CA1323294C - Method of treatment of central nervous system diseases such as alzheimer's disease and parkinson's disease and method of diagnosing alzheimer's disease - Google Patents
Method of treatment of central nervous system diseases such as alzheimer's disease and parkinson's disease and method of diagnosing alzheimer's diseaseInfo
- Publication number
- CA1323294C CA1323294C CA000555899A CA555899A CA1323294C CA 1323294 C CA1323294 C CA 1323294C CA 000555899 A CA000555899 A CA 000555899A CA 555899 A CA555899 A CA 555899A CA 1323294 C CA1323294 C CA 1323294C
- Authority
- CA
- Canada
- Prior art keywords
- levels
- disease
- patient
- alzheimer
- dopa
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 208000024827 Alzheimer disease Diseases 0.000 title claims abstract description 80
- 238000000034 method Methods 0.000 title claims abstract description 48
- 208000018737 Parkinson disease Diseases 0.000 title abstract description 8
- 208000015114 central nervous system disease Diseases 0.000 title abstract description 6
- 229940088597 hormone Drugs 0.000 claims abstract description 64
- 239000005556 hormone Substances 0.000 claims abstract description 64
- 238000012360 testing method Methods 0.000 claims abstract description 51
- 102000018997 Growth Hormone Human genes 0.000 claims abstract description 44
- 108010051696 Growth Hormone Proteins 0.000 claims abstract description 44
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 claims abstract description 37
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 claims abstract description 37
- 102000004218 Insulin-Like Growth Factor I Human genes 0.000 claims abstract description 29
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 claims abstract description 28
- 206010039966 Senile dementia Diseases 0.000 claims abstract description 25
- 210000004369 blood Anatomy 0.000 claims abstract description 18
- 239000008280 blood Substances 0.000 claims abstract description 18
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 claims abstract description 12
- 229940076279 serotonin Drugs 0.000 claims abstract description 6
- -1 cathecoline Chemical compound 0.000 claims abstract 2
- 230000028327 secretion Effects 0.000 claims description 20
- 210000002966 serum Anatomy 0.000 claims description 16
- 241000282414 Homo sapiens Species 0.000 claims description 12
- GJSURZIOUXUGAL-UHFFFAOYSA-N Clonidine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NCCN1 GJSURZIOUXUGAL-UHFFFAOYSA-N 0.000 claims description 4
- 102000051325 Glucagon Human genes 0.000 claims description 4
- 108060003199 Glucagon Proteins 0.000 claims description 4
- 229960002896 clonidine Drugs 0.000 claims description 4
- MASNOZXLGMXCHN-ZLPAWPGGSA-N glucagon Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 MASNOZXLGMXCHN-ZLPAWPGGSA-N 0.000 claims description 4
- 229960004666 glucagon Drugs 0.000 claims description 4
- OZVBMTJYIDMWIL-AYFBDAFISA-N bromocriptine Chemical compound C1=CC(C=2[C@H](N(C)C[C@@H](C=2)C(=O)N[C@]2(C(=O)N3[C@H](C(N4CCC[C@H]4[C@]3(O)O2)=O)CC(C)C)C(C)C)C2)=C3C2=C(Br)NC3=C1 OZVBMTJYIDMWIL-AYFBDAFISA-N 0.000 claims description 3
- 229960002802 bromocriptine Drugs 0.000 claims description 3
- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol Chemical compound C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 claims description 3
- 108090000371 Esterases Proteins 0.000 claims description 2
- 102000013275 Somatomedins Human genes 0.000 claims description 2
- 238000009534 blood test Methods 0.000 claims description 2
- 239000012530 fluid Substances 0.000 claims description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 37
- 201000010099 disease Diseases 0.000 abstract description 35
- 102000002265 Human Growth Hormone Human genes 0.000 abstract description 32
- 108010000521 Human Growth Hormone Proteins 0.000 abstract description 32
- 239000000854 Human Growth Hormone Substances 0.000 abstract description 32
- 230000001195 anabolic effect Effects 0.000 abstract description 21
- 238000003745 diagnosis Methods 0.000 abstract description 17
- 239000000122 growth hormone Substances 0.000 abstract description 17
- 230000007812 deficiency Effects 0.000 abstract description 11
- 239000003163 gonadal steroid hormone Substances 0.000 abstract description 11
- 206010012289 Dementia Diseases 0.000 abstract description 5
- 206010044565 Tremor Diseases 0.000 abstract description 5
- 206010008027 Cerebellar atrophy Diseases 0.000 abstract description 3
- 201000006517 essential tremor Diseases 0.000 abstract description 3
- KWTSXDURSIMDCE-QMMMGPOBSA-N (S)-amphetamine Chemical compound C[C@H](N)CC1=CC=CC=C1 KWTSXDURSIMDCE-QMMMGPOBSA-N 0.000 abstract description 2
- 206010008096 Cerebral atrophy Diseases 0.000 abstract description 2
- 229940025084 amphetamine Drugs 0.000 abstract description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 abstract 2
- 208000032862 Clinical Deterioration Diseases 0.000 abstract 1
- 230000003110 anti-inflammatory effect Effects 0.000 abstract 1
- 229960003638 dopamine Drugs 0.000 abstract 1
- 230000001939 inductive effect Effects 0.000 abstract 1
- 150000003431 steroids Chemical class 0.000 abstract 1
- 229940124549 vasodilator Drugs 0.000 abstract 1
- 239000003071 vasodilator agent Substances 0.000 abstract 1
- 229960004502 levodopa Drugs 0.000 description 21
- 210000004556 brain Anatomy 0.000 description 20
- 239000003098 androgen Substances 0.000 description 17
- 239000003814 drug Substances 0.000 description 14
- 229940079593 drug Drugs 0.000 description 13
- 238000003127 radioimmunoassay Methods 0.000 description 12
- 206010062767 Hypophysitis Diseases 0.000 description 10
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 10
- 210000003635 pituitary gland Anatomy 0.000 description 10
- 230000000694 effects Effects 0.000 description 8
- 208000024891 symptom Diseases 0.000 description 8
- 239000003263 anabolic agent Substances 0.000 description 7
- 229940030486 androgens Drugs 0.000 description 7
- 239000000427 antigen Substances 0.000 description 7
- 102000036639 antigens Human genes 0.000 description 7
- 108091007433 antigens Proteins 0.000 description 7
- 238000004519 manufacturing process Methods 0.000 description 7
- 229960001751 fluoxymesterone Drugs 0.000 description 6
- YLRFCQOZQXIBAB-RBZZARIASA-N fluoxymesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1CC[C@](C)(O)[C@@]1(C)C[C@@H]2O YLRFCQOZQXIBAB-RBZZARIASA-N 0.000 description 6
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 5
- 102000004877 Insulin Human genes 0.000 description 5
- 108090001061 Insulin Proteins 0.000 description 5
- 102100022831 Somatoliberin Human genes 0.000 description 5
- 101710142969 Somatoliberin Proteins 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 5
- 230000003412 degenerative effect Effects 0.000 description 5
- 230000001419 dependent effect Effects 0.000 description 5
- 239000008103 glucose Substances 0.000 description 5
- 230000001456 gonadotroph Effects 0.000 description 5
- 229940125396 insulin Drugs 0.000 description 5
- 210000003734 kidney Anatomy 0.000 description 5
- 210000004185 liver Anatomy 0.000 description 5
- 210000002569 neuron Anatomy 0.000 description 5
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 description 4
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 4
- 206010003694 Atrophy Diseases 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 4
- 229960001138 acetylsalicylic acid Drugs 0.000 description 4
- 230000037444 atrophy Effects 0.000 description 4
- 230000009286 beneficial effect Effects 0.000 description 4
- 230000001413 cellular effect Effects 0.000 description 4
- 229940035811 conjugated estrogen Drugs 0.000 description 4
- 229960002768 dipyridamole Drugs 0.000 description 4
- IZEKFCXSFNUWAM-UHFFFAOYSA-N dipyridamole Chemical compound C=12N=C(N(CCO)CCO)N=C(N3CCCCC3)C2=NC(N(CCO)CCO)=NC=1N1CCCCC1 IZEKFCXSFNUWAM-UHFFFAOYSA-N 0.000 description 4
- 229960005309 estradiol Drugs 0.000 description 4
- 229930182833 estradiol Natural products 0.000 description 4
- 229940011871 estrogen Drugs 0.000 description 4
- 239000000262 estrogen Substances 0.000 description 4
- 210000003016 hypothalamus Anatomy 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 230000000638 stimulation Effects 0.000 description 4
- 101000599951 Homo sapiens Insulin-like growth factor I Proteins 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 150000003943 catecholamines Chemical class 0.000 description 3
- 210000003169 central nervous system Anatomy 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000002405 diagnostic procedure Methods 0.000 description 3
- 230000003291 dopaminomimetic effect Effects 0.000 description 3
- QTTMOCOWZLSYSV-QWAPEVOJSA-M equilin sodium sulfate Chemical compound [Na+].[O-]S(=O)(=O)OC1=CC=C2[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4C3=CCC2=C1 QTTMOCOWZLSYSV-QWAPEVOJSA-M 0.000 description 3
- 230000003340 mental effect Effects 0.000 description 3
- 208000015122 neurodegenerative disease Diseases 0.000 description 3
- 239000002858 neurotransmitter agent Substances 0.000 description 3
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 3
- 230000002285 radioactive effect Effects 0.000 description 3
- 230000014616 translation Effects 0.000 description 3
- DNXHEGUUPJUMQT-UHFFFAOYSA-N (+)-estrone Natural products OC1=CC=C2C3CCC(C)(C(CC4)=O)C4C3CCC2=C1 DNXHEGUUPJUMQT-UHFFFAOYSA-N 0.000 description 2
- DNXHEGUUPJUMQT-CBZIJGRNSA-N Estrone Chemical compound OC1=CC=C2[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 DNXHEGUUPJUMQT-CBZIJGRNSA-N 0.000 description 2
- 108010086677 Gonadotropins Proteins 0.000 description 2
- 102000006771 Gonadotropins Human genes 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 102000005157 Somatostatin Human genes 0.000 description 2
- 108010056088 Somatostatin Proteins 0.000 description 2
- 241000473945 Theria <moth genus> Species 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 210000004958 brain cell Anatomy 0.000 description 2
- 230000003727 cerebral blood flow Effects 0.000 description 2
- 229960001231 choline Drugs 0.000 description 2
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 2
- 229960003399 estrone Drugs 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 239000002622 gonadotropin Substances 0.000 description 2
- 229940094892 gonadotropins Drugs 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- 238000010855 neuropsychological testing Methods 0.000 description 2
- 210000001428 peripheral nervous system Anatomy 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 238000001243 protein synthesis Methods 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 230000003716 rejuvenation Effects 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- NHXLMOGPVYXJNR-ATOGVRKGSA-N somatostatin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CSSC[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(=O)N1)[C@@H](C)O)NC(=O)CNC(=O)[C@H](C)N)C(O)=O)=O)[C@H](O)C)C1=CC=CC=C1 NHXLMOGPVYXJNR-ATOGVRKGSA-N 0.000 description 2
- 229960000553 somatostatin Drugs 0.000 description 2
- 229960004532 somatropin Drugs 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- PROQIPRRNZUXQM-UHFFFAOYSA-N (16alpha,17betaOH)-Estra-1,3,5(10)-triene-3,16,17-triol Natural products OC1=CC=C2C3CCC(C)(C(C(O)C4)O)C4C3CCC2=C1 PROQIPRRNZUXQM-UHFFFAOYSA-N 0.000 description 1
- CXENHBSYCFFKJS-OXYODPPFSA-N (Z,E)-alpha-farnesene Chemical compound CC(C)=CCC\C(C)=C\C\C=C(\C)C=C CXENHBSYCFFKJS-OXYODPPFSA-N 0.000 description 1
- GCKMFJBGXUYNAG-UHFFFAOYSA-N 17alpha-methyltestosterone Natural products C1CC2=CC(=O)CCC2(C)C2C1C1CCC(C)(O)C1(C)CC2 GCKMFJBGXUYNAG-UHFFFAOYSA-N 0.000 description 1
- NKQVYJRZBVRXRU-UHFFFAOYSA-N 2-methyl-2-(methylamino)propanenitrile Chemical compound CNC(C)(C)C#N NKQVYJRZBVRXRU-UHFFFAOYSA-N 0.000 description 1
- 206010001497 Agitation Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 206010008190 Cerebrovascular accident Diseases 0.000 description 1
- 108010058699 Choline O-acetyltransferase Proteins 0.000 description 1
- 102100023460 Choline O-acetyltransferase Human genes 0.000 description 1
- 102000011022 Chorionic Gonadotropin Human genes 0.000 description 1
- 108010062540 Chorionic Gonadotropin Proteins 0.000 description 1
- 108010069514 Cyclic Peptides Proteins 0.000 description 1
- 102000001189 Cyclic Peptides Human genes 0.000 description 1
- 206010012374 Depressed mood Diseases 0.000 description 1
- 208000030453 Drug-Related Side Effects and Adverse reaction Diseases 0.000 description 1
- 206010013883 Dwarfism Diseases 0.000 description 1
- 206010014418 Electrolyte imbalance Diseases 0.000 description 1
- 229920013685 Estron Polymers 0.000 description 1
- 239000000095 Growth Hormone-Releasing Hormone Substances 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010022998 Irritability Diseases 0.000 description 1
- 241000252067 Megalops atlanticus Species 0.000 description 1
- WRWBCPJQPDHXTJ-DTMQFJJTSA-N Methandriol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@](C)(O)[C@@]1(C)CC2 WRWBCPJQPDHXTJ-DTMQFJJTSA-N 0.000 description 1
- GCKMFJBGXUYNAG-HLXURNFRSA-N Methyltestosterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@](C)(O)[C@@]1(C)CC2 GCKMFJBGXUYNAG-HLXURNFRSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- QSLJIVKCVHQPLV-PEMPUTJUSA-N Oxandrin Chemical compound C([C@@H]1CC2)C(=O)OC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@](C)(O)[C@@]2(C)CC1 QSLJIVKCVHQPLV-PEMPUTJUSA-N 0.000 description 1
- 208000027089 Parkinsonian disease Diseases 0.000 description 1
- 206010034010 Parkinsonism Diseases 0.000 description 1
- 241001163743 Perlodes Species 0.000 description 1
- 102000001105 Phosphofructokinases Human genes 0.000 description 1
- 108010069341 Phosphofructokinases Proteins 0.000 description 1
- LKAJKIOFIWVMDJ-IYRCEVNGSA-N Stanazolol Chemical compound C([C@@H]1CC[C@H]2[C@@H]3CC[C@@]([C@]3(CC[C@@H]2[C@@]1(C)C1)C)(O)C)C2=C1C=NN2 LKAJKIOFIWVMDJ-IYRCEVNGSA-N 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 206010070863 Toxicity to various agents Diseases 0.000 description 1
- 230000001800 adrenalinergic effect Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 230000036626 alertness Effects 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000013528 artificial neural network Methods 0.000 description 1
- 210000003050 axon Anatomy 0.000 description 1
- 210000004227 basal ganglia Anatomy 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000006800 cellular catabolic process Effects 0.000 description 1
- 210000001638 cerebellum Anatomy 0.000 description 1
- 210000003710 cerebral cortex Anatomy 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000001713 cholinergic effect Effects 0.000 description 1
- 229940015047 chorionic gonadotropin Drugs 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 239000004927 clay Substances 0.000 description 1
- 208000010877 cognitive disease Diseases 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000001054 cortical effect Effects 0.000 description 1
- WZHCOOQXZCIUNC-UHFFFAOYSA-N cyclandelate Chemical compound C1C(C)(C)CC(C)CC1OC(=O)C(O)C1=CC=CC=C1 WZHCOOQXZCIUNC-UHFFFAOYSA-N 0.000 description 1
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 210000001787 dendrite Anatomy 0.000 description 1
- LLHRMWHYJGLIEV-UHFFFAOYSA-N desoxy Chemical group COC1=CC(CCN)=CC(OC)=C1C LLHRMWHYJGLIEV-UHFFFAOYSA-N 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 238000012631 diagnostic technique Methods 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 206010014599 encephalitis Diseases 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 229960001348 estriol Drugs 0.000 description 1
- PROQIPRRNZUXQM-ZXXIGWHRSA-N estriol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H]([C@H](O)C4)O)[C@@H]4[C@@H]3CCC2=C1 PROQIPRRNZUXQM-ZXXIGWHRSA-N 0.000 description 1
- 150000002167 estrones Chemical class 0.000 description 1
- AOXRBFRFYPMWLR-XGXHKTLJSA-N ethylestrenol Chemical compound C1CC2=CCCC[C@@H]2[C@@H]2[C@@H]1[C@@H]1CC[C@](CC)(O)[C@@]1(C)CC2 AOXRBFRFYPMWLR-XGXHKTLJSA-N 0.000 description 1
- 229960001460 ethylestrenol Drugs 0.000 description 1
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 1
- 150000002303 glucose derivatives Chemical class 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000000971 hippocampal effect Effects 0.000 description 1
- 210000001320 hippocampus Anatomy 0.000 description 1
- MSYBLBLAMDYKKZ-UHFFFAOYSA-N hydron;pyridine-3-carbonyl chloride;chloride Chemical compound Cl.ClC(=O)C1=CC=CN=C1 MSYBLBLAMDYKKZ-UHFFFAOYSA-N 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 230000002989 hypothyroidism Effects 0.000 description 1
- 208000003532 hypothyroidism Diseases 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 229960004164 isoxsuprine hydrochloride Drugs 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- FQXXSQDCDRQNQE-UHFFFAOYSA-N markiertes Thebain Natural products COC1=CC=C2C(N(CC3)C)CC4=CC=C(OC)C5=C4C23C1O5 FQXXSQDCDRQNQE-UHFFFAOYSA-N 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229960001833 methandriol Drugs 0.000 description 1
- 229960001566 methyltestosterone Drugs 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 208000005346 nocturnal enuresis Diseases 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- QKQQEIVDLRUZRP-UHFFFAOYSA-N northebaine Natural products COC1=CC=C2C(NCC3)CC4=CC=C(OC)C5=C4C23C1O5 QKQQEIVDLRUZRP-UHFFFAOYSA-N 0.000 description 1
- 229960000464 oxandrolone Drugs 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- ICMWWNHDUZJFDW-DHODBPELSA-N oxymetholone Chemical compound C([C@@H]1CC2)C(=O)\C(=C/O)C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@](C)(O)[C@@]2(C)CC1 ICMWWNHDUZJFDW-DHODBPELSA-N 0.000 description 1
- 229960005244 oxymetholone Drugs 0.000 description 1
- ICMWWNHDUZJFDW-UHFFFAOYSA-N oxymetholone Natural products C1CC2CC(=O)C(=CO)CC2(C)C2C1C1CCC(C)(O)C1(C)CC2 ICMWWNHDUZJFDW-UHFFFAOYSA-N 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- XQYZDYMELSJDRZ-UHFFFAOYSA-N papavarine Natural products C1=C(OC)C(OC)=CC=C1CC1=NC=CC2=CC(OC)=C(OC)C=C12 XQYZDYMELSJDRZ-UHFFFAOYSA-N 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 229960002702 piroxicam Drugs 0.000 description 1
- QYSPLQLAKJAUJT-UHFFFAOYSA-N piroxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 QYSPLQLAKJAUJT-UHFFFAOYSA-N 0.000 description 1
- 230000001817 pituitary effect Effects 0.000 description 1
- 230000001242 postsynaptic effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000003518 presynaptic effect Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 229920002477 rna polymer Polymers 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229960000912 stanozolol Drugs 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 230000002739 subcortical effect Effects 0.000 description 1
- 230000000153 supplemental effect Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000002123 temporal effect Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 229960002044 tolmetin sodium Drugs 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 230000036448 vitalisation Effects 0.000 description 1
- 208000002670 vitamin B12 deficiency Diseases 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/74—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving hormones or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/24—Follicle-stimulating hormone [FSH]; Chorionic gonadotropins, e.g. HCG; Luteinising hormone [LH]; Thyroid-stimulating hormone [TSH]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/27—Growth hormone [GH], i.e. somatotropin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
- G01N33/5091—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing the pathological state of an organism
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
- G01N2333/46—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans from vertebrates
- G01N2333/47—Assays involving proteins of known structure or function as defined in the subgroups
- G01N2333/4701—Details
- G01N2333/4709—Amyloid plaque core protein
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
- G01N2333/575—Hormones
- G01N2333/61—Growth hormones [GH] (Somatotropin)
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
- G01N2333/575—Hormones
- G01N2333/65—Insulin-like growth factors (Somatomedins), e.g. IGF-1, IGF-2
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Chemical & Material Sciences (AREA)
- Immunology (AREA)
- General Health & Medical Sciences (AREA)
- Endocrinology (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Biomedical Technology (AREA)
- Hematology (AREA)
- Urology & Nephrology (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Analytical Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- General Physics & Mathematics (AREA)
- Pathology (AREA)
- Biotechnology (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Physics & Mathematics (AREA)
- Biochemistry (AREA)
- Food Science & Technology (AREA)
- Microbiology (AREA)
- Cell Biology (AREA)
- Reproductive Health (AREA)
- Physiology (AREA)
- Tropical Medicine & Parasitology (AREA)
- Investigating Or Analysing Biological Materials (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
A method of treating humans suffering from central nervous system diseases, such as Alzheimer's disease, cerebral atrophy, Parkinson's disease, senile dementia, senile tremor, essential tremor, multiple schlerosis, cerebovascular accidents, and cerebellar atrophy, as well as diseases where dementia is present.
The treatment consists of inducing into the patient's blood stream at least one from the group consisting of:
sex hormones and anabolic hormones. (HGH, NCG, trophobostic hormone). Ergolid myselates, dopamine, cathecoline, serotonin, amphetamine may be used in conjunction with the hormone, as well as a vasodilator and non-steroid anti-inflammatory. Growth hormone may also be used in those patients in advanced stages of the disease, or in those patients where it has been determined that a low level o growth hormone is present, clinical deterioration not having been corrected by other hormones.
A method of diagnosing Alzheimer's disease, senile dementia, by the determination of the levels of the hormones somatotropin (human growth hormone) and somatomedin-C (IGF-I) after the administration of the Aroonsakul-Allen provocative test. Blood-sera samples are taken every thirty minutes for a two hour period after the administration of L-Dopa, and the samples are tested for the levels of these hormones. These levels are then compared against the levels for normal subjects in the age group of between fifty years and sixty years. If the levels of the patient being diagnosed falls below the statistical mean corrected for error, then a diagnosis of Alzheimer's disease is indicated what is equivalent to severe HGH deficiency, mild and moderate, HGH deficiency indicating senile dementia in early and late stage.
A method of treating humans suffering from central nervous system diseases, such as Alzheimer's disease, cerebral atrophy, Parkinson's disease, senile dementia, senile tremor, essential tremor, multiple schlerosis, cerebovascular accidents, and cerebellar atrophy, as well as diseases where dementia is present.
The treatment consists of inducing into the patient's blood stream at least one from the group consisting of:
sex hormones and anabolic hormones. (HGH, NCG, trophobostic hormone). Ergolid myselates, dopamine, cathecoline, serotonin, amphetamine may be used in conjunction with the hormone, as well as a vasodilator and non-steroid anti-inflammatory. Growth hormone may also be used in those patients in advanced stages of the disease, or in those patients where it has been determined that a low level o growth hormone is present, clinical deterioration not having been corrected by other hormones.
A method of diagnosing Alzheimer's disease, senile dementia, by the determination of the levels of the hormones somatotropin (human growth hormone) and somatomedin-C (IGF-I) after the administration of the Aroonsakul-Allen provocative test. Blood-sera samples are taken every thirty minutes for a two hour period after the administration of L-Dopa, and the samples are tested for the levels of these hormones. These levels are then compared against the levels for normal subjects in the age group of between fifty years and sixty years. If the levels of the patient being diagnosed falls below the statistical mean corrected for error, then a diagnosis of Alzheimer's disease is indicated what is equivalent to severe HGH deficiency, mild and moderate, HGH deficiency indicating senile dementia in early and late stage.
Description
MET~IOD OF TREATMENT OF
CENTRAL NERVOUS SYSTEM DISEASES
SUCH AS ALZHEIMER'S DISEASE AND PARKINSON'S DIS~ASE
~ND METHOD OF DIAGNOSING ALZHEIMER'S DISEASE
~ACKGROUND OF TME INVENTION
The present invention is directed to a method of treatment for central nervous system diseases. These diseases for which the present inventive method has been found useful are: Alzheimer's disease; Parkinson's disease; senile dementia; essential tremor; senile tremor; and cerebellar atrophy and cerebral atrophy;
multiple sclerosis; cerebrovascular accident. Each of these has been found to affect dif~Eerent portions of the brain. Alzheimer's disease affects the portion of the brain vital to memory retention, tlle cortex. It is generally believed that the disease cuts off the cholinergic pathways by deficiencies of the en2yme choline acetyltranspherase, which is the chemical messenger from the nucleus basalis to the cortex.
Parkinson's disease is known to affect the nerve cells of the basal ganglia. Cerebellar atrophy is known to affect the nerve cells of the cerebellum. It has also been determined that in each of the above diseases, intrinsic depression develops, which is usually associated with an entirely different portion of the brain than those affected by the above-named diseases. It is generally known that the cerebellar and extra-pyrimadal tract - . . ~ - . ,. . . ~ , .
'; ~ '~ - ` - '. : ~
.
, ~ : :
:.
1 3232~4 portions of the brain are directly a tremor and essential tremor. It is also known that in each of these diseases characterized by biochemical lesions in enzymes, membran~s, or structure proteins of particular components, cellular atrophy is the result, which is a slow process of cellular deterioration, sometimes deferred bes, bu~ leading to cellular atrophy, and eventually resulting in serious functional loss, causing the symptoms associated with each of the diseases. Such cellular atrophy generally occurs with advancing age, but, owing to these diseases, the processes are somehow speeded up, in a manner not known or understood at the present time. What is certain, however, is that in any cellular break-down, the enzymes required for protein synthesis are lacking. Further, it is also apparent that this lack of enzyme formation, and concomitant lack of protein synthesis, are caused by some interruption in the neural network through which biochemical signals are generated and transported. Thus, the very problem of each of these diseases runs to the basic structure of life: To wit, RNA and DNA, ribo nucleic acid and desoxy ribonucleic acidl which program each cell to provide the necessary enz~mes for life-sustaining activity.
Heretofore, there has been no effective method of treatment oE each of the above-named diseases. In the case of Parkinson's disaase, L-Dopa has been employed and . 1 3~32q4 has achieved some success. I~owever, the period of efficacy of L-Dopa is limited to a few months, after which all of its beneficial effects disappear leaving only contraindication. In the case of Alzheimer's disease, and the remainder of the abcve-named diseases, ergoloid myselates have been used to some small success, but only in a very limited way, and have been successful only for a short time period. Further, ergoloid myselates suffer from the disadvantage of also causing unwanted side effects, that are often dangerous to the health and well-beiny of the patient. Just how this drug works is not known at this time, but it does offer some relief, though only temporary, to help restore mental acuteness, awareness and faculty.
The present invention is directed to a method of diagnosing Alzheimer's Disease in human ~eings.
~lzheimer's disease is the fourth leading cause of death in the Vnited States, the precise cause of which is not yet known. At present, it is a dif~icult and time-consuming tas~ to de~initively determine whether a patient is suffering from Alzheimer's disease or another ailment having similar manifestations and/or symptoms.
Presently-used techni~ues for determining Alzheimer's disease include neuropsychological testing which compares the mental status of the patient relative to a norm, as well as the patient's cognitive dysfunction. Such testing also tests for mood depressions, agitation, irritability, .. . . .
, , . .. - , . . .
.. - . ....
- . ~ . . .
: . .: .
~, . . ,, . . i ,, . , . :: ., .. - .. .. ,;.,, and the like, all of which are symptoms of Alzheimer's disease when combined with other diagnostic indications.
These other diagnostic tools and methods are: The use of a brain atlas beam test or EEG (electroencephalogram) which demonstrate increases in delta and theta waves.
Further, CAT, computed axial tomograph, scans of the brain or nuclear magnetic resonance (NMR) are used in the diagnosis by showing reduced uptakes of the brain's cells in the temporal areas or at the hippocampal region, which is a sign of cortical atrophy, associated with Alzheimer's disease, since the cortex and hippocampus of the brain are those usually affected by ~lzheimer's disease, such effect being caused, it is thought, by the deficiency of the enzyme choline acetyltransEerase.
Choline acetyltransferase is the chemical messenger from the nucleus basalis to the cortex. Still another method used in the diagnosis of ~lzheimer's disease, based on the fact that it has been discovered that in Alzheimer's patients the brain is found to have consumed from 30~-50~
less glucose in each of the four cortical regions and one subcortical region is the PET, positron emission tomograph, scan. The reduction o~ the consumption of glucose in these portions of the brain results, it is generally thought, from the deficiency of the enzyme phosphofructokinase, which is necessary for the conversion of glucose to high-energy intermediates. The ,: . .
-: :
..~, ;~ `'..
,. . :
1 3232q~
determination o glucose reduction in these portions of the brain is typically carried out by the PET scan, which detects the presence of the glucose analogue -(F-18)-2-fluoro-2-deoxy-D-glucose (FDG).
It has hitherto been the conventional practice in order to make a diagnosis for Alzheimer's disease to utilize the positive indication of any of the above-mentioned tests. However, the results of these tests are often not definitive, since any one or more of them may show that the symptoms are not those of Alzheimer's disease even though the patient may be suffering therefrom. On the other hand, each of the above-mentioned tests may show that the diagnosis is that of Alzheimer's disease when, in fact, it is not. The frequency of these ~alse positives may be high. For example, a false positive may occur if the patient is sufferinc~ from neurosyphylis, follic acid deficiency, Vitamin B12 deficiency, hypothyroidism, encephalitis, electrolyte imbalance, drug toxicity, other metabolic disorders, virus infection of central nervous system, cns, as well as others.
It is, of course, most important that a correct diagnosis be determined in order to decide upon the best treatmentO The present invention is directed towards the incorporation to a novel diagnosis ~or senile dementia Alzheimer type Alzheimer's disease and senile dementia, that may be used in conjunction with other standard ;.... . . ..
testing methods, or may be used alone for such determination, since this novel diagnosis has been found to be very accurate, especially when used in conjunction with conventional diagnostic tests for other chronic degenerative diseases of the cns form which similar indications may result, as to those of the method of the present invention, are not at all likely to affect the patient for whom Alzheimer's disease may be a likely diagnosis.
It has been known that the drug, levodopa (L-Dopa), a common drug for treating Parkinson's disease, causes increased secretion of the clrowth hormone somatotropin (HGH-human growth hormone). This finding of Aroonsakul and Allen provocative tlest (AA provocative test) such as L-Dopa's provocative stimulation of the pituitary gland to secrete HGH wac;used as the basis for viewing the functioning of the peripheral nervous system, (P~S), as an aminergic neuronetwork. Furthermore, since the hormone somatomedin-C (often referred to as IGF-I, for insulin-like growth factor, since it resembles insulin in many ways~ is directly dependent upon the secretion of HGH by the pituitary gland, there has been established a direct linkage between increased secretion of HGH and increased production of the hormone somatomedin-C, which is produced chiefly in the liver and kidneys. The use of L-Dopa to markedly increase the 1 32329~
secretions of somatotropin and, consequently, the production of somatomedin-C in the human body has led to what is generally termed the "L-Dopa provocative test".
This test is used to determine the normal functioning of the anterior region of the pituitary gland responsible for the HGH production. Generally, the AA provocative test is used by detecting the increase of HGH and IGF-I
in a blood serum by the use of radioimmunoassay (RIA), which determines the presence or absence or the amounts of a certain hormone in a serum by the use of a radioactive agent, used in vitro. Radioimmunoassay techniques were first discovered by the observation that unlabelled insulin displaces radioactive iodine-labelled insulin from insulin antibodies, in vitro. With the antibody concentration and radio-iodine-nated antigen held constant, the binding of the label is quantitatively related to the amount of unlabelled antigen that is added. Thus, any amount of an unlabelled antigen may be determined by the known standards therefor. The amount of unlabelled antigen in a serum-sample can be guaged by measuring the fraction of bound, labelled antigen in its presence from a standard. RIA involves separation of the labelled antigen that is of interest into bound-unbound fractions after the interaction with an antibody in the presence of the unknown quantity of unlabelled antigen to be measured. RI~ has been used in the past for measuring the amount of HGH in a serum taken from a subgroup of ' , . :. . :, 1 3232q4 children, for treating diseases in children related to growth. The radioactive element used in this determination is usually I-125.
Somatotropin is a growth hormone (polypeptic-link amino acid in character), secreted by the anterior region of the pituitary gland, which is most known for its capability of causing growth of the human skeleton.
This is also known as the human growth hormone (HGH), and is the precursor of the hormone somatomedin-C (IGF-I), produced by the liver and kidneys. According to the present invention, it has been discovered that patients suffering from Alzheimer's disease have a deficiency of somatotropin production which leads to a deficiency of somatomedin-C levels, and that exogenous stimulation by a drug to cause increased secretions of HGH in normal human subjects, does not function normally in Alzheimer's patients. Though it has been known to have increased levels of IGF-I in the blood with reduced levels o~ HGH, these instances are rare and can be taken into consideration when determining the diagnosis according to the present invention.
:. ' `- : ' 1 3232~4 SUMMARY OF THE INVENTION
The present invention consists of a method o treating patients suffering from the above-named diseases with the hormones: sex hormones and anabolic hormones.
For male patients, androgens are used, or suitable anabolic hormone substitutes are used. For female patients estrogens are used in combination with androgens or anabolic hormones. For both male and female patients, additional drugs may be used to ensure that the induction of hormone into the blood stream is effected, so that the hormone or hormones are delivered to the site of the brain causing the dysfunction and symptoms. Thus, nonsteroidal anti-inflammatory drugs and vasodilaters may be used in combination with the hormone treatment to ensure that the blood delivers the hormone or hormones to the brain. Further, the hormone method of treatment may be supplemented with growth hormones, which are known for their anabolic tendencies, especially in those cases where there has been detected a noticeable loss of such growth hormone in the patient's system, which growth hormones also exhibit remarkable rejuvenating properties.
It is, therefore, the primary objective of the present invention to provide a novel diagnostic technique and method by which positive identification o Alzheimer's disease in a human being may be established definitively.
'`
t 323294 It ls another ob~ective of the present invent iOIl to provide a novel dlagnostic method to be used in conjunctlon with presently-avallable and presently--used techni~ues for the determinatlon of Alzhelmer's dlsease.
It is yet another objectlve of the present lnvention to provlde another technique for diagnosing Alzheimer's disease in human belngs that is easily performed by conventional radiolmmunoassay techniques.
Tt is stlll another ob~ectlve of the present lnventlon to provlde for the use of the dlagnostic method of the present lnvention over a perlod of two days using the L-Dopa provocatlve test, by whlch the levels ln blood-sera of the hormones somatotropln and somatomedln-C are gauged and compared wlth levels ln blood--sera of normal persons withln the same age range, as lt has been discovered that a depletlon and lack of efflcaclous capablllty of producing these two hormones ln the body lndlcates a strong llkellhood that the patlent ls sufferlng from Alzhelmer's dlsease.
It ls also an ob~ective of t.he present lnventlon to use any dopamlnergic drug, catecholamine, serotonin, amphetamine, causing immedlate excess secretlon of the hormones HGH and IGF-I, as well as any drug creatlng the same excess secretion.
Accordlng to an aspect of the present lnventlon, there ls provlded a novel methocl of dlagnoslng Alzhelmer's dlsease whereby a patlent suspected of sufferlng from thls disease ls sub~ectecl to the L-Dopa AA provocatlve test, by which a specified dosage ls admlnlstered on a flrst clay, and ' ' 10 " .
~' "~.",~
followecl Oll lhe ne~t ~ay with a hi~her dosage, immed:Lately aEter which blood-serum samples are -ta~en a~ 30 minute in-tervals, up to 120 minutes after the lnitlal administration of the L-Dopa on the second day, for subsequent analysls hy RIA techniques in order to determine the absolute and relatlve levels of somatotropin and somatomedin-C hormones in each sample, for subsequent comparison with levels of normal persons in the same age bracket. By comparing the test-sample levels with those of normal persons, a firm dlagnosis of Alzhelmer's disease may be made, if the increase of these hormones fall below a critical value established by statistical techniques based on normal sub~ects.
According to another aspect of the present invention, there is provided a method of diagnosing Alzhe:lmer's dlsease, senile dementia in human beinc~s comprising: (a) sub~ecting a patient suspected of suffering rom Alzheimer's disease to a somatotropin secretion-stimulation test~ (b) determining the levels of somatotropin in at least one blood serum sample taken from the patient after the somatotropin secretlon-stimulation test; and (c) comparlng the levels from the at least one blood serum sample obtained during said step (b) with the levels of normal sub~ects within the a~e group of the patient beiny dla~nosed to see iE any lncrease of somatotropin caused by sald step (a~
statistically-match the increases thereof in normal sub~ects.
Accordlng to yet another aspect of the present lnventlon there is provided a method of diagnosing Alzheimer's 10a .~
, '` `
.' `
, . . "
1 3232~4 clisease, sen:Lle deIllerltla, :Ln whlch the L-Dopa provocative test, or the equlvalen-t thereof, has been given -tIle patien-t being dlagnose~, comprising: ~a) determinlng the levels of at least one of the hormones somatotropin and somatomedin-C after the administratlon of the L-Dopa, or the equivalent thereof;
and sonotropin only in venous blood of two hour period; (b) comparlng the levels obtained from said (a) with levels of normal sub~ects within the same age bracket as the patlent being tested for Alzheimer's disease, in order to determine if any increase, or lack thereof, in the levels from sald step (a) falls below the statlstlcal levels of the normal subiects.
Accordlng to yet another aspect of the present lnventlon, there is provided a method of dlagnosing Alzheimer's dlsease and senile dementia in a human being comprising: (a) sub~ectlng a patient to a somatotropin secretlon-stimulation test; (b) determlning the levels of somatotropin in at least one blood serum sample taken from the patient after the somatotropin secretl.on-stimulation test; and (c) comparing the levels from the at 1.east one blood serum sample obtalned during said step (b) with the levels of normal sub~ects withln the age group of the patient being diagnosed to see if any increase of somatotropin caused by said step ~a) statistically-match a two-three hour period of increase thereo~ in normal sub~ects; (d) determinlng the levels of cerebrosplnd fluid of cholineacethylesterase of acetylechollne esterase in the blood sample after sald step (a), and fluctuation of two hour venous blood test of HGH; and (e) comparing the levels found from said step (d) wlth the levels 10b 1 3232q4 of normal sub~ects with:Ln the age group of the patient belng diagnosed to see lf any increases of cholineacethylesterase caused by said step (a) statistically-match the increase thereof in the normal sub~ects.
BRIEF DESCRIPTION OF THE DRAWINGS
The inventlon will be more readily understood with reference to the accompanylng drawing, wherein:
Flgure 1 ls a bar-chart showlng the levels of the hormone somatotropln in blood sera at the end of 30 mlnutes, 60 mlnutes, ~0 mlnutes and 120 mlnutes, as well as at the tlme of lnitlal admlnlstratlon, obtained from the results of the L-Dopa AA provocative test, for determlning levels thereof relat:l.ve to a statistlcal average of nor~al sub~ects according to the method of the r,~
', ' ' ' ' I . ' , , , ,, ': .
., , ' , : , :
: :, ~ '` .'. :' ' present invention for diagnosing Alzheimer's disease in human beings;
Figure 2 is a bar-chart similar to Figure 1 showing the same information for the hormone somatomedin-C;
Figure 3 is graph showing the comparison betweenthe human growth hormone levels of a group of normal subjects as well as the graphs for those diagnosed as suffering from Alzheimer's disease and senile dementia;
and other cen-tral nervous system disorders; and Figure 4 is a graph showing the levels of brain neuro-transmitter, cholineacethylesterase, present in blood samples according to the method of diagnosing of the present invention for a group of normal control subjects, patients suffering from Alzheimer's disease, and patients suffering from senile dementia.
DETAILED DESCRIPTION OF THE INVENTION
To reverse the degenerative nature of central nervous disorder disease, such as Parkinson's disease, Senile Dementia, Alzheimer's disease, senile tremor, and the like, and diseases especially associated with dementia, it nas been discovered that treatment methods utilizing the synthesizing, metabolic effects of androgens, estrogens, and anabolic hormones have reversed the degenerative nature of the diseases, and have : ,. . .
: .. ., :, .','`.' ': ::
::. - ~
: . ~ . : ~ : , :
1 3232~4 restored patients suffering from the diseases to more normal and productive lives, with the alleviation of many of the symptoms of the diseases. Further, upon continual and prolonged treatment with the above-named group of hormones, there has not been found any diminution of efficacy of the treatment, nor any serious contraindications and adverse side effects that would tend to discourage such treatment.
In one patient suffering from diagnosed Alæheimer's disease and early stage Parkinson's disease, which patient was sixty years old and weighed one-hundred eighty pounds, he was given 10 mg. of fluoxymesterone USP
daily. In conjunction with the fluoxymesterone, the patient was given 1 mg. of ergolid myselates four times a day; 50 mg. of dipyridamole, four times a day; and acetyl salicylic acid enteric coated, four times a day, all taken orally. Within one week of the start of this treatment, the patient experienced noticeable improvement, including the cessation of Parkinsonism tremor, and a wider span of attentiveness. In about one month from the start of the treatment, the patient stopped bed-wetting, and was able to concentrate on television, and other mentally-s~imulating activities.
Within about two months, the patient's intellectual capacity increased so that he could carry on a conversation with another person. Within about three .:'. ~ -. ' - .
1 32329~
months, the patient was able to dress himself, and take a bath by himself. Within about four months, the patient was able to smile, and laugh occasionally. Within about five months, the patient was able to retain in his memory recent occurrences and happenings. When the above-described treatment and medicine was eliminated, the patient regressed, starting to revert back to the original condition before the treatment with the fluoxymesterone was begun. After resumption of the treatment with fluoxymesterone, with the other drugs above-named, and in their previously given doses, the patient again responded and started to recover from the degenerative nature of the diseases.
In the treatment oE central nervous system disorders, and especially those where dementia is present, it has been found that treating patients with the following hormones has caused alleviation of the degenerative nature o~ the diseases, and has resulted in putting the patient back on the road toward normalcy.
These hormones belong to the group: Androgens for male patients; androgen-estrogen combination for female patients; anabolic hormones for either male or female patients; or a combination of any of the three classes within this group.
In the above-cited case history of one male patient who was treated with the synthetic androgen and .: .- .,, 329~
chorionic gonadotropin, any of the following other androgens could have been used in lieu of, or in conjunction with, the fluoxymesterone; Testesterone;
methyltesterone; and oxymethone. Furthermore, the patient could have been treated with any of the following anabolic hormones in lieu of the androgen, or in combination therewith: Oxymetholone; oxandrolone;
ethylestrenol; stanozolol; nandolone; phenpropionate;
decanoate; and methandriol. Whereas in the case of using the fluoxymesterone, a daily dosage of 10 mg. was provided the patient, in the case of the use of other androgens, either singly or in combination with another androgen, the precise dose could vary. However, it has been found that a minimum dose of 1 mg. of any type of androgen above-named is preferred. Below such level, the beneficial results above-noted would likely not occur.
Further, combinations of anabolic hormones alone, or anabolic hormones with androgens, may also be used to find the precisely-desired anabolic effect to be had on the central nervous system of the patient, again with the minimum daily dosage of 1 mg., either for combinations, or individually-administered hormones.
Since a patient suffering from the diseases of the central nervous system, for which the treatment of the present invention has proven successful, also suffers from other ailments, either because these ;
.. . ~ .
.:
diseases strike primarily those advanced in age or because of other factors, it has been found ne~essary to also treat the patient with other drugs in order to ensure that the hormone used is adequately and safely delivered into the blood stream of the patient, and to the site in the brain affected by the disease, so as to act on the degenerative nerve cells. Toward this end, as shown by the above-cited case, the patient is typically treated also with vasodilater and non-steroidal anti-inflammatory drugs, to ensure that the hormone is delivered to the brain. Further, ergoloid myselates are also used, the use of which for dementia has been known in the art. Among vasodilaters, any of the followin~
group may be used, either singly, or in combination:
Dipyridamole; cyclospasmol; nylidinhydrochloride;
papavarine hydrochloride; and isoxsuprine hydrochloride.
Further, any well-known vasodilater may be used, the above being given only by way of example. For non-steroidal anti-imflammatory drugs, any o~ the following may be used singly or in combination: Aspirin; ibuprofen, indomethacin; tolmetin sodium; and piroxicam. Also, any other well-known non-steroidal anti-inflammatory drug may be used, the above being given only by way of example.
Patients who are in the late and/or vegetative stages need other medication in addition to the medication mentioned above. For women, estradiol, a major anabolic sex hormone in a female is needed. For men, , ~
, . . ..
,: , : . ': ~ ' "`.
.. :.. : :, ' , : : :: . : .,: :
... .. .
1 3232')~
androgen, a major anabolic sex hormone in a male is needed. Thus, in one case history of a female patient 7 years of age, weighing approximately one-hundred fifty pounds, diagnosed as having Alzheimer's disease, the patient was given the following, orally: 1.25 mgu conjugated estrogen once a day; 10 mg. methyltetosterone once a day; 1 mg. ergoloid myselate USP four times a day;
50 mg. dipyridamole four times a day; and 300 mg. acetyl salicylic acid enteric coated four times day.
The ergolid myselate helps, it is thought in the art, that i~ will serve to prevent the cell's temporary loss of protein; the dipyridamole increase cerebral blood flow; and the acetyl salicylic acid helps to prevent clots among other beneficial results. Just as in the case of the male patient noted above, this emale patient experienced marked and fast rejuvenation, dissipation of dementia, increased mental alertness, and a general vitalization such that many of her Alzheimer disease symptoms by conventional diagnosis; but senile dementia disappeared by new biochemical diagnosis in figure 3 and 4.
Besides the use of conjugated estrogen, any estrogen from the following group may be used singly or in combination: Estradiol; estrone; estriol. Further, gonadotropins and chorionic gonadotropins may also be used, singly or in combination. Also, another androgen or .,.
1 3232~4 an anabolic hormone could have been used successfully instead of the methyltestosterone.
In conjunction with the above-disclosed treatment, in these patients where it has been determined that the level of growth hormone in their system is below normal for their size, sex, and age bracket, the above-administering of drugs is supplemented with a growth hormone to re-establish normal levels thereof in the patients. These growth hormones, also of potent anabolic efficacy, serve to restor~ body function to a state receptive to treatment of the present invention in those cases where growth hormone levels are deficient. Further, the growth hormone may also be used in those patients having normal levels of old age thereof, if it has been found that treatment with the androgen or anabolic hormones alone or in combination have not adequately provided success. Typically, if, after six months treatment with the present invention, improvement has not been shown, administering of growth hormones should be instituted, e.g. chorionic gonodotropin in combination.
In the advanced stages of the diseases, a growth hormone is also used at the outset of treatment, since owing to its increased and magnified positive metabolic effect, a greater and more concentrated inducement of nerve cell regeneration is needed as described in the diagnostic method of senile dementia Alzheimer style.
It is also indicated that the method of :
, - , ~
1 32329~
treatment as described in the present invention is successful for the alleviating of at least some symptoms for most patients in the incipient, beginning or intermediate stages of the above-named diseases because of the following:
1. General increase in cerebral blood flow which enhances oxidation, including the normal metabolism of the brain cells;
CENTRAL NERVOUS SYSTEM DISEASES
SUCH AS ALZHEIMER'S DISEASE AND PARKINSON'S DIS~ASE
~ND METHOD OF DIAGNOSING ALZHEIMER'S DISEASE
~ACKGROUND OF TME INVENTION
The present invention is directed to a method of treatment for central nervous system diseases. These diseases for which the present inventive method has been found useful are: Alzheimer's disease; Parkinson's disease; senile dementia; essential tremor; senile tremor; and cerebellar atrophy and cerebral atrophy;
multiple sclerosis; cerebrovascular accident. Each of these has been found to affect dif~Eerent portions of the brain. Alzheimer's disease affects the portion of the brain vital to memory retention, tlle cortex. It is generally believed that the disease cuts off the cholinergic pathways by deficiencies of the en2yme choline acetyltranspherase, which is the chemical messenger from the nucleus basalis to the cortex.
Parkinson's disease is known to affect the nerve cells of the basal ganglia. Cerebellar atrophy is known to affect the nerve cells of the cerebellum. It has also been determined that in each of the above diseases, intrinsic depression develops, which is usually associated with an entirely different portion of the brain than those affected by the above-named diseases. It is generally known that the cerebellar and extra-pyrimadal tract - . . ~ - . ,. . . ~ , .
'; ~ '~ - ` - '. : ~
.
, ~ : :
:.
1 3232~4 portions of the brain are directly a tremor and essential tremor. It is also known that in each of these diseases characterized by biochemical lesions in enzymes, membran~s, or structure proteins of particular components, cellular atrophy is the result, which is a slow process of cellular deterioration, sometimes deferred bes, bu~ leading to cellular atrophy, and eventually resulting in serious functional loss, causing the symptoms associated with each of the diseases. Such cellular atrophy generally occurs with advancing age, but, owing to these diseases, the processes are somehow speeded up, in a manner not known or understood at the present time. What is certain, however, is that in any cellular break-down, the enzymes required for protein synthesis are lacking. Further, it is also apparent that this lack of enzyme formation, and concomitant lack of protein synthesis, are caused by some interruption in the neural network through which biochemical signals are generated and transported. Thus, the very problem of each of these diseases runs to the basic structure of life: To wit, RNA and DNA, ribo nucleic acid and desoxy ribonucleic acidl which program each cell to provide the necessary enz~mes for life-sustaining activity.
Heretofore, there has been no effective method of treatment oE each of the above-named diseases. In the case of Parkinson's disaase, L-Dopa has been employed and . 1 3~32q4 has achieved some success. I~owever, the period of efficacy of L-Dopa is limited to a few months, after which all of its beneficial effects disappear leaving only contraindication. In the case of Alzheimer's disease, and the remainder of the abcve-named diseases, ergoloid myselates have been used to some small success, but only in a very limited way, and have been successful only for a short time period. Further, ergoloid myselates suffer from the disadvantage of also causing unwanted side effects, that are often dangerous to the health and well-beiny of the patient. Just how this drug works is not known at this time, but it does offer some relief, though only temporary, to help restore mental acuteness, awareness and faculty.
The present invention is directed to a method of diagnosing Alzheimer's Disease in human ~eings.
~lzheimer's disease is the fourth leading cause of death in the Vnited States, the precise cause of which is not yet known. At present, it is a dif~icult and time-consuming tas~ to de~initively determine whether a patient is suffering from Alzheimer's disease or another ailment having similar manifestations and/or symptoms.
Presently-used techni~ues for determining Alzheimer's disease include neuropsychological testing which compares the mental status of the patient relative to a norm, as well as the patient's cognitive dysfunction. Such testing also tests for mood depressions, agitation, irritability, .. . . .
, , . .. - , . . .
.. - . ....
- . ~ . . .
: . .: .
~, . . ,, . . i ,, . , . :: ., .. - .. .. ,;.,, and the like, all of which are symptoms of Alzheimer's disease when combined with other diagnostic indications.
These other diagnostic tools and methods are: The use of a brain atlas beam test or EEG (electroencephalogram) which demonstrate increases in delta and theta waves.
Further, CAT, computed axial tomograph, scans of the brain or nuclear magnetic resonance (NMR) are used in the diagnosis by showing reduced uptakes of the brain's cells in the temporal areas or at the hippocampal region, which is a sign of cortical atrophy, associated with Alzheimer's disease, since the cortex and hippocampus of the brain are those usually affected by ~lzheimer's disease, such effect being caused, it is thought, by the deficiency of the enzyme choline acetyltransEerase.
Choline acetyltransferase is the chemical messenger from the nucleus basalis to the cortex. Still another method used in the diagnosis of ~lzheimer's disease, based on the fact that it has been discovered that in Alzheimer's patients the brain is found to have consumed from 30~-50~
less glucose in each of the four cortical regions and one subcortical region is the PET, positron emission tomograph, scan. The reduction o~ the consumption of glucose in these portions of the brain results, it is generally thought, from the deficiency of the enzyme phosphofructokinase, which is necessary for the conversion of glucose to high-energy intermediates. The ,: . .
-: :
..~, ;~ `'..
,. . :
1 3232q~
determination o glucose reduction in these portions of the brain is typically carried out by the PET scan, which detects the presence of the glucose analogue -(F-18)-2-fluoro-2-deoxy-D-glucose (FDG).
It has hitherto been the conventional practice in order to make a diagnosis for Alzheimer's disease to utilize the positive indication of any of the above-mentioned tests. However, the results of these tests are often not definitive, since any one or more of them may show that the symptoms are not those of Alzheimer's disease even though the patient may be suffering therefrom. On the other hand, each of the above-mentioned tests may show that the diagnosis is that of Alzheimer's disease when, in fact, it is not. The frequency of these ~alse positives may be high. For example, a false positive may occur if the patient is sufferinc~ from neurosyphylis, follic acid deficiency, Vitamin B12 deficiency, hypothyroidism, encephalitis, electrolyte imbalance, drug toxicity, other metabolic disorders, virus infection of central nervous system, cns, as well as others.
It is, of course, most important that a correct diagnosis be determined in order to decide upon the best treatmentO The present invention is directed towards the incorporation to a novel diagnosis ~or senile dementia Alzheimer type Alzheimer's disease and senile dementia, that may be used in conjunction with other standard ;.... . . ..
testing methods, or may be used alone for such determination, since this novel diagnosis has been found to be very accurate, especially when used in conjunction with conventional diagnostic tests for other chronic degenerative diseases of the cns form which similar indications may result, as to those of the method of the present invention, are not at all likely to affect the patient for whom Alzheimer's disease may be a likely diagnosis.
It has been known that the drug, levodopa (L-Dopa), a common drug for treating Parkinson's disease, causes increased secretion of the clrowth hormone somatotropin (HGH-human growth hormone). This finding of Aroonsakul and Allen provocative tlest (AA provocative test) such as L-Dopa's provocative stimulation of the pituitary gland to secrete HGH wac;used as the basis for viewing the functioning of the peripheral nervous system, (P~S), as an aminergic neuronetwork. Furthermore, since the hormone somatomedin-C (often referred to as IGF-I, for insulin-like growth factor, since it resembles insulin in many ways~ is directly dependent upon the secretion of HGH by the pituitary gland, there has been established a direct linkage between increased secretion of HGH and increased production of the hormone somatomedin-C, which is produced chiefly in the liver and kidneys. The use of L-Dopa to markedly increase the 1 32329~
secretions of somatotropin and, consequently, the production of somatomedin-C in the human body has led to what is generally termed the "L-Dopa provocative test".
This test is used to determine the normal functioning of the anterior region of the pituitary gland responsible for the HGH production. Generally, the AA provocative test is used by detecting the increase of HGH and IGF-I
in a blood serum by the use of radioimmunoassay (RIA), which determines the presence or absence or the amounts of a certain hormone in a serum by the use of a radioactive agent, used in vitro. Radioimmunoassay techniques were first discovered by the observation that unlabelled insulin displaces radioactive iodine-labelled insulin from insulin antibodies, in vitro. With the antibody concentration and radio-iodine-nated antigen held constant, the binding of the label is quantitatively related to the amount of unlabelled antigen that is added. Thus, any amount of an unlabelled antigen may be determined by the known standards therefor. The amount of unlabelled antigen in a serum-sample can be guaged by measuring the fraction of bound, labelled antigen in its presence from a standard. RIA involves separation of the labelled antigen that is of interest into bound-unbound fractions after the interaction with an antibody in the presence of the unknown quantity of unlabelled antigen to be measured. RI~ has been used in the past for measuring the amount of HGH in a serum taken from a subgroup of ' , . :. . :, 1 3232q4 children, for treating diseases in children related to growth. The radioactive element used in this determination is usually I-125.
Somatotropin is a growth hormone (polypeptic-link amino acid in character), secreted by the anterior region of the pituitary gland, which is most known for its capability of causing growth of the human skeleton.
This is also known as the human growth hormone (HGH), and is the precursor of the hormone somatomedin-C (IGF-I), produced by the liver and kidneys. According to the present invention, it has been discovered that patients suffering from Alzheimer's disease have a deficiency of somatotropin production which leads to a deficiency of somatomedin-C levels, and that exogenous stimulation by a drug to cause increased secretions of HGH in normal human subjects, does not function normally in Alzheimer's patients. Though it has been known to have increased levels of IGF-I in the blood with reduced levels o~ HGH, these instances are rare and can be taken into consideration when determining the diagnosis according to the present invention.
:. ' `- : ' 1 3232~4 SUMMARY OF THE INVENTION
The present invention consists of a method o treating patients suffering from the above-named diseases with the hormones: sex hormones and anabolic hormones.
For male patients, androgens are used, or suitable anabolic hormone substitutes are used. For female patients estrogens are used in combination with androgens or anabolic hormones. For both male and female patients, additional drugs may be used to ensure that the induction of hormone into the blood stream is effected, so that the hormone or hormones are delivered to the site of the brain causing the dysfunction and symptoms. Thus, nonsteroidal anti-inflammatory drugs and vasodilaters may be used in combination with the hormone treatment to ensure that the blood delivers the hormone or hormones to the brain. Further, the hormone method of treatment may be supplemented with growth hormones, which are known for their anabolic tendencies, especially in those cases where there has been detected a noticeable loss of such growth hormone in the patient's system, which growth hormones also exhibit remarkable rejuvenating properties.
It is, therefore, the primary objective of the present invention to provide a novel diagnostic technique and method by which positive identification o Alzheimer's disease in a human being may be established definitively.
'`
t 323294 It ls another ob~ective of the present invent iOIl to provide a novel dlagnostic method to be used in conjunctlon with presently-avallable and presently--used techni~ues for the determinatlon of Alzhelmer's dlsease.
It is yet another objectlve of the present lnvention to provlde another technique for diagnosing Alzheimer's disease in human belngs that is easily performed by conventional radiolmmunoassay techniques.
Tt is stlll another ob~ectlve of the present lnventlon to provlde for the use of the dlagnostic method of the present lnvention over a perlod of two days using the L-Dopa provocatlve test, by whlch the levels ln blood-sera of the hormones somatotropln and somatomedln-C are gauged and compared wlth levels ln blood--sera of normal persons withln the same age range, as lt has been discovered that a depletlon and lack of efflcaclous capablllty of producing these two hormones ln the body lndlcates a strong llkellhood that the patlent ls sufferlng from Alzhelmer's dlsease.
It ls also an ob~ective of t.he present lnventlon to use any dopamlnergic drug, catecholamine, serotonin, amphetamine, causing immedlate excess secretlon of the hormones HGH and IGF-I, as well as any drug creatlng the same excess secretion.
Accordlng to an aspect of the present lnventlon, there ls provlded a novel methocl of dlagnoslng Alzhelmer's dlsease whereby a patlent suspected of sufferlng from thls disease ls sub~ectecl to the L-Dopa AA provocatlve test, by which a specified dosage ls admlnlstered on a flrst clay, and ' ' 10 " .
~' "~.",~
followecl Oll lhe ne~t ~ay with a hi~her dosage, immed:Lately aEter which blood-serum samples are -ta~en a~ 30 minute in-tervals, up to 120 minutes after the lnitlal administration of the L-Dopa on the second day, for subsequent analysls hy RIA techniques in order to determine the absolute and relatlve levels of somatotropin and somatomedin-C hormones in each sample, for subsequent comparison with levels of normal persons in the same age bracket. By comparing the test-sample levels with those of normal persons, a firm dlagnosis of Alzhelmer's disease may be made, if the increase of these hormones fall below a critical value established by statistical techniques based on normal sub~ects.
According to another aspect of the present invention, there is provided a method of diagnosing Alzhe:lmer's dlsease, senile dementia in human beinc~s comprising: (a) sub~ecting a patient suspected of suffering rom Alzheimer's disease to a somatotropin secretion-stimulation test~ (b) determining the levels of somatotropin in at least one blood serum sample taken from the patient after the somatotropin secretlon-stimulation test; and (c) comparlng the levels from the at least one blood serum sample obtained during said step (b) with the levels of normal sub~ects within the a~e group of the patient beiny dla~nosed to see iE any lncrease of somatotropin caused by sald step (a~
statistically-match the increases thereof in normal sub~ects.
Accordlng to yet another aspect of the present lnventlon there is provided a method of diagnosing Alzheimer's 10a .~
, '` `
.' `
, . . "
1 3232~4 clisease, sen:Lle deIllerltla, :Ln whlch the L-Dopa provocative test, or the equlvalen-t thereof, has been given -tIle patien-t being dlagnose~, comprising: ~a) determinlng the levels of at least one of the hormones somatotropin and somatomedin-C after the administratlon of the L-Dopa, or the equivalent thereof;
and sonotropin only in venous blood of two hour period; (b) comparlng the levels obtained from said (a) with levels of normal sub~ects within the same age bracket as the patlent being tested for Alzheimer's disease, in order to determine if any increase, or lack thereof, in the levels from sald step (a) falls below the statlstlcal levels of the normal subiects.
Accordlng to yet another aspect of the present lnventlon, there is provided a method of dlagnosing Alzheimer's dlsease and senile dementia in a human being comprising: (a) sub~ectlng a patient to a somatotropin secretlon-stimulation test; (b) determlning the levels of somatotropin in at least one blood serum sample taken from the patient after the somatotropin secretl.on-stimulation test; and (c) comparing the levels from the at 1.east one blood serum sample obtalned during said step (b) with the levels of normal sub~ects withln the age group of the patient being diagnosed to see if any increase of somatotropin caused by said step ~a) statistically-match a two-three hour period of increase thereo~ in normal sub~ects; (d) determinlng the levels of cerebrosplnd fluid of cholineacethylesterase of acetylechollne esterase in the blood sample after sald step (a), and fluctuation of two hour venous blood test of HGH; and (e) comparing the levels found from said step (d) wlth the levels 10b 1 3232q4 of normal sub~ects with:Ln the age group of the patient belng diagnosed to see lf any increases of cholineacethylesterase caused by said step (a) statistically-match the increase thereof in the normal sub~ects.
BRIEF DESCRIPTION OF THE DRAWINGS
The inventlon will be more readily understood with reference to the accompanylng drawing, wherein:
Flgure 1 ls a bar-chart showlng the levels of the hormone somatotropln in blood sera at the end of 30 mlnutes, 60 mlnutes, ~0 mlnutes and 120 mlnutes, as well as at the tlme of lnitlal admlnlstratlon, obtained from the results of the L-Dopa AA provocative test, for determlning levels thereof relat:l.ve to a statistlcal average of nor~al sub~ects according to the method of the r,~
', ' ' ' ' I . ' , , , ,, ': .
., , ' , : , :
: :, ~ '` .'. :' ' present invention for diagnosing Alzheimer's disease in human beings;
Figure 2 is a bar-chart similar to Figure 1 showing the same information for the hormone somatomedin-C;
Figure 3 is graph showing the comparison betweenthe human growth hormone levels of a group of normal subjects as well as the graphs for those diagnosed as suffering from Alzheimer's disease and senile dementia;
and other cen-tral nervous system disorders; and Figure 4 is a graph showing the levels of brain neuro-transmitter, cholineacethylesterase, present in blood samples according to the method of diagnosing of the present invention for a group of normal control subjects, patients suffering from Alzheimer's disease, and patients suffering from senile dementia.
DETAILED DESCRIPTION OF THE INVENTION
To reverse the degenerative nature of central nervous disorder disease, such as Parkinson's disease, Senile Dementia, Alzheimer's disease, senile tremor, and the like, and diseases especially associated with dementia, it nas been discovered that treatment methods utilizing the synthesizing, metabolic effects of androgens, estrogens, and anabolic hormones have reversed the degenerative nature of the diseases, and have : ,. . .
: .. ., :, .','`.' ': ::
::. - ~
: . ~ . : ~ : , :
1 3232~4 restored patients suffering from the diseases to more normal and productive lives, with the alleviation of many of the symptoms of the diseases. Further, upon continual and prolonged treatment with the above-named group of hormones, there has not been found any diminution of efficacy of the treatment, nor any serious contraindications and adverse side effects that would tend to discourage such treatment.
In one patient suffering from diagnosed Alæheimer's disease and early stage Parkinson's disease, which patient was sixty years old and weighed one-hundred eighty pounds, he was given 10 mg. of fluoxymesterone USP
daily. In conjunction with the fluoxymesterone, the patient was given 1 mg. of ergolid myselates four times a day; 50 mg. of dipyridamole, four times a day; and acetyl salicylic acid enteric coated, four times a day, all taken orally. Within one week of the start of this treatment, the patient experienced noticeable improvement, including the cessation of Parkinsonism tremor, and a wider span of attentiveness. In about one month from the start of the treatment, the patient stopped bed-wetting, and was able to concentrate on television, and other mentally-s~imulating activities.
Within about two months, the patient's intellectual capacity increased so that he could carry on a conversation with another person. Within about three .:'. ~ -. ' - .
1 32329~
months, the patient was able to dress himself, and take a bath by himself. Within about four months, the patient was able to smile, and laugh occasionally. Within about five months, the patient was able to retain in his memory recent occurrences and happenings. When the above-described treatment and medicine was eliminated, the patient regressed, starting to revert back to the original condition before the treatment with the fluoxymesterone was begun. After resumption of the treatment with fluoxymesterone, with the other drugs above-named, and in their previously given doses, the patient again responded and started to recover from the degenerative nature of the diseases.
In the treatment oE central nervous system disorders, and especially those where dementia is present, it has been found that treating patients with the following hormones has caused alleviation of the degenerative nature o~ the diseases, and has resulted in putting the patient back on the road toward normalcy.
These hormones belong to the group: Androgens for male patients; androgen-estrogen combination for female patients; anabolic hormones for either male or female patients; or a combination of any of the three classes within this group.
In the above-cited case history of one male patient who was treated with the synthetic androgen and .: .- .,, 329~
chorionic gonadotropin, any of the following other androgens could have been used in lieu of, or in conjunction with, the fluoxymesterone; Testesterone;
methyltesterone; and oxymethone. Furthermore, the patient could have been treated with any of the following anabolic hormones in lieu of the androgen, or in combination therewith: Oxymetholone; oxandrolone;
ethylestrenol; stanozolol; nandolone; phenpropionate;
decanoate; and methandriol. Whereas in the case of using the fluoxymesterone, a daily dosage of 10 mg. was provided the patient, in the case of the use of other androgens, either singly or in combination with another androgen, the precise dose could vary. However, it has been found that a minimum dose of 1 mg. of any type of androgen above-named is preferred. Below such level, the beneficial results above-noted would likely not occur.
Further, combinations of anabolic hormones alone, or anabolic hormones with androgens, may also be used to find the precisely-desired anabolic effect to be had on the central nervous system of the patient, again with the minimum daily dosage of 1 mg., either for combinations, or individually-administered hormones.
Since a patient suffering from the diseases of the central nervous system, for which the treatment of the present invention has proven successful, also suffers from other ailments, either because these ;
.. . ~ .
.:
diseases strike primarily those advanced in age or because of other factors, it has been found ne~essary to also treat the patient with other drugs in order to ensure that the hormone used is adequately and safely delivered into the blood stream of the patient, and to the site in the brain affected by the disease, so as to act on the degenerative nerve cells. Toward this end, as shown by the above-cited case, the patient is typically treated also with vasodilater and non-steroidal anti-inflammatory drugs, to ensure that the hormone is delivered to the brain. Further, ergoloid myselates are also used, the use of which for dementia has been known in the art. Among vasodilaters, any of the followin~
group may be used, either singly, or in combination:
Dipyridamole; cyclospasmol; nylidinhydrochloride;
papavarine hydrochloride; and isoxsuprine hydrochloride.
Further, any well-known vasodilater may be used, the above being given only by way of example. For non-steroidal anti-imflammatory drugs, any o~ the following may be used singly or in combination: Aspirin; ibuprofen, indomethacin; tolmetin sodium; and piroxicam. Also, any other well-known non-steroidal anti-inflammatory drug may be used, the above being given only by way of example.
Patients who are in the late and/or vegetative stages need other medication in addition to the medication mentioned above. For women, estradiol, a major anabolic sex hormone in a female is needed. For men, , ~
, . . ..
,: , : . ': ~ ' "`.
.. :.. : :, ' , : : :: . : .,: :
... .. .
1 3232')~
androgen, a major anabolic sex hormone in a male is needed. Thus, in one case history of a female patient 7 years of age, weighing approximately one-hundred fifty pounds, diagnosed as having Alzheimer's disease, the patient was given the following, orally: 1.25 mgu conjugated estrogen once a day; 10 mg. methyltetosterone once a day; 1 mg. ergoloid myselate USP four times a day;
50 mg. dipyridamole four times a day; and 300 mg. acetyl salicylic acid enteric coated four times day.
The ergolid myselate helps, it is thought in the art, that i~ will serve to prevent the cell's temporary loss of protein; the dipyridamole increase cerebral blood flow; and the acetyl salicylic acid helps to prevent clots among other beneficial results. Just as in the case of the male patient noted above, this emale patient experienced marked and fast rejuvenation, dissipation of dementia, increased mental alertness, and a general vitalization such that many of her Alzheimer disease symptoms by conventional diagnosis; but senile dementia disappeared by new biochemical diagnosis in figure 3 and 4.
Besides the use of conjugated estrogen, any estrogen from the following group may be used singly or in combination: Estradiol; estrone; estriol. Further, gonadotropins and chorionic gonadotropins may also be used, singly or in combination. Also, another androgen or .,.
1 3232~4 an anabolic hormone could have been used successfully instead of the methyltestosterone.
In conjunction with the above-disclosed treatment, in these patients where it has been determined that the level of growth hormone in their system is below normal for their size, sex, and age bracket, the above-administering of drugs is supplemented with a growth hormone to re-establish normal levels thereof in the patients. These growth hormones, also of potent anabolic efficacy, serve to restor~ body function to a state receptive to treatment of the present invention in those cases where growth hormone levels are deficient. Further, the growth hormone may also be used in those patients having normal levels of old age thereof, if it has been found that treatment with the androgen or anabolic hormones alone or in combination have not adequately provided success. Typically, if, after six months treatment with the present invention, improvement has not been shown, administering of growth hormones should be instituted, e.g. chorionic gonodotropin in combination.
In the advanced stages of the diseases, a growth hormone is also used at the outset of treatment, since owing to its increased and magnified positive metabolic effect, a greater and more concentrated inducement of nerve cell regeneration is needed as described in the diagnostic method of senile dementia Alzheimer style.
It is also indicated that the method of :
, - , ~
1 32329~
treatment as described in the present invention is successful for the alleviating of at least some symptoms for most patients in the incipient, beginning or intermediate stages of the above-named diseases because of the following:
1. General increase in cerebral blood flow which enhances oxidation, including the normal metabolism of the brain cells;
2. Decrease of catabolism of protein and amino acids;
3. Enhancement of protein anabolism, leading to increased activity of brain cells, with the concomitant increase in red blood cell production;
4. Increase in the retention of calcium and ~ sodium, which improve the axon-pr~synaptic-postsynaptic cell transmission;
5. Increase of intercellular protein, which increases the formation of DNA andd RNA;
6. The revitalization of the nerve cell body dendrite and axons of the pre-synaptic and post-synaptic cells.
It is, of course, to be understood that the dosage given during the use of the treatment of the present invention is dependent upon the weight, size, age, and the like of the patient being treated. Further, I
' - ~ "
. . : .
- . . .
. ' ' ':
1 32329~ `
any other well-known and equivalent sex hormone and anabolic hormone may be used in addition to those listed above, as long as the anabolic manifestations thereof are prevalent. Though the use of sex hormones, growth hormones, and anabolic hormones have been suspected of causing carcinoma, however, that in the doses above-stated for use in the treatment of the present invention, such likelihood is not of great probability. (Suspected cancer patients will be excluded from the treatment.) Further, since many of the patients for whom the present treatment would be useful and for whom it would prove successful, are quite advanced in age, and since their conditions are at present hopeless and their lives, for all intents and purposes, less than totally productive, it is definitely shown that the beneficial and successful attributes of the treatment of the present invention far outweigh the possible negative side effects and hazards.
It has also been determined that, for female patients suffering from the above-named central nervous system degenerative diseases, the use of estradiol alone in suitable dosage provides sufficient anabolic effect, so that the use of an anabolic hormone supplemental to the female sex hormone is not needed. Estradiol has ample anabolic effect itself to preclude the need of the additional use of an androgen or anabolic hormone. The same holds true for the female gonadotropic sex hormones.
Since gonadotropic sex hormones offer potent anabolic ~0 ,, -, 1 3232~4 effects as well, the use of an androgen and/or anabolic hormone is not needed. However, owing to the relative lack of anabolic effect of conjugated estrogens and estrones, then androgen and/or anabolic hormone would be required in a female patient, when treating her with either a conjugated estrogen or estrone sex hormone. In advanced stages of the above-named degenerative diseases, the use of a gonadotropic female sex hormone is desirable, either alone or in combination with a growth hormone or somatropin aloneO The dosage, of course, will vary depending upon the age, size, and weight of the patient. The amount of initial dosage of gonadotropic hormone and chorionic gonadotropic hormone preferably is that dosage presently-used to treat: men and women having low levels of sex anabolic hormones.
In order to properly diagnose Alzheimer's disease, it has been discovered that patients suffering from this disease show a depletion of the human growth hormone somatotropin (HGH) and the HGH-dependent hormone somatomedin-C (IGH-I) which makes connective tissue, die on skin and joints. The growth hormone is secreted -by the pituitary gland, while somatomedin-C is secreted mainly by the liver and kidneys by stimulation of somatotropin. This discovery of the lack of proper levels of these two hormones, in combination with the fact that Alzheimer's patients lack the capabilities of ., : . .
. ,~, .; :
1 3232~
producing these hormones endogenously even when exogenous stimuli are created in the body of the patient, has led to the method of diagnosis of the present invention.
According to the present invention, the L-Dopa provocative test of Aroonsakul and Allen is used to cause increased secretions of these two hormones, or somatropin alone, in order to determine if the pituitary gland, and the liver and kidneys, are capable of producing these hormones in response to this provocative test. It is important that not only the absolute levels of these two hormones in the peripheral blood serum be tested before the L-Dopa provocative test of Aroonsakul and Allen but also the levels of the increase, if any, produced by the L-Dopa provocative test, in order to determine the current stimulation-capabilities oi- the peripheral nervous system and the hypothalamu~, as well as the beta-adrenergic, alph adrenergic, and dopaminergic control systems. It is believed that the dominant control system is the dopaminergic, which is why L-Dopa causes increased secretions of HGH. For example clonidine propenolol, serotonin, ergoloid myselate causes andrenergic stimulation of the brain which will increase HGH.
The secretion of somatotropin by the pituitary gland is dependant upon many factors, some of them being well-known, such as physical exercise, physical and hypoglycemic stresses, low-protein intake and others.
Endogenous triggers of HGH release include sleep. Whether :
, . :
1 32329~
exogenous or endogenous, the changes in the secretion of the growth hormone (somatotropin) by the pituitary gland are directly dependent upon by the hormone "growth-hormone releasing-hormone" (GHRH) produced by the hypothalamus, which acts directly upon the pituitary gland in order to cause increase secretion of HGH.
Exogenous injection of GHRH into the blood system will result in direct increased secretion of HGH. The secretion of HGH, in turn, causes the increased secretion of somatomedin-C by the liver and kidneys, which somatomedin-C is also used as a feedback loop to the hypothalamus to regulate the secretion of GHRH and, thus, the secretion of HGH. The secretion of ~IGH is also inhibited by the hormone somatostatin, a cyclic peptide having fourteen amino acids, produced by the pancreas.
Somatostatin also acts in a feedback loop with the hypothalamus to inhibit production of GHRH and HGH.
It has been the discovery, according to the present invention that patients suffering from Alzheimer's disease lack proper and normal levels of HGH and somatomedin-C, and also lack the capabilities of producing increased amounts of these hormones in response to exogenous stimuli that tend to cause substantially large and immediate increases of secretions in these two hormones, such as occurs during the Aroonsokul-Allen provocative test (dopomine, catecholamine, serotonin). It . .
,: :
,~.
. .
i- , ,,~,.. , ~ :, ' ~. .
1 3~3294 is the method of the present invention to use the L-Dopa provocative test to cause sudden and substantial increases in the secretions of the hormones HGH and somatomedin-C. By using radioimmunoassay techniques for detecting the levels of these hormones in the blood serum at chosen time intervals, the results therof may be compared with the norm for the age of the patient, to thereby guage if the pituitary gland is capable of reacting to this stimuli to increase production of HGH, so that a firm diagnosis of Alzheimer's disease may be made.
According to the method of the present invention for diagnosing Alzheimer's disease, one day prior to the use of the Aroonsokul-Allen provocative test provocative test, a dosage of 8mg. og L-dopa per kilogram-of-weight of the patient is administered to the patient in order to activate the HGH-secreting capabilities of the pituitary glandO On the next dayr after an overnight fast, the L-dopa provocative test is given, with a dosage o~ 15mg. of -dopa per kilogram-of-weight of the patient. A blood sample is taken just prior to the dosage of 8mg. of L-dopa per kg. on the day prior to the L-Dopa provocative test, and blood samples are also taken immedidately before the start of the L-Dopa provocative testing, and every 30 minutes after the dosage of 15mg./kg. has been administered. Each blood serum is then tested by RIA
techniques to determine the absolute levels of `
somatotropin and somatomedin-C, and compared against the normal values for the age of the patient being tested.
Referring to Figure 1, there is shown a bar-chart comparing the levels of somatotropin and somatomedin-C
obtained by RIA techniques for the five blood sera taken during the provocative test with the levels for normal subjects aged fifty and over. The shaded bars represent typical levels of a patient who has Alzheimer's disease, while the unshaded bars indicate the levels for a normal person aged fifty and over, for the five sera assayed. As it may be seen, for normal subjects, the readings at times: 0 minutes, 30 minutes, 60 minutes, 90 minutes, and 120 minutes are, approximately: 2.00 ng/ml; 3.75 ng/ml;
It is, of course, to be understood that the dosage given during the use of the treatment of the present invention is dependent upon the weight, size, age, and the like of the patient being treated. Further, I
' - ~ "
. . : .
- . . .
. ' ' ':
1 32329~ `
any other well-known and equivalent sex hormone and anabolic hormone may be used in addition to those listed above, as long as the anabolic manifestations thereof are prevalent. Though the use of sex hormones, growth hormones, and anabolic hormones have been suspected of causing carcinoma, however, that in the doses above-stated for use in the treatment of the present invention, such likelihood is not of great probability. (Suspected cancer patients will be excluded from the treatment.) Further, since many of the patients for whom the present treatment would be useful and for whom it would prove successful, are quite advanced in age, and since their conditions are at present hopeless and their lives, for all intents and purposes, less than totally productive, it is definitely shown that the beneficial and successful attributes of the treatment of the present invention far outweigh the possible negative side effects and hazards.
It has also been determined that, for female patients suffering from the above-named central nervous system degenerative diseases, the use of estradiol alone in suitable dosage provides sufficient anabolic effect, so that the use of an anabolic hormone supplemental to the female sex hormone is not needed. Estradiol has ample anabolic effect itself to preclude the need of the additional use of an androgen or anabolic hormone. The same holds true for the female gonadotropic sex hormones.
Since gonadotropic sex hormones offer potent anabolic ~0 ,, -, 1 3232~4 effects as well, the use of an androgen and/or anabolic hormone is not needed. However, owing to the relative lack of anabolic effect of conjugated estrogens and estrones, then androgen and/or anabolic hormone would be required in a female patient, when treating her with either a conjugated estrogen or estrone sex hormone. In advanced stages of the above-named degenerative diseases, the use of a gonadotropic female sex hormone is desirable, either alone or in combination with a growth hormone or somatropin aloneO The dosage, of course, will vary depending upon the age, size, and weight of the patient. The amount of initial dosage of gonadotropic hormone and chorionic gonadotropic hormone preferably is that dosage presently-used to treat: men and women having low levels of sex anabolic hormones.
In order to properly diagnose Alzheimer's disease, it has been discovered that patients suffering from this disease show a depletion of the human growth hormone somatotropin (HGH) and the HGH-dependent hormone somatomedin-C (IGH-I) which makes connective tissue, die on skin and joints. The growth hormone is secreted -by the pituitary gland, while somatomedin-C is secreted mainly by the liver and kidneys by stimulation of somatotropin. This discovery of the lack of proper levels of these two hormones, in combination with the fact that Alzheimer's patients lack the capabilities of ., : . .
. ,~, .; :
1 3232~
producing these hormones endogenously even when exogenous stimuli are created in the body of the patient, has led to the method of diagnosis of the present invention.
According to the present invention, the L-Dopa provocative test of Aroonsakul and Allen is used to cause increased secretions of these two hormones, or somatropin alone, in order to determine if the pituitary gland, and the liver and kidneys, are capable of producing these hormones in response to this provocative test. It is important that not only the absolute levels of these two hormones in the peripheral blood serum be tested before the L-Dopa provocative test of Aroonsakul and Allen but also the levels of the increase, if any, produced by the L-Dopa provocative test, in order to determine the current stimulation-capabilities oi- the peripheral nervous system and the hypothalamu~, as well as the beta-adrenergic, alph adrenergic, and dopaminergic control systems. It is believed that the dominant control system is the dopaminergic, which is why L-Dopa causes increased secretions of HGH. For example clonidine propenolol, serotonin, ergoloid myselate causes andrenergic stimulation of the brain which will increase HGH.
The secretion of somatotropin by the pituitary gland is dependant upon many factors, some of them being well-known, such as physical exercise, physical and hypoglycemic stresses, low-protein intake and others.
Endogenous triggers of HGH release include sleep. Whether :
, . :
1 32329~
exogenous or endogenous, the changes in the secretion of the growth hormone (somatotropin) by the pituitary gland are directly dependent upon by the hormone "growth-hormone releasing-hormone" (GHRH) produced by the hypothalamus, which acts directly upon the pituitary gland in order to cause increase secretion of HGH.
Exogenous injection of GHRH into the blood system will result in direct increased secretion of HGH. The secretion of HGH, in turn, causes the increased secretion of somatomedin-C by the liver and kidneys, which somatomedin-C is also used as a feedback loop to the hypothalamus to regulate the secretion of GHRH and, thus, the secretion of HGH. The secretion of ~IGH is also inhibited by the hormone somatostatin, a cyclic peptide having fourteen amino acids, produced by the pancreas.
Somatostatin also acts in a feedback loop with the hypothalamus to inhibit production of GHRH and HGH.
It has been the discovery, according to the present invention that patients suffering from Alzheimer's disease lack proper and normal levels of HGH and somatomedin-C, and also lack the capabilities of producing increased amounts of these hormones in response to exogenous stimuli that tend to cause substantially large and immediate increases of secretions in these two hormones, such as occurs during the Aroonsokul-Allen provocative test (dopomine, catecholamine, serotonin). It . .
,: :
,~.
. .
i- , ,,~,.. , ~ :, ' ~. .
1 3~3294 is the method of the present invention to use the L-Dopa provocative test to cause sudden and substantial increases in the secretions of the hormones HGH and somatomedin-C. By using radioimmunoassay techniques for detecting the levels of these hormones in the blood serum at chosen time intervals, the results therof may be compared with the norm for the age of the patient, to thereby guage if the pituitary gland is capable of reacting to this stimuli to increase production of HGH, so that a firm diagnosis of Alzheimer's disease may be made.
According to the method of the present invention for diagnosing Alzheimer's disease, one day prior to the use of the Aroonsokul-Allen provocative test provocative test, a dosage of 8mg. og L-dopa per kilogram-of-weight of the patient is administered to the patient in order to activate the HGH-secreting capabilities of the pituitary glandO On the next dayr after an overnight fast, the L-dopa provocative test is given, with a dosage o~ 15mg. of -dopa per kilogram-of-weight of the patient. A blood sample is taken just prior to the dosage of 8mg. of L-dopa per kg. on the day prior to the L-Dopa provocative test, and blood samples are also taken immedidately before the start of the L-Dopa provocative testing, and every 30 minutes after the dosage of 15mg./kg. has been administered. Each blood serum is then tested by RIA
techniques to determine the absolute levels of `
somatotropin and somatomedin-C, and compared against the normal values for the age of the patient being tested.
Referring to Figure 1, there is shown a bar-chart comparing the levels of somatotropin and somatomedin-C
obtained by RIA techniques for the five blood sera taken during the provocative test with the levels for normal subjects aged fifty and over. The shaded bars represent typical levels of a patient who has Alzheimer's disease, while the unshaded bars indicate the levels for a normal person aged fifty and over, for the five sera assayed. As it may be seen, for normal subjects, the readings at times: 0 minutes, 30 minutes, 60 minutes, 90 minutes, and 120 minutes are, approximately: 2.00 ng/ml; 3.75 ng/ml;
7.90 ng/ml; 6.05 ng/ml; and 4.45 ng/ml. For patients suffering rom Alzheimer's disease the corresponding values are, approximately: 0.02 ng/ml; between 0.03 ng/ml and 1.85 ng/ml; 2.15 ng/ml; 2.05 ng/ml; and 1.85 ng/ml.
The values indicated for the normal subjects are the statistical mean average. The highest value shown in Figure 1, for a patient suf~ering from Alzheimer's disease, for each of the sera tested by RIA is that lying outside of the standard statistical error associated with the RIA testing.
Figure 2 shows similar results for the RIA of the hormone somatomedin-C. For normal subjects age 50 and .
.,: - . ~ .
. . . :~ :
. : ,. ,. ,: : :
,. .. .. ::
~: . - . :, 1 32329~
over, the values from RIA of this hormone are appproximately: 1.95 ng/ml; 4.00 ng/ml; 8.05 ng/ml; 5.90 ng/ml; and ~.45 mg/ml. The corresponding values of Alzheimer's disease patients, are approximately: 0.10 ng/ml; 1.65 ng/ml; 2.15 ng/ml; 2.00 ng/ml; and 2.05 ng/ml.
It is, of course, possible to use different time periods in which the blood sera are taken for subsequent RIA analysis, with these results being compared to a standard for subjects aged 50 and over for the same time periods tested. According to the present invention, substantial differences in levels of these two hormones during the AA provocative test as compared with the normal subjects is a positive and clefinitive indication of Alzheimer's diseasse. Furthermore, the absolute differences between the tested sera~ and the levels for normal subjects may also be used ~or an indicat~on as to the state of advancement o~ Alzheirner's disease in the patient. Tested levels far outside the statistical norm adjusted ~or standard statistical error would mean a more advanced stage of the disease.
There will be some instances where the levels of somatotropin will increase and be similar to those of normal subjects, but the levels of somatomedin-C will fall far short of those for normal subjects, as could occur if the patient were suffering from liver disease.
Thus, the AA provocative test would show a mixed result.
.. ,. .... ~ . , ~ . :
. . :
.. . . ..
.: ., ~,. , :, . : ,, ., : :
1 3232q4 In this case, further testing would be required, and a positive determination of Alzheimer's disease would have to be confirmed in conjunction with other, currently-used, prior art methods of diagnosis, such as EEG
testiny, neuropsychological testing, and the like. Also, where the results from the AA provocate test do not show enough differences between the patient being tested and the norm, such as might occur if the values determined by RIA were not outside the statistical mean error of the normal group, then these other conventional methods of diagnosis would be used in conjunction with the method of the present invention. Whereas, both HGH and IGF-I
deficiency in children may occur, as in dwarfism, such matched deficiency in adults is not known to indicate any other disease but that discovered according to the present invention. Since during bas,al, morning conditions there usually cannot be detected any diferences between normal subjects and those with HG~ deficiency, the provocative test is reguired, as described above.
Any other HGH-provocative agent may be used instead of L-Dopa. For example, bromocriptine, propanolol, serotonin, catecholamine clonidine, other dopaminergic stimuli, and glucagon, a small peptide that mediates the flow of glucose to insulin-independent tissues. Of course, the time periods between which the blood sera are taken will depend upon the somatotropin~provocative agent , ~. .................... .
. . ::
~. . ~ : - . : ::.. ..
,. . :. . : -, ~. j . ~ .: , .
: ., .. . ~. .:: : . -': ' ' ' 1 3232~
used. Other constraints and conditions will, of course, change dependent upon the HGH-provocative used, and will be obvious to one having ordinary skill in the art. For example, for glucagon as the HGH-provocative, overnight fasting ~ould not be required.
The same type of provocative test above described may also be used for diagnosing senile dementia in human heings, as shown in figures 3 and 4, which are graphs of the levels of the hormone being detected for the subject patient diagnosed as suffering from Alzheimer's disease or senile dementia as compared to a controlled group thereof. The same method of diagnosing is carried out as above described when using the desired provocative test. It has also been discovered that the detection of the proportion of the brain neuro-transmitter, cholineacethylesterase, is also indicative of a diagnosis of Alzheimer's disease or senile dementia, as shown in the graphs of Figure 4 where the ordinate is time and the abcissa is the proportion of the brain neuro-transmitter, acetylcholineesterase, to the total blood sample for normal subjects and those suffering from Alzheimer's disease or senile dementia. In Figure 4, the graph labelled 1 shows the readings of the proportion of the bain transmitter acetlycholineestrase for normal subjects, while the graph labelled 2 shows the upward limit of the readings for the proportion of the brain transmitter indicative of Senile Dementia. The graph -- ~ . .
: , 1 3232~
labelled 4 indicates the readings at or below which is an indication of Alzheimer's Disease. The region between the graphs labelled 3 and 4 is a transition region, readings lying therein not being clearly definitive as to Senile Dementia or Alzheimer's Disease, though at least one is present.
While a specific embodiment of the invention has been set forth, it is to be understood that numerous changes, modifications, and alterations to the present method for diagnosing Alzheimer's disease may be made without departing from the scope and spirit of the invention as set forth in the appended claims.
::
:~: , -~ . :
:~. . .
The values indicated for the normal subjects are the statistical mean average. The highest value shown in Figure 1, for a patient suf~ering from Alzheimer's disease, for each of the sera tested by RIA is that lying outside of the standard statistical error associated with the RIA testing.
Figure 2 shows similar results for the RIA of the hormone somatomedin-C. For normal subjects age 50 and .
.,: - . ~ .
. . . :~ :
. : ,. ,. ,: : :
,. .. .. ::
~: . - . :, 1 32329~
over, the values from RIA of this hormone are appproximately: 1.95 ng/ml; 4.00 ng/ml; 8.05 ng/ml; 5.90 ng/ml; and ~.45 mg/ml. The corresponding values of Alzheimer's disease patients, are approximately: 0.10 ng/ml; 1.65 ng/ml; 2.15 ng/ml; 2.00 ng/ml; and 2.05 ng/ml.
It is, of course, possible to use different time periods in which the blood sera are taken for subsequent RIA analysis, with these results being compared to a standard for subjects aged 50 and over for the same time periods tested. According to the present invention, substantial differences in levels of these two hormones during the AA provocative test as compared with the normal subjects is a positive and clefinitive indication of Alzheimer's diseasse. Furthermore, the absolute differences between the tested sera~ and the levels for normal subjects may also be used ~or an indicat~on as to the state of advancement o~ Alzheirner's disease in the patient. Tested levels far outside the statistical norm adjusted ~or standard statistical error would mean a more advanced stage of the disease.
There will be some instances where the levels of somatotropin will increase and be similar to those of normal subjects, but the levels of somatomedin-C will fall far short of those for normal subjects, as could occur if the patient were suffering from liver disease.
Thus, the AA provocative test would show a mixed result.
.. ,. .... ~ . , ~ . :
. . :
.. . . ..
.: ., ~,. , :, . : ,, ., : :
1 3232q4 In this case, further testing would be required, and a positive determination of Alzheimer's disease would have to be confirmed in conjunction with other, currently-used, prior art methods of diagnosis, such as EEG
testiny, neuropsychological testing, and the like. Also, where the results from the AA provocate test do not show enough differences between the patient being tested and the norm, such as might occur if the values determined by RIA were not outside the statistical mean error of the normal group, then these other conventional methods of diagnosis would be used in conjunction with the method of the present invention. Whereas, both HGH and IGF-I
deficiency in children may occur, as in dwarfism, such matched deficiency in adults is not known to indicate any other disease but that discovered according to the present invention. Since during bas,al, morning conditions there usually cannot be detected any diferences between normal subjects and those with HG~ deficiency, the provocative test is reguired, as described above.
Any other HGH-provocative agent may be used instead of L-Dopa. For example, bromocriptine, propanolol, serotonin, catecholamine clonidine, other dopaminergic stimuli, and glucagon, a small peptide that mediates the flow of glucose to insulin-independent tissues. Of course, the time periods between which the blood sera are taken will depend upon the somatotropin~provocative agent , ~. .................... .
. . ::
~. . ~ : - . : ::.. ..
,. . :. . : -, ~. j . ~ .: , .
: ., .. . ~. .:: : . -': ' ' ' 1 3232~
used. Other constraints and conditions will, of course, change dependent upon the HGH-provocative used, and will be obvious to one having ordinary skill in the art. For example, for glucagon as the HGH-provocative, overnight fasting ~ould not be required.
The same type of provocative test above described may also be used for diagnosing senile dementia in human heings, as shown in figures 3 and 4, which are graphs of the levels of the hormone being detected for the subject patient diagnosed as suffering from Alzheimer's disease or senile dementia as compared to a controlled group thereof. The same method of diagnosing is carried out as above described when using the desired provocative test. It has also been discovered that the detection of the proportion of the brain neuro-transmitter, cholineacethylesterase, is also indicative of a diagnosis of Alzheimer's disease or senile dementia, as shown in the graphs of Figure 4 where the ordinate is time and the abcissa is the proportion of the brain neuro-transmitter, acetylcholineesterase, to the total blood sample for normal subjects and those suffering from Alzheimer's disease or senile dementia. In Figure 4, the graph labelled 1 shows the readings of the proportion of the bain transmitter acetlycholineestrase for normal subjects, while the graph labelled 2 shows the upward limit of the readings for the proportion of the brain transmitter indicative of Senile Dementia. The graph -- ~ . .
: , 1 3232~
labelled 4 indicates the readings at or below which is an indication of Alzheimer's Disease. The region between the graphs labelled 3 and 4 is a transition region, readings lying therein not being clearly definitive as to Senile Dementia or Alzheimer's Disease, though at least one is present.
While a specific embodiment of the invention has been set forth, it is to be understood that numerous changes, modifications, and alterations to the present method for diagnosing Alzheimer's disease may be made without departing from the scope and spirit of the invention as set forth in the appended claims.
::
:~: , -~ . :
:~. . .
Claims (8)
- CLAIM 1. A method of diagnosing Alzheimer's disease senile dementia in human beings comprising:
(a) subjecting a patient suspected of suffering from Alzheimer's disease to a somatotropin secretion-stimulation test;
(b) determining the levels of somatotropin in at least one blood serum sample taken from the patient after the somatotropin secretion-stimulation test; and (c) comparing the levels from the at least one blood serum sample obtained during said step (b) with the levels of normal subjects within the age group of the patient being diagnosed to see if any increase of somatotropin caused by said step (a) statistically-match the increases thereof in normal subjects. - CLAIM 2. The method of diagnosing Alzheimer's disease, senile dementia, according to Claim 1, further comprising the steps of:
(d) determining the levels of the hormone somatomedin-C in the at least one blood serum sample after said step (a); and (e) comparing the levels found from said step (d) with the levels of normal subjects within the age group of the patient being diagnosed to see if any increases of somatomedin-C caused by said step (a) statistically-match the increases thereof in the normal subjects. - CLAIM 3. The method of diagnosing Alzheimer's disease according to Claim 1, wherein said step (a) comprises administering L-Dopa provocative test to the patient, said step further comprising taking sample-sera from the patient being tested every thirty minutes after administration of the L-Dopa of the L-Dopa provocative test.
- CLAIM 4. The method according to Claim 3 wherein said step (a) comprises administering approximately 15 mg/kg-of-weight of the patient being tested, said step further comprising administering a dosage of L-Dopa on a day before said step (a) is performed, said dosage of L-Dopa on the day before being approximately 8mg/kg-of-weight of the patient.
- CLAIM 5. The method of diagnosing Alzheimer's disease, senile dementia, according to Claim 1, wherein said step (a) comprises administering to the patient being diagnosed at least one from the following group: L-Dopa, bromocriptine,serotonin, cathecolamine, propanolol, glucagon, and clonidine in sufficient dosages so as to tend to cause sudden, dramatic, increased secretions of the said hormones somatotropin and somatomedin.-C.
- CLAIM 6. A method of diagnosing Alzheimer's disease, senile dementia, in which the L-Dopa provocative test, or the equivalent thereof, has been given the patient being diagnosed, comprising:
(a) determining the levels of at least one of the hormones somatotropin and somatomedin-C after the administration of the L-Dopa, or the equivalent thereof; and sonotropin only in venous blood of two hour period;
(b) comparing the levels obtained from said (a) with levels of normal subjects within the same age bracket as the patient being tested for Alzheimer's disease, in order to determine if any increase, or lack thereof, in the levels from said step (a) falls below the statistical levels of the normal subjects. - CLAIM 7. The method of diagnosing Alzheimer's disease and senile dementia in a human being comprising:
(a) subjecting a patient to a somatotropin secretion-stimulation test;
(b) determining the levels of somatotropin in at least one blood serum sample taken from the patient after the somatotropin secretion-stimulation test; and (c) comparing the levels from the at least one blood serum sample obtained during said step (b) with the levels of normal subjects within the age group of the patient being diagnosed to see if any increase of somatotropin caused by said step (a) statistically-match a two-three hour period of increase thereof in normal subjects.
(d) determining the levels of cerebrospind fluid of cholineacethylesterase of acetylecholine esterase in the blood sample after said step (a), and fluctuation of two hour venous blood test of HGH; and (e) comparing the levels found from said step (d) with the levels of normal subjects within the aye group of the patient being diagnosed to see if any increases of cholineacethylesterase caused by said step (a) statistically-match the increase thereof in the normal subjects. - CLAIM 8. The method according to Claim 7, wherein said step (a) comprises administering a provocative test to the patient suspected of suffering from Alzheimer's disease or senile dementia; said provocative test (Aroonsakul and Allen provocative test) comprising administering at least one from the following group: L-Dopa, bromocriptine, propanolol, glucagon, and serotanin, cathecolamine, amphetemine, clonidine in sufficient dosages; said step (a) further comprising sample-sera from the patient being tested every thirty minutes after administration of L-Dopa of the L-Dopa provocative test, one of said sample-sera being taken immediately prior to the administration of the L-Dopa of said step (a).
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US06/852,645 US4727041A (en) | 1986-04-16 | 1986-04-16 | Method of diagnosing Alzheimer's disease |
CA000555899A CA1323294C (en) | 1986-04-16 | 1988-01-05 | Method of treatment of central nervous system diseases such as alzheimer's disease and parkinson's disease and method of diagnosing alzheimer's disease |
US07/293,017 US4902680A (en) | 1984-10-29 | 1989-01-03 | Treating central nervous system diseases |
US07/456,516 US5017470A (en) | 1984-10-29 | 1989-12-04 | Method of diagnosing alzheimer's disease and senile dementia |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US06/852,645 US4727041A (en) | 1986-04-16 | 1986-04-16 | Method of diagnosing Alzheimer's disease |
CA000555899A CA1323294C (en) | 1986-04-16 | 1988-01-05 | Method of treatment of central nervous system diseases such as alzheimer's disease and parkinson's disease and method of diagnosing alzheimer's disease |
Publications (1)
Publication Number | Publication Date |
---|---|
CA1323294C true CA1323294C (en) | 1993-10-19 |
Family
ID=25671652
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA000555899A Expired - Fee Related CA1323294C (en) | 1984-10-29 | 1988-01-05 | Method of treatment of central nervous system diseases such as alzheimer's disease and parkinson's disease and method of diagnosing alzheimer's disease |
Country Status (1)
Country | Link |
---|---|
CA (1) | CA1323294C (en) |
-
1988
- 1988-01-05 CA CA000555899A patent/CA1323294C/en not_active Expired - Fee Related
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US4897389A (en) | Treating central nervous system diseases | |
US4902680A (en) | Treating central nervous system diseases | |
KOURIDES et al. | Pituitary secretion of free alpha and beta subunit of human thyrotropin in patients with thyroid disorders | |
Santen et al. | Short-and long-term effects of clomiphene citrate on the pituitary-testicular axis | |
Stowe et al. | Sertraline and desmethylsertraline in human breast milk and nursing infants | |
DeKosky et al. | Elevated corticosterone levels: A possible cause of reduced axon sprouting in aged animals | |
Schleifer et al. | Lymphocyte function in major depressive disorder | |
ASSIES et al. | Prolactin in human cerebrospinal fluid | |
US4791099A (en) | Method of treatment for central nervous system diseases such as Alzheimer's's disease | |
Shoupe et al. | Evidence for altered catecholamine metabolism in polycystic ovary syndrome | |
US4898856A (en) | Method for treating central nervous system diseases | |
US4727041A (en) | Method of diagnosing Alzheimer's disease | |
Eaton | Glucagon secretion and activity in the cobalt chloride-treated rat | |
US5017470A (en) | Method of diagnosing alzheimer's disease and senile dementia | |
US4898857A (en) | Treating control nervous system diseases | |
Ward et al. | A sensitive radioimmunoassay for human proinsulin, with sequential use of antisera to C-peptide and insulin. | |
Halbreich et al. | Growth hormone response to dextroamphetamine in depressed patients and normal subjects | |
EP0324037B1 (en) | Use of anabolic hormones for the manufacture of a medicament for the treatment of Alzheimer's disease and senile dementia | |
CA1323294C (en) | Method of treatment of central nervous system diseases such as alzheimer's disease and parkinson's disease and method of diagnosing alzheimer's disease | |
Kendall-Taylor et al. | Antibody that blocks stimulation of cortisol secretion by adrenocorticotrophic hormone in Addison's disease | |
AU604820B2 (en) | Method of treatment of central nervous system diseases such as alzheimer's disease and parkinson's disease and method of diagnosing alzheimer's disease | |
Gwinup et al. | Clinical testing of the hypothalamic-pituitary-adrenocortical system in states of hypo-and hypercortisolism | |
Nemeroff et al. | Growth hormone response to growth hormone releasing factor in Alzheimer’s disease | |
Saad et al. | Occult Cushing's disease presenting with acute psychosis | |
Gordis et al. | Disulfiram therapy in alcoholism: Patient compliance studied with a urine‐detection procedure |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
MKLA | Lapsed |