drug-receptor interactions, 46 79 synergism, 47 pregnancy and, 78–79 tolerance, 47 sapropterin dihydrochloride as treatment pharmacokinetics, 35–52. See also therapy, 79–80 bioavailability, of drugs; clearance, with diet, 77–78, 82–83 of drugs; drug metabolism FDA approval, 80 children and, variables for, 51–52 future developments, 83 clinical approach, 50–52 primary benefits, 82 definition, 36 responsiveness testing, 80–82 drug development and, 47–50 results of, 80–83 drug-dosing, 43–45 side effects, 80 continuous infusion, 44 synthesis, 79–80 design criteria, 45 screening tests, 77 multiple regimens, 44–45 severity spectrum, 77 plateau principle, 43–44 treatment outcomes, 78 single regimens, 44 phosphocysteamine, 111 key abbreviations, 36 phospholipase A2, 161 of nitisinone, 122–123 PKU. See phenylketonuria principles, 37–43 plateau principle, drug-dosing, 43–44 alternative administrations, 37 steady-state concentrations, 43–44 bioavailability, 37–38 directly proportional, 44 clearance, 39–40 inversely proportional, 44 drug absorption, 37 positron emission tomography (PET), in drug distribution, 38–39 drug development, 50 elimination routes, 42–43 pregnancy half-life, 39 PKU and, 78–79 metabolism, 40–41 Wilson disease during, zinc therapy and, for UCDs, 144–145 195 sodium benzoate, 144–145 Prescription Drug User Free Act (U.S.), 5 sodium phenylacetate, 144–145 primary carnitine deficiency, 88 pharmacologically guided dose escalation case reports, 89–90 (PGDE) scheme, 48–49 definition, 88 1-phenyl-2-decanoylamino-3-morpholino- incidence rate, 88–89 propanol (PDMP) inhibitors, L-carnitine therapy for, 90–92 157–163 in muscles, 89 additional activities, 161 from OCTN2 deficiency, 89–90 as cationic amphiphilic drug, Progeria Research Foundation, 21 160–161 propionyl-CoA carboxylase (PCC), 57 phospholipase A2 inhibition, 161 protein kinase C (PKC), 103 combination therapy with, 168 proximal tubular dysfunction (PTD), 128 functional groups, 158 PTD. See proximal tubular dysfunction glucosylceramide synthase inhibition, 159–160 Radin, Norman, 156, 168 in vitro/in vivo proof-of-concept RAID. See Rapid Access to Interventional studies, 161–162 Development program homologue development, clinical trials Rapid Access to Interventional for, 162–163 Development (RAID) program, 32 Genz-112638, 163–165 Rare Diseases Clinical Research Network miglustat, 165–167 (RDCRN), 26–28 phenylacetylglutamine (PAGN) nitrogen, consortia of organizations, 26 140 goals of, 26 phenylalanine hydroxylase (PAH), 76 patient participation, 26–28 inheritance factors, 79 researched diseases, 26 phenylketonuria (PKU), 76–79 RDCRN. See Rare Diseases Clinical Research clinical presentation, 76–77 Network long-term consequences, 78 Reagan, Ronald, 3

222 Index

relative bioavailability, 37 mechanism of action, 192 remethylation disorders, 175–176 side effects, 197 betaine therapy, 177 therapeutic orphans, 7, 16 cblC disorder, 175 Therapeutics for Rare and Neglected betaine therapy, 177 Diseases (TRND), 32–33 MTHFR deficiency, 176 NGCC and, 33 betaine therapy, 177 TM. See tetrathiomolybdate (TM), for renal failure, from nephropathic cystinosis, Wilson disease 109 tolerance, 47 restrictive pulmonopathy, 102 transsulfuration disorder, 174–175 Roadmap for Medical Research, 30–31 treprostinil, 12 trientine, for Wilson disease, 190–191 SA. See succinylacetoacetate zinc therapy with, 195–196 sapropterin dihydrochloride, in PKU TRND. See Therapeutics for Rare and therapy, 79–80 Neglected Diseases with diet, 77–78, 82–83 FDA approval, 80 UCDs. See urea cycle disorders future developments, 83 Ucephan, 8 primary benefits, 82 UDP. See Undiagnosed Diseases Program responsiveness testing, 80–82 ultraviolet (UV) light, 64 results, 80–83 Undiagnosed Diseases Program (UDP), side effects, 80 23–25 synthesis, 79–80 goals, 24 saturable kinetics of Michaelis-Menten natural history of disease studies, 24 type, 41 urea cycle disorders (UCDs), 135–139. See Schwartz equation, 51 also waste nitrogen disposal secondary carnitine deficiency, 88, 92–96 therapies, for UCDs clinical presentation, 92–94 AS, 135 inborn errors of metabolism, 93 AL, 135 L-carnitine therapy, 94–96 clinical presentation, 136 clinical study history, 95 CPS, 135 pathophysiology, 92 hyperammonemia, 136–137 screening, 95 chronic, 138–139 symptoms, 92 treatment therapies, 140 selegiline, 12 incidence rates, 135 small copper complexes, in treatment inheritance factors, 139 therapies, 207–209 molecular genetics of, 139 sodium benzoate, 144–145 mortality/morbidity rates, 136 sodium phenylacetate, 144–145 NAGS, 135 sodium phenylbutyrate, 144 OTC, 135 sphingolipids, 153–154 pathophysiology, 136–139 biological functions, 154 ammonium ions, 138 definition, 153 glutamine hypothesis, 138 Spinella, Giovanna, 23 hyperammonemia, 136–137 Stevens-Johnson syndrome, 108 waste nitrogen disposal therapies, succinylacetoacetate (SA), 117 140–143, 150 SWAN. See Symptoms Without a Name alternative pathway, 148–149 Symptoms Without a Name (SWAN), 25 amino acylation products, 142–144 synergism, 47 dosage, 145–146 synthesis inhibition therapy, for lysosomal FDA status, 147 storage disorders, 156–157 future developments, 149–150 synthetic porcine secretin, 8 glycol phenylbutyrate, 150 HIP nitrogen, 140 tax credits, under Orphan Drug Act, 5, 16 long-term results, 144, 147–149 Tay-Sachs disease, 157 mechanism of action, 140–145 tetrathiomolybdate (TM), for Wilson PAGN nitrogen, 140 disease, 192–193 pharmacokinetics of Ammonul, case studies, 196 144–145 dosage, 193 side effects, 146–147 FDA status, 197 urea cycle intermediates, 141–142

Index 223

UV. See ultraviolet light hepatic, 185–186 neurologic, 186 VD. See volume of distribution diagnosis, 186–189 vitamin B12. See cobalamin criteria, 188 Vitamin C, 120 tests for, 187 volume of distribution (VD), 38–39 inheritance factors, 187 apparent, 39 liver failure presentation, 195 vomiting, as side effect therapeutic treatment therapies, 190 of Ammonul therapy, 147 anticopper drugs, 189 of cysteamine treatment, 108 future developments, 198 long-term results, 193 waste nitrogen disposal therapies, for penicillamine, 189–190 UCDs, 140–143, 150 TM therapy, 192–193 alternative pathway, 148–149 case studies, 196 amino acylation products, dosage, 193 142–144 FDA status, 197 Ammonul, pharmacokinetics of, mechanism of action, 192 144–145 side effects, 197 alternative therapy uses, 149 trientine therapy, 190–191 dosage, 146 zinc therapy with, 195–196 FDA status, 147 zinc therapy, 191–192 HIP, 144–145 dosage, 194 long-term therapy results, 144, efﬁcacy monitoring, 192 147–149 failure reports, 194 side effects, 147 MT induction, 191 dosage, 145–146 in pediatric patients, 195 FDA status, 147 during pregnancy, 195 future developments, 149–150 in presymptomatic patients, 195 glycol phenylbutyrate, 150 side effects, 192 HIP nitrogen, 140 with trientine, 195–196 long-term results, 147–149 mechanism of action, 140–145 zinc therapy, for Wilson disease, 191–192 PAGN nitrogen, 140 dosage, 194 side effects, 146–147 efﬁcacy monitoring, 192 urea cycle intermediates, 141–142 failure reports, 194 Waxman, Henry, xi, 3 MT induction, 191 Wilson disease, 185–198. See also in pediatric patients, 195 tetrathiomolybdate (TM), for Wilson during pregnancy, 195 disease; zinc therapy, for Wilson in presymptomatic patients, 195 disease side effects, 192 clinical presentation, 185–186 trientine therapy and, 195–196