Treatment of Alzheimer disease.

Alzheimer disease is the most common form of dementia, affecting nearly one-half [corrected] of Americans older than 85 years. It is characterized by progressive memory loss and cognitive decline. Amyloid plaque accumulation, neurofibrillary tau tangles, and depletion of acetylcholine are among the pathologic manifestations of Alzheimer disease. Although there are no proven modalities for preventing Alzheimer disease, hypertension treatment, omega-3 fatty acid supplementation, physical activity, and cognitive engagement demonstrate modest potential. Acetylcholinesterase inhibitors are first-line medications for the treatment of Alzheimer disease, and are associated with mild improvements in cognitive function, behavior, and activities of daily living; however, the clinical relevance of these effects is unclear. The most common adverse effects of acetylcholinesterase inhibitors are nausea, vomiting, diarrhea, dizziness, confusion, and cardiac arrhythmias. Short-term use of the N-methyl-D-aspartate receptor antagonist memantine can modestly improve measures of cognition, behavior, and activities of daily living in patients with moderate to severe Alzheimer disease. Memantine can also be used in combination with acetylcholinesterase inhibitors. Memantine is generally well tolerated, but whether its benefits produce clinically meaningful improvement is controversial. Although N-methyl-D-aspartate receptor antagonists and acetylcholinesterase inhibitors can slow the progression of Alzheimer disease, no pharmacologic agents can reverse the progression. Atypical antipsychotics can improve some behavioral symptoms, but have been associated with increased mortality rates in older patients with dementia. There is conflicting evidence about the benefit of selegiline, testosterone, and ginkgo for the treatment of Alzheimer disease. There is no evidence supporting the beneficial effects of vitamin E, estrogen, or nonsteroidal anti-inflammatory drug therapy.

Metabolism of pentacarboxylate porphyrinogens by highly purified human coproporphyrinogen oxidase: further evidence for the existence of an abnormal pathway for heme biosynthesis.

An abnormal series of porphyrin tetracarboxylic acids known as the isocoproporphyrins, are commonly excreted by patients suffering from the disease porphyria cutanea tarda (PCT). These porphyrins appear to arise by bacterial degradation of dehydroisocoproporphyrinogen that is generated by the premature metabolism of the normal pentacarboxylate intermediate (5dab) by coproporphyrinogen oxidase (copro'gen oxidase). This porphyrinogen can be further metabolized by uroporphyrinogen decarboxylase to give harderoporphyrinogen, one of the usual intermediates in heme biosynthesis. Therefore, it is possible that some of the heme formed under abnormal conditions may originate from the 'isocopro-type' porphyrinogen intermediate. In order to investigate the feasibility of alternative pathways for heme biosynthesis, the four type III pentacarboxylate isomeric porphyrinogens were incubated with purified, cloned human copro'gen oxidase at 37 degrees C with various substrate concentrations under initial velocity conditions. Of the four isomers, only 5dab was a substrate for copro'gen oxidase and this gave dehydroisocoproporphyrin. The structure of the related porphyrin tetramethyl ester was confirmed by proton NMR spectroscopy and mass spectrometry. The K(m) value for proto'gen-IX formation from copro'gen, an indicator of molecular recognition, was similar to the K(m) value for monovinyl product formation with 5dab, although copro'gen-III has an approximately twofold higher K(cat) value. Although 5dab is a slightly poorer substrate than copro'gen-III, these results support the hypothesis that an abnormal route for heme biosynthesis is possible in humans suffering from PCT or related syndromes such as hexachlorobenzene poisoning.

An effective chromatographic separation of chicken red blood cell coproporphyrinogen oxidase and uroporphyrinogen decarboxylase, two enzymes in heme biosynthesis.

Of the heme biosynthetic pathway enzymes, coproporphyrinogen oxidase is one of the least understood. Substrate recognition studies [Prepr. Biochem. Biotech.1997, 27, 47, J. Org. Chem.1999, 64, 464] have been done using chicken blood hemolysates (CBH) as the source of this enzyme. However, the enzyme uroporphyrinogen decarboxylase is also present in these preparations and separation of these two enzymes from CBH had not yet been achieved. Thus, a substrate ligand column was developed by covalently linking coproporphyrin-III to a sepharose resin following a similar procedure previously used for the purification of uroporphyrinogen decarboxylase [Int. J. Biochem.1992, 24, 105]. The ligand-resin chromatography step rapidly separates coproporphyrinogen oxidase from uroporphyrinogen decarboxylase as well as the majority of the hemoglobin.