摘要:

AbstractAt the onset of Alzheimer's disease (AD), specific lesions occur in the hippocampus, i.e., neuropile‐capillary amyloid (AM) plaques and neuronal paired‐helical filaments (PHF)‐neurofibrillary tangles (NFT). The hippocampus is the area of brain with the highest zinc content. Chemical investigations demonstrated that in AD, the cerebral zinc decreases, especially in the hippocampus. The mechanism may be the following: The primary, genetically determined, microvascular AM (asymptomatic) disturbs the blood‐brain barrier, and metals (calcium, iron, aluminium, silicon, mercury, etc.( reach the cerebral cortex, where their levels increase and displace the zinc (whose level decreases) in some enzymes which become nonfunctional. The secondary production of PHF‐NFT and the neuronal dysfunction responsible of the clinical symptoms of dementia may be related to the functional deficiency of the following zinc‐enzymes: (1) those of DNA metabolism giving rise to abnormal DNA and therefore synthesis of abnormal proteins, constituting the NFT; (2) those involved in phosphorylating mechanisms at a post‐transcriptional (ribosomal‐mitochondrial) level, producing the abnormally phosphorylated tau protein, constituting the PHF; 3) that of glutamate (GLU) catabolism, resulting in a neurotoxic increase of GLU, producing PHF by abnormal phosphorylation of the neurofilaments; 4) those of neuronal detoxification contributing to the neuronal dysfunction. In regard to potential for therapeutic intervention, the timing needed for the AM‐induced production of NFT, in the various areas of the brain, has been estimated to be about 14–67 months. During this time it may be possible to influence the AM‐induced production of NFT: The chronic administration of neuroleptics enhances it, and the chronic administration of other drugs may reduce it. Such drugs may be zinc compounds, which will give an excess of zinc in the brain, will inhibit the above‐mentioned AM induced by zinc deficiency, mechanisms producing the NFT related to the clinical symptoms of dementia, and therefore, may prevent, stop, delay, and even improve them. Preliminary trials with zinc‐aspartate give promising results. Research is in progress to consolidate this zinc theory and to find more appropriate zinc compounds for this treatmen

ISSN:0272-4391    

DOI:10.1002/ddr.430270102

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractIncorporation of interleukin‐2 (IL‐2) into multilamellar vesicles, IL‐2 liposomes, significantly modifies the biodistribution and prolongs the clearance of the cytokine. The rat was used to evaluate and characterize subacute toxicity and short‐term pathologic effects of intravenous (i.v.) IL‐2 liposomes. Once daily i.v. IL‐2 liposomes in doses of 0.3 × 106u/kg, 1.5 × 106u/kg, 4.0 × 106u/kg, and 20 × 106u/kg were given to rats for 15 days; control rats received i.v. empty liposomes or buffered saline. Hematologic parameters, serum chemistry, and gross pathologic and histopathologic findings were recorded. Only at the highest dose of IL‐2 liposomes were effects consistently severe enough to produce weight loss, decreased food consumption, hepatitis, anemia, and death. At this dose females were more susceptible to mortality than males; only 1 of 5 females survived compared to 4 of 5 males. Peripheral blood leukocyte increases after IL‐2 liposomes were mainly associated with lymphocytosis with only minor changes in neutrophils, monocytes, and eosinophils. The marrow had significant dose‐related hematopathologic findings limited to decreased percentages of lymphocytes and increased myeloid:erythroid (M:E) ratio in the 20 × 106u/kg group. No increases in marrow eosinophils or eosinophilic precursors were demonstrated. The major toxic effects of IL‐2 liposomes in rats were hepatic. Dose‐related elevations in liver enzyme serum chemistries (aspartate aminotransferase [AST], alanine aminotransferase [ALT], bilirubin, γ‐glutamyl transferase [GGT], and alkaline phosphatase) were seen. Occasional rats had evidence of bridging fibrosis in addition to centrilobular and periportal lymphocytic and eosinophilic infiltration of the liver. Pulmonary histopathology was characterized by peribronchial and perivascular lymphoid and eosinophilic infiltration with minimal or no septa1 involvement. In summary, the spectrum of pathologic and toxicologic changes in rats receiving once daily IL‐2 liposomes are similar to those previously reported in rats given the free cytokine twice daily, but occur at reduced doses with less lung pathology. Thus, compared to free cytokine i.v. IL‐2 liposomes in rats have increased potency and decreased pulmonary

ISSN:0272-4391    

DOI:10.1002/ddr.430270103

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractTwo studies were undertaken to investigate the sedative and congnitive effects of cyclobenzaprine (Flexeril®) in volunteers, using a computerized battery of congnitive tests and subjective rating scales. In Study 1 the effect of acute administration of two doses of cyclobenzaprine (2.5, 5 mg orally) were compared with a single dose of diphenhydramine (Benadryl; 50 mg orally) and placebo. On most tests diphenhydramine produced a significant impairment compared to placebo, whereas there were typically no significant differences between cyclobenzaprine and placebo. In Study 2 the effects of repeated dosing with cyclobenzaprine (5 mg three times daily for 10 doses) were compared to placebo. The test battery was administered after the fourth and tenth doses. There was a small but mainly nonsignificant trend for subjects receiving cyclobenzaprine to do worse at the first test session. No differences between treatments were apparent by the second test session. The battery of tests used here would appear to be useful for assessing sedation. © 1992 Wiley‐Liss,

ISSN:0272-4391    

DOI:10.1002/ddr.430270104

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractAlpha‐tocopherol and its water‐soluble derivative, Trolox, are capable of terminating free radical chain reactions and limiting reperfusion‐induced cell damage. In the present study, we have quantitated the effects of two relatively potent analogs of alpha‐tocopherol/Trolox, WIN 62079 and U‐78517F, which attenuated exogenously generated free radical damage in cultured cells and reperfusion injury in vivo. In a cultured rat renal tubular epithelial cell line (NRK‐52E), millimolar concentrations of ascorbate or the combination of Trolox plus ascorbate reduced cellular damage (quantitated as lactate dehydrogenase [LDH] release) induced by radicals generated by hypoxanthine/xanthine oxidase. In contrast, WIN 62079 and U‐78517F attenuated damage at micromolar concentrations. Similarly, intravenous administration of WIN 62079 (three hourly doses of 3 mg/kg) and U‐78517F (10 mg/kg infused over 5 min) reduced reperfusion‐induced myocardial damage in rabbit coronary‐occulded hearts: Trolox (three hourly doses of 100 mg/kg) was less potent and required ascorbate (three hourly doses of 150 mg/kg) as a cofactor. These data demonstrate that is feasible to design potent, water‐soluble analogs of Trolox which are efficacious against free radical‐mediated cell death and which do not require ascorbate as a cofactor. Moreover, since U‐78517F and WIN 62079 are two to three orders of magnitude more potent than Trolox, and since they contain different amino side chains, these data further support the concept that side chain modifications of the chromane ring nucleus of alpha‐tocopherol derivatives significantly affect activity, possibly by providing additional activity or by enhancing availability to the cellular site of act

ISSN:0272-4391    

DOI:10.1002/ddr.430270105

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractThe present study was performed to examine the mechanism of action of neurokinin A (NKA) on guinea pig gallbaldder smooth muscle. Muscle strips were prepared and mounted in 10 mL tissue bath containing Krebs' solution under 1 g tension. NKA induced a concentration‐dependent increase in gallbladder muscle tension and reached a maximal response at 1 μM. The EC50value was approximately 30nM. Preincubation of the muscle strips with neurotoxins, tetrodotoxin (1 μM), or omega‐conotoxin (0.1 μM) had no effect on the NKA contractile response. NKA‐induced gallbladder contractions were insensitive to cyclooxygenase inhibitors (5 μM) piroxicam and indomethacin. In contrast, the calcium channel blockers verapamil and diltiazem (0.1–1 μM) significantly blocked the contractile response to NKA. The intracellular calcium chelator BAPTA/AM had no significant effect on NKA activity. The removal of extracellular calcium, however, completely abolished the contractile response of NKA. These data suggest that NKA has a direct contractile effect on guinea pig gallbladder smooth muscle, which is independent of prostaglandin release. The primary source of calcium involved in mediating the NKA contractile response is the extracellular pool, suggesting that NKA might act via activation of L‐type voltage‐operated calcium channels to mediate its action. © 199

ISSN:0272-4391    

DOI:10.1002/ddr.430270106

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractThe present study examined the gastric protective effects of zinc L‐carnosine (Z‐103) in reserpinized rats. We also studied whether this antiulcer effect is related to the preservation of mast cells degranulation in the glandular mucosa. Reserpine administration (5 mg/kg, intraperitoneally [i.p.]) produced severe hemorrhagic glandular ulcers which were accompained with a marked decrease in mucosal mast cell counts. The severity of ulcers and mast cell degranulation were reduced by Z‐103 when given orally 30 min before and 6 hr after reserpinization. However, this protection was not observed when the drug was administered as a single dose 30 min beforehand. The present findings extended the antiulcer action of Z‐103 from stress‐ and ethanol‐induced gastric damage to those on reserpine‐provoked gastric ulcers. It also indicates that the protective action on reserpine ulceration is likely to be due to the stabilization on mast cell membrane in the glandular mucosa. © 1992 W

ISSN:0272-4391    

DOI:10.1002/ddr.430270107

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractMilacemide, both an MAO‐B inhibitor and a prodrug for glycine, has demonstrated cognitive enhancing effects in animal models, in cognitively intact young and elderly, and has been suggested as a potential treatment for senile dementia of the Alzheimer type (SDAT). This multicenter open‐label trial evaluated the safety and potential efficacy of long‐term milacemide treatment in 209 SDAT outpatients (50–87 years of age). Milacemide treatment was intiated at 400 mg/day and was titrated up to a maximum dose of 1,600 mg/day. Laboratory screening tests, adverse effects reports, the Clinical Global Impression Scale, and the Patient Global Improvement Rating Scale were collected to assess patients' physical and cognitive functioning. Only 8 of 209 patients completed 1 year of treatment and the remaining patients were withdrawn due to adverse effects (73), protocol violations (89), treatment failure (34), and failure to follow‐up (5). Liver function tests became elevated in 145 patients and required study withdrawal of 67 of these patients. There was no evidence of cognitive enhancement or reduction in disease progression. It does not appear that milacemide is a viable treatment for SDAT patients. © 1992 Wiley

ISSN:0272-4391    

DOI:10.1002/ddr.430270108

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractThe interaction of a pulsed (100 and 50 Hz) magnetic field (90 μT) with the effect of atropine on small intestine transit was studied in mice. Both frequencies of the magnetic field significantly potentiated the atropine‐induced delay in intestinal transit but did not affect intestinal transit per se. This result further strengthens previous observations on interactions between electromagnetic fields and the actions of drugs. © 1992 Wiley‐Liss

ISSN:0272-4391    

DOI:10.1002/ddr.430270109

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

ISSN:0272-4391    

DOI:10.1002/ddr.430270101

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY