Delayed onset of Alzheimer's disease with nonsteroidal anti-inflammatory and histamine H2 blocking drugs

Factors that modify onset of Alzheimer's disease (AD) may be revealed by comparing environmental exposures in affected and unaffected members of discordant twin pairs or sibships. Among siblings at high risk of AD, sustained use of nonsteroidal anti-inflammatory drugs (NSAIDs) was associated with delayed onset and reduced risk of AD. After adjustment for use of NSAIDs, there was minimal effect on onset with reported history of any of three common illnesses (arthritis, diabetes, or acid-peptic disease). However, independent of exposure to NSAIDs, onset was unexpectedly delayed in those reporting extended use of histamine H2 blocking drugs. Randomized clinical trials will be needed to affirm the utility of these drugs for prevention, but the present findings may have implications for pathogenesis: because NSAIDs block the calcium-dependent postsynaptic cascade that induces excitotoxic cell death in NMDA-reactive neurons, and because histamine potentiates such events, excitotoxicity may deserve additional investigation in AD.     

Polyamine-enhanced NMDA receptor activity: effect of ethanol

Gastrointestinal symptoms and lesions are often associated with the clinical use of non-steroidal antiinflammatory drugs (NSAIDs). An open-label, single arm multicenter Italian study evaluated if misoprostol, a prostaglandin E1 analogue with gastroduodenal mucosal protective activity, was effective in the prevention and treatment of NSAID-induced gastroduodenal lesions. Patients affected by rheumatoid arthritis (RA) or osteoarthritis (OA), in treatment with NSAIDs and suffering from gastric symptoms or gastroduodenal lesions related to NSAID use, were admitted to the study. Gastrointestinal and arthritic symptoms were assessed before and after 4 weeks co-administration of an NSAID (the most frequent was diclofenac, used in 35% of the RA and in 22% of the OA patients, followed by piroxicam and tenoxicam respectively) + misoprostol (200 mcg two times daily in 58% of the cases, 200 mcg three times daily in 39%, 200 mcg four times daily in 3%). On admission and after 4 weeks of therapy a gastrointestinal endoscopy was performed to evaluate the condition of the gastroduodenal mucosa. Final results showed that: (i) NSAID-related gastric lesions were more frequent than duodenal lesions; (ii) when patients were given misoprostol and NSAIDs, 96% of them did not develop gastric lesions and 97% did not develop duodenal lesions; (iii) even when NSAID therapy was continued, gastric or duodenal lesions induced by NSAIDs healed or in any case did not worsen in 92% and 91% respectively of the cases; (iv) during the period of coadministration of NSAIDs+misoprostol, NSAID-related UGI symptoms disappeared or improved in 77% of the cases.(ABSTRACT TRUNCATED AT 250 WORDS)     

Risk of ulcer and its prophylaxis in therapy with non-steroidal antirheumatic drugs

Nonsteroidal antiinflammatory drugs (NSAIDs) are among the most frequently prescribed drugs in western countries. The high incidence of adverse gastrointestinal effects which are potentially life-threatening require steps for prevention. The use of NSAIDs should be restricted to patients with inflammatory rheumatic diseases. If NSAIDs are indicated it is important to identify patients who are at high risk to develop serious gastrointestinal side effects. These patients should receive Misoprostol at a dose of 2 to 3 x 200 micrograms per day. Up to date Misoprostol is the only drug with proven efficacy with respect to the prevention of gastroduodenal ulcer and its complications. NSAIDs inhibit the key enzyme of prostaglandin synthesis, the cyclooxygenase. Recently published data show that 2 isoenzymes of the cyclooxygenase exists. Cyclooxygenase-1 is primarily involved in the maintenance of organ function whereas cyclooxygenase-2 is expressed in inflamed tissue. Specific cyclooxygease-2 inhibitors have been developed. Clinical trials have to prove if the concept of a selective cyclooxygenase-2 inhibition with high antiinflammatory potency but lack of gastrointestinal side effects holds true in humans.     

Suppression of A beta-induced monocyte neurotoxicity by antiinflammatory compounds

Previous work from this laboratory has demonstrated that prior exposure of peripheral blood monocytes (PBM) to aggregated beta-amyloid peptide (A beta), the major protein comprising the amyloid plaques characteristically present in the brain of Alzheimer disease (AD)-afflicted individuals, activates these cells to a neurotoxic state when co-cultured with brain tissue. In this report we extend these findings to further show that such A beta-induced PBM neurotoxicity can be inhibited by three differentially-acting antiinflammatory drugs, indomethacin, dexamethasone, and colchicine, which are typically used clinically to treat peripheral inflammatory disease. In addition, evidence is presented that these toxic effects are initiated, in large part, by soluble factors released from A beta-stimulated PBM. Our results suggest a rationale for antiinflammatory therapy in the treatment of AD.     

Nonsteroidal antiinflammatory drug use and reduced risk of large bowel carcinoma

BACKGROUND: Animal experiments and epidemiologic data have suggested that the use of nonsteroidal antiinflammatory drugs (NSAIDs) may decrease the incidence of large bowel carcinoma. Our purpose was to assess the relation of the use of aspirin and nonaspirin NSAIDs with the risk of large bowel carcinoma. METHODS: A population-based case-control study of colon and rectal carcinoma was conducted in Massachusetts from 1992 to 1994. Data on NSAID use and risk factors for large bowel carcinoma were collected by interview from 1201 incident cases of large bowel carcinoma and 1201 controls matched by age, gender, and area of residence. RESULTS: Regular NSAID use that continued into the year before diagnosis was associated with a significantly decreased relative risk estimate overall (0.7; 95% confidence interval [CI], 0.5-0.8) and among Stage II-IV tumors (0.6; 95% CI, 0.4-0.7). There was no reduction in risk for discontinued use. The inverse association with regular continuing use was present across age and gender and for both colon and rectal carcinoma. Similar inverse associations were present for regular continuing use of aspirin and nonaspirin NSAIDs. There was no significant evidence of a trend for the relative risk to decrease as the duration of use increased, nor was there a trend across the dose of aspirin, which ranged from less than one-half of a 325 mg tablet per day to > or = 2 tablets per day. Discontinuation of use in response to symptoms of carcinoma did not appear to explain the inverse association, nor did bias related to diagnosis of the carcinoma. CONCLUSIONS: These data add to the growing body of evidence that suggests a protective effect of NSAIDs against large bowel carcinoma.     

Prostaglandin E2 induces interleukin-6 synthesis in human astrocytoma cells

Prostaglandins (PGs) and cytokines, such as interleukin-1 (IL-1) and interleukin-6 (IL-6), have been implicated in the etiopathology of various inflammatory and degenerative disorders, including Alzheimer's disease (AD) and prion diseases. Nonsteroidal antiinflammatory drugs (NSAIDs), potent inhibitors of PG synthesis, appear to be beneficial in the treatment of AD. To assess whether PGs are able to induce IL-6 synthesis in cells of the CNS, IL-6 mRNA and protein syntheses were measured in a human astrocytoma cell line after stimulation with different PGs. PGE1 and PGE2, but not PGD2 and PGF2 alpha, led to a rapid and transient induction of IL-6 mRNA, followed by IL-6 protein synthesis. Furthermore, PGE2 potentiated IL-1 beta-induced IL-6 mRNA synthesis. These results are discussed with respect to the participation of PGs in neurodegenerative diseases (and its inhibition by NSAIDs) by affecting cytokine expression.     

Helicobacter pylori and non-steroidal anti-inflammatory drugs: lone agents or partners in crime?

A variety of mechanisms are responsible for the gastric and duodenal mucosal injury known to result from the consumption of non-steroidal anti-inflammatory drugs (NSAIDs). Many of these mechanisms may be influenced by coexistent infection with Helicobacter pylori. However, evidence of increased risk from NSAIDs in patients with this bacterium is contradictory. While some authors have reported that symptoms, severity and prevalence of mucosal damage are higher in H. pylori-positive individuals taking NSAIDs than in those who are H. pylori negative, others have noted no significant difference. Reasons for this conflict may include the age of the subjects studied, duration of treatment, toxicity of the NSAID employed and pathogenicity factors related to different strains of H. pylori.     

A systematic review of randomized controlled trials of pharmacological therapy in osteoarthritis of the knee, with an emphasis on trial methodology

We systematically reviewed randomized controlled trials (RCTs) of pharmacological therapy in knee osteoarthritis (OA), published between 1966 and August 1994. RCTs were identified by MEDLINE, supplemented by a manual search of reference lists. Qualitative assessment of RCTs was performed using Gotzsche's method; design and analysis features were rated on a scale of 0 (worst) to 8 (best). Heller et al's method was used to compare efficacy of nonsteroidal antiinflammatory drugs (NSAIDs) in comparative trials. A total of 80 RCTs were analyzed (45 involved NSAIDs, 3 analgesics, 5 intraarticular [IA] steroids, 9 biological agents, including IA hyaluronic acid, and 18 mixed modalities, including topical capsaicin). The median design and analysis scores for all 80 RCTs were 2 and 5, respectively. NSAIDs were superior to placebo in all short-term trials, but in the 32 comparative NSAID trials, only five (16%) found significant differences in efficacy. Heller et al's method identified differences in 14 NSAID comparisons; etodolac (600 mg/day) was superior in five of its nine comparisons. Indomethacin and aspirin were the most toxic NSAIDs. IA steroids were superior to placebo in short-term efficacy (< 1 month). Biological agents were superior to placebo and generally well tolerated over a mean follow-up of 48 weeks. Acetaminophen was superior to placebo and was comparably efficacious to low-dose naproxen and ibuprofen (< 2,400 mg/day). The data support the use of acetaminophen, topical capsaicin, IA steroids, IA hyaluronic acid, and NSAIDs in the treatment of patients with knee OA.     

Efficacy and safety of nonsteroidal antiinflammatory drugs for cancer pain: a meta-analysis

PURPOSE: To assess the efficacy and safety of nonsteroidal antiinflammatory drugs (NSAIDs) in the treatment of cancer pain by meta-analyses of the published randomized control trials (RCTs). PATIENTS AND METHODS: Twenty-five studies met inclusion criteria for analysis. Of these, 13 tested a single-dose effect, nine multiple-dose effects, and three both single- and multiple-dose effects of 16 different NSAIDs in a total of 1,545 patients. Baseline pain intensity (when provided) of moderate or higher was indicated in 81% of patients. RESULTS: Single-dose NSAID studies found greater analgesic efficacy than placebo, with rough equivalence to 5 to 10 mg of intramuscular morphine. Pain scores differed insignificantly for aspirin versus three other NSAIDs. Analgesic responses to low- and high-dose NSAIDs suggested a dose-response relationship, but this was not statistically significant. Recommended and supramaximal single doses of three NSAIDs produced comparable changes in pain scores, which indicates a ceiling analgesic effect. Common side effects included upper gastrointestinal symptoms, dizziness, and drowsiness. The incidence of side effects showed a trend to increase with dose, without a ceiling effect, and to increase with multiple doses. Single or multiple doses of weak opioids (WO) alone or in combination (WO/C) with nonopioid analgesics did not produce greater analgesia than NSAIDs alone. Single doses of WO/C analgesics produced more side effects than NSAIDs alone, although both side effect incidence and patient dropout rates were equal when multiple doses were administered. CONCLUSION: These findings question whether the traditional World Health Organization (WHO) second analgesic step (addition of a weak opioid when pain is inadequately treated by a nonopioid analgesic alone) is warranted. A lack of comparable studies precluded testing the hypothesis that NSAIDs are particularly effective for malignant bone pain.     

HIV-infected subjects with the E4 allele for APOE have excess dementia and peripheral neuropathy

HIV produces a chronic viral infection of the central nervous system that elicits chronic glial activation and overexpression of glial cytokines that are also implicated in Alzheimer disease (AD) pathogenesis. A genetic risk factor for AD is the E4 isoform for apolipoprotein E (APOE). Here we compare the frequency of neurologic symptoms for subjects with and without the E4 isoform (E4(+)and E4(-), respectively) in an HIV cohort. Compared with E4(-) subjects, twice as many E4(+) subjects were demented (30% compared with 15%) or had peripheral neuropathy (70% compared with 39%) at least once, and they had threefold more symptomatic examinations (13% compared with 3% and 42% compared with 14%, respectively)(P < 0.0001). Thus, neurologic symptoms for HIV-infection and AD are linked through an etiologic risk factor. Long-term survivors of HIV infection with E4 may be at high risk for AD; conversely, gene-viral interactions may speed AD pathogenesis.     

Advances in the research on Alzheimer's disease--overview]

The number of patients suffering from dementia in Japan has been estimated to exceed 1,250,000 and is expected to increase rapidly in the near future. It is quickly becoming a serious medical and social issue. Alzheimer's disease (AD) is a leading cause of dementia, and can be classified into two genetic categories: single-gene and polygenic diseases. Familial Alzheimer's disease (FAD) is classified as a single-gene disease, while sporadic AD is classified as a polygenic disease which involves multiple genetic and environmental factors. Using positional cloning, most of the genes which lead to FAD have recently been identified e.g., the amyloid precursor protein (APP) gene on chromosome 21, presenilin I on chromosome 14 and presenilin II on chromosome 1. Recent studies indicate that mutations in these genes can result in either overproduction of A beta or in production of A beta 1-42. Although the accumulation of A beta has been suggested to be the "primary cause" not only in FAD but also in sporadic AD, it remains unclear how neurodegeneration in AD is related to the accumulation of A beta. The discovery of ApoE4 as a major genetic risk factor for AD has created a new step of research on AD as a polygenic disease. Although it is confirmed that the presence of the ApoE4 allele greatly accelerates age at onset of AD, the role of ApoE4 as a risk factor for AD remains to be fully elucidated. Now that major genes involved in the pathogenesis of AD have been identified, future research should be directed toward elucidation of the molecular mechanisms of how these gene products are involved in the pathogenesis of AD on protein as well as cellular levels.     

Hemofiltration and double high flux dialysis: risks and benefits

Patients with systemic lupus erythematosus require adequate information (sun avoidance, fair compliance, smoking discontinuation, adequate contraception and diet, pregnancy planning). Nonsteroidal antiinflammatory drugs and antimalarials are effective in patients presenting with skin and articular involvement. Visceral lesions and hemocytopenias require the use of steroids, alone or in association with immunosuppressive agents. Long-term anticoagulation with an INR of 3-3.5 achieves the prevention of recurrent thrombotic events. Experimental data suggest that more specific treatments and even regimens aimed at eradication of human lupus might soon arise.     

Multiple abdominal telangiectases and lymphangiectases. A limited form of Osler-Weber-Rendu disease?

Nonsteroidal antiinflammatory drugs (NSAIDs) are widely used and may cause small intestinal inflammation and damage. Reactive oxygen metabolites are involved in various gastrointestinal inflammatory processes, but there is little information about their role in small intestinal mucosal damage induced by NSAIDs. We studied the effect of the oxygen radical scavengers superoxide dismutase (SOD), catalase (CAT), and allopurinol (ALLO) on indomethacin (INDO)-induced intestinal ulceration in the rat. Ulceration was produced by s.c. injection of 30 mg/kg of INDO 30 min after refeeding 24 h-fasted rats. Total ulcer area was measured 24 h after INDO administration. Study groups each consisted of eight animals which received either i.p. CAT, SOD, or both together, at a dosage of 5,000 U/kg each. All drugs were divided into five doses, given once an hour over a 4-h period, starting at the time of INDO injection. Another group received 100 mg/kg ALLO in two doses. Total ulcer area was reduced by SOD from 228 +/- 12 (sq mm, mean +/- SEM) to 153 +/- 12 (p < 0.001), by CAT to 179 +/- 13 (p < 0.01), and by both together to 95 +/- 5 (p < 0.0001). ALLO administration reduced the total ulcer area to 176 +/- 7 (p < 0.003). The protective effect of oxyradical scavengers supports the hypothesis that oxygen radicals are involved in the pathogenesis of INDO-induced small intestinal ulceration in the rat.     

The major mental disorders: New evidence requires new policy and practice.

Reviews research and argues that new mental health policy and programs are needed to deal with the major mental disorders (schizophrenia, major depression, and bipolar disorder). Data show that many of the persons who are afflicted with these disorders continue to suffer throughout their adult lives, despite treatment. Not only do these individuals present all of the symptoms and social impairments usually associated with the major disorders, they are also at increased risk for premature death, substance abuse/dependence, criminality, violence, homelessness, and infectious disease. Two findings suggest that prevention may be possible: (1) many of the children at risk for the major mental disorders can be identified by their family history of mental disorder; and (2) non-genetic factors, biological and/or psychosocial, can limit the expression of the hereditary factors associated with each of these disorders. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Increased expression of cyclooxygenases and peroxisome proliferator-activated receptor-gamma in Alzheimer's disease brains

Recent studies suggest that inflammatory events are associated with plaque formation in the brains of patients with Alzheimer's disease (AD). Treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) of these patients appears to slow the progression of disease. We assessed the occurrence of cyclooxygenases (COX-1 and -2) and peroxisome proliferator-activated receptor-gamma (PPARgamma) in temporal cortex from normal and AD brains using specific antibodies. In AD brains, protein levels of COX-1 were increased in both cytosolic and particulate fractions, and COX-2 protein was also increased in the particulate fraction. On the other hand, PPARgamma level was increased in the cytosolic fraction but not in the particulate fraction. Thus, expression levels of COX-1, COX-2, and PPARgamma may change in AD brains. In addition, several NSAIDs which are also PPARgamma activators, such as indomethacin, inhibited COX-2 expression in glial cells. These results suggest that PPARgamma activators have inhibitory effects on inflammatory events in AD brains.     

How peer education changed peer sexuality educators'' self-esteem, personal development, and sexual behavior

Series of well-documented case reports strongly suggest a causal association between tiaprofenic acid and a form of aseptic cystitis, which can cause serious and long-term morbidity if the drug is not withdrawn promptly. These findings are supported in the Australian and UK spontaneous reporting data-bases. Using sales data as the denominator, a comparison of NSAIDs in the WHO drug monitoring data-base indicates that the reaction is specific to tiaprofenic acid and cannot be accounted for by changes in reporting patterns in certain countries or years. Delayed recognition is an important feature of this reaction and possible reasons for this are discussed. Comparison of the risk profiles of seven NSAIDs indicated that tiaprofenic acid had the poorest risk profile, compared with NSAIDs of similar efficacy, when cystitis reports were included. The results suggest that combining spontaneous reports, classified according to severity, with sales data may enhance the ability of drug monitoring data-bases to contribute to risk benefit appraisals.     

Immunohistochemical detection of 4-hydroxy-2-nonenal adducts in Alzheimer's disease is associated with inheritance of APOE4

Cumulative oxidative damage, including lipid peroxidation, is a central component of cellular aging and is thought to play a role in the pathogenesis of late-onset Alzheimer's disease (AD). Lipid peroxidation produces several cytotoxic aldehydes, one of the most potent being 4-hydroxy-2-nonenal (HNE). We have shown previously that HNE is a potent neurotoxin that covalently modifies and cross-links neuronal cytoskeletal protein in neuroglial cultures, suggesting that HNE may contribute to the pathogenesis of AD. In addition to aging, inheritance of the epsilon 4 allele of APOE is the other major risk factor for development of late-onset AD; however, the mechanisms through which aging and apolipoprotein E isoforms may collaborate in the onset or progression of AD are not known. We tested the hypothesis that HNE may yield a particular type of protein modification, pyrrole adduction, and that this may contribute to the pathogenesis of AD. Our data demonstrated that HNE formed pyrrole adducts with protein. Polyclonal antiserum was raised that specifically recognized HNE pyrrole adducts, and immunohistochemical analysis was performed on hippocampus and temporal cortex of 10 patients with histologically verified AD. Pyramidal neuron cytoplasm was immunoreactive in 4 of 4 APOE4 homozygotes, 2 of 3 APOE3/4 heterozygotes, and none of 3 APOE3 homozygotes (P < 0.05). The pattern of staining was highly suggestive of neurofibrillary tangles as the primary immunoreactive structure. These data suggest that differences in neuronal protein modification by HNE may account in part for the APOE-associated stratification of risk for late-onset AD.     

Prostheses PORP and TORP prepared by the authors'' method

Although the incidence of gastric cancer varies widely between countries it is nonetheless a leading cause of cancer deaths worldwide. Migration studies indicate that dietary choices are an important exogenous factor. The United States has a very low incidence of gastric cancer, suggesting that exogenous etiological agents are at a minimum and providing a favorable setting for detecting important endogenous etiological factors. Dehydroepiandrosterone and dehydroepiandrosterone sulfate are endogenous steroids produced in the adrenal gland. Epidemiological studies show that the risk of developing specific cancers is related to the serum or urinary levels of these steroids. In addition, dehydroepiandrosterone prevents a variety of spontaneous and chemically induced tumors when administered to laboratory animals. To examine the association between circulating levels of dehydroepiandrosterone and dehydroepiandrosterone sulfate and the development of gastric cancer, we measured the serum levels of these steroids in 13 individuals who donated serum to the Washington County Maryland serum bank in 1974 and who subsequently developed gastric cancer and in 52 matched controls. Prediagnostic serum levels of dehydroepiandrosterone were 38% lower in cases as compared to controls (P = 0.09). The risk of developing gastric cancer increased with decreasing levels of both steroids. Adjustment for confounding factors such as smoking or the interval between blood donation and time to diagnosis did not alter the findings. These results suggest that there may be a role for this steroid in the prevention of gastric cancer.     

Nicotine prevents glutamate-induced proteolysis of the microtubule-associated protein MAP-2 and glutamate neurotoxicity in primary cultures of cerebellar neurons

The aim of this work was to assess whether nicotine prevents glutamate neurotoxicity in primary cultures of cerebellar neurons, to try to identify the receptor mediating the protective effect and to shed light on the step of the neurotoxic process which is prevented by nicotine. It is shown that nicotine prevents glutamate and NMDA neurotoxicity in primary cultures of cerebellar neurons. The protective effect of nicotine is not prevented by atropine, mecamylamine or dihydro-beta-erythroidine, but is slightly prevented by hexamethonium and completely prevented by tubocurarine and alpha-bungarotoxin, indicating that the protective effect is mediated by activation of alpha7 neuronal nicotinic receptors. Moreover, alpha-bungarotoxin potentiates glutamate neurotoxicity, suggesting a tonic prevention of glutamate neurotoxicity by basal activation of nicotinic receptors. Nicotine did not prevent glutamate-induced rise of free intracellular calcium nor depletion of ATP. Nicotine prevents glutamate-induced proteolysis of the microtubule-associated protein MAP-2 and disaggregation of the neuronal microtubular network. The possible mechanism responsible for this prevention is discussed.