タイトル厚生労働科学研究費補助金（難治性疾患克服研究事業）「Menkes 病・occipital horn 症候群の実態調査、早期診断基準確立、治療法開発に関する研究」平成23-24年度 総合研究報告書

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厚生労働科学研究費補助金（難治性疾患克服研究事業）「Menkes 病・occipital horn 症候群の実態調査、早期診断基準確立、治療法開発に関する研究」平成23-24年度 総合研究報告書

246 Current Drug Metabolism, 2012, Vol. 13, No. 3 Kodama et al.Table 3. Pharmacological Therapy for Wilson’s DiseaseDrug Mode of Action Maintenance Dose Side effectsTrientineInduction of urinarycopper excretionby chelating action750-1,000 mg/day three timesa day; children, 20-25mg/kg/dayGastritis, in rare cases aplastic anemia and sideroblasticanemia, neurological deterioration during initial phase oftreatment (about 26% [130])D-PenicillamineInduction of urinary copper excretionby chelating action750-1,000 mg/day three timesa day; children: 20 mg/kg/dayFever, rash, proteinuria, lupus-like reation, aplastic anemia,leukopenia, thrombocytopenia, nephrotic syndrome,degenerative change in skin, elastosis perforans serpingosa,serous retinitis, hepatotoxicity, neurological deteriorationduring initial phase of treatment (about 50% [110])ZincBlockage of copper absorption byinducing metallothionein in enterocytes150 mg/day, three times aday; children: 50-75 mg/dayGastritis, biochemical pancreatitis, zinc accumulation,possible changes in immune functionTetrathiomolybdateDetoxifying copper in plasma andblocking copper absorption by complexationwith copper20 mg, three times with mealsand three times betweenmeals [108]Anemia, neutropenia, hepatotoxicity, neurologic deteriorationduring initial treatment (about 4% [108])tients who receive the full treatment [100]. Urinary copper excretionincreases above 1000 ?g/day for a few months following penicillamineor trientine treatment (initial treatment). These levelsrange between 200-500 ?g/day during maintenance therapy with achelating agent [89].PenicillamineWhile penicillamine is the most effective treatment for removingcopper through urine excretion, it is associated with severe sideeffects [101]. These side effects include immunological conditions(e.g., lupus-like reactions, nephrotic syndrome, myasthenia gravis,and Goodpasture syndrome), skin defects (e.g., degenerativechanges and elastosis perforans serpiginosa), and joint disorders(e.g., arthropathy). Given these side effects, trientine is now thepreferred method of treatment [89,99].TrientineFigure 14 shows the chemical structure of trientine. Trientine isknown to remove copper from the blood compartment, and increasesurinary copper excretion. Zinc and iron are also excretedwith trientine, although in lesser amounts [102]. Trientine sharessome of penicillamine’s side effects, but appears to be significantlyless toxic and as efficacious as penicillamine [103]. For this reason,trientine is the recommended chelator for treatment of patients withhepatic WD [99].ZincZinc is a recommended treatment for presymptomatic patientsand for maintenance therapy of WD [99]. Zinc treatment of patientswith WD results in increased levels of non-toxic zinc-bound metallothionein.The enterocyte metallothionein induced by zinc inhibitscopper uptake from the intestinal tract, resulting in a negative copperbalance [104]. Zinc is also thought to protect against coppertoxicity in the liver by promoting sequestration of free copper in anon-toxic, metallothionein-bound form [105]. Treatment adequacyis determined by measuring non-ceruloplasmin-bound copper levelsin the serum (5-15 ?g/dL), 24-hour urinary copper excretion (<75?g/day) [89], or by spot urinary copper excretion with less than0.075 ?g/mg creatinine [106]. Non-ceruloplasmin-bound copperlevels in the serum can usually be calculated from serum copperand ceruloplasmin levels using the following equation:non-ceruloplasmin-bound copper levels in the serum (?g/dL) =serum copper level (?g/dL) ? 3 x serum ceruloplasmin level(mg/dL)This is possible because approximately 3.15 ?g of copper isbound to one mg of ceruloplasmin.Tetrathiomolybdate (TTM)TTM is an anti-copper drug with a unique mechanism of actiondeveloped for patients with neurological WD. It has 4 sulfur groupsthat allow it to form a tripartite and stable interaction with copper(Fig 14). If given with food, TTM forms a stable complex withcopper, rendering it unavailable for absorption. When given withoutfood, however, it is well absorbed and complexes with free serumcopper. TTM treatment does not result in serum copper spikes typicallyobserved with penicillamine and trientine [107]. This mayexplain why neurological worsening is rare with TTM treatmentversus other chelating agents [108], although a patient receivingTTM treatment was reported to develop status epilepticus [109].While TTM is now preferred over other chelating agents for treatmentof neurological WD, the FDA recently decided that furtherstudies are required before it can be used in patients with neurologicalWD (from HP of Pipex Parmaceuticals Comp).Patients with Neurological SymptomsIn patients with neurological symptoms, clinical worsening isobserved during the first few weeks of treatment in approximately50% and 26% of patients treated with penicillamine and trientine,respectively. In addition, 25% of patients treated with penicillamineare at risk of permanent neurological damage and may not recoverto baseline levels of function [110]. Neurological worsening duringinitiation of anti-copper therapy is attributed to spikes in levels ofserum non-ceruloplasmin-bound copper which occur during mobilizationof large stores of copper in the liver [107]. Although neurologicalworsening is also observed in a few patients treated withzinc, which is slow-acting, zinc alone or combination therapy withzinc and trientine are now recommended in patients with neurologicalWD [99,111,112]. Another problem is that neurological symptomssometimes do not completely subside with treatment. Livertransplantation in some patients with neurological disorders wasreported to resolve neurological symptoms associated with WD.However, detailed neurological evaluations in these patients werenot carried out [113]. Because early treatment is critical in patientsexhibiting neurological disorders, medical education efforts targetingprimary care physicians should be implemented in order toimprove early diagnosis [81].35