A placebo-controlled, double-blind, randomized trial of an extract of Ginkgo biloba for dementia. North American EGb Study Group.

CONTEXT: EGb 761 is a particular extract of Ginkgo biloba used in Europe to alleviate symptoms associated with numerous cognitive disorders. Its use in dementias is based on positive results from only a few controlled clinical trials, most of which did not include standard assessments of cognition and behavior. OBJECTIVE: To assess the efficacy and safety of EGb in Alzheimer disease and multi-infarct dementia. DESIGN: A 52-week, randomized double-blind, placebo-controlled, parallel-group, multicenter study. PATIENTS: Mildly to severely demented outpatients with Alzheimer disease or multi-infarct dementia, without other significant medical conditions. INTERVENTION: Patients assigned randomly to treatment with EGb (120 mg/d) or placebo. Safety, compliance, and drug dispensation were monitored every 3 months with complete outcome evaluation at 12, 26, and 52 weeks. PRIMARY OUTCOME MEASURES: Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog), Geriatric Evaluation by Relative's Rating Instrument (GERRI), and Clinical Global Impression of Change (CGIC). RESULTS: From 309 patients included in an intent-to-treat analysis, 202 provided evaluable data for the 52-week end point analysis. In the intent-to-treat analysis, the EGbgroup had an ADAS-Cog score 1.4 points better than the placebo group (P=.04) and a GERRI score 0.14 points better than the placebo group (P=.004). The same patterns were observed with the evaluable data set in which 27% of patients treated with EGb achieved at least a 4-point improvement on the ADAS-Cog, compared with 14% taking placebo (P=.005); on the GERRI, 37% were considered improved with EGb, compared with 23% taking placebo (P=.003). No difference was seen in the CGIC. Regarding the safety profile of EGb, no significant differences compared with placebo were observed in the number of patients reporting adverse events or in the incidence and severity of these events. CONCLUSIONS: EGb was safe and appears capable of stabilizing and, in a substantial number of cases, improving the cognitive performance and the social functioning of demented patients for 6 months to 1 year. Although modest, the changes induced by EGb were objectively measured by the ADAS-Cog and were of sufficient magnitude to be recognized by the caregivers in the GERRI.

Erythrocytes from magnesium-deficient hamsters display an enhanced susceptibility to oxidative stress.

Previous studies in our laboratory have indicated a role for free radical participation in magnesium deficiency cardiomyopathy. We have demonstrated the ability of various antioxidant drugs and nutrients to protect against magnesium deficiency-induced myocardial injury. In this study, we have examined erythrocytes from normal and magnesium-deficient animals and compared their susceptibility to an in vitro oxidative stress. Syrian male hamsters were placed on either magnesium-deficient or magnesium-supplemented diets. Animals from each group also received vitamin E in doses of 10 and 25 mg as subcutaneous implants. Erythrocytes obtained after 14 days on the diet were exposed to an exogenous hydroxyl (.OH) radical generating system (dihydroxyfumarate not equal to Fe3+ ADP) at 37 degrees C for 20 min. Erythrocyte crenation was observed and quantified by scanning electron microscopy. Lipid peroxidation, hemolysis (%), and intracellular glutathione levels were determined. In addition, serum lipid changes and membrane phospholipids were characterized. Our data demonstrate that erythrocytes from magnesium-deficient animals are more susceptible to free radical injury, supporting our hypothesis that magnesium deficiency reduces the threshold antioxidant capacity.

Magnesium-deficient myocardium demonstrates an increased susceptibility to an in vivo oxidative stress.

Previous studies in our laboratory have indicated free radical participation in magnesium deficiency cardiomyopathy. In this study, we examined the capacity of the magnesium-deficient animals to withstand an in vivo oxidative stress. Syrian hamsters were placed on either magnesium-deficient diet or a magnesium-supplemented control diet. Animals from each group also received vitamin E. After 14 days some of animals were given the catecholamine isoprenaline; 2 days later the animals were killed. The severity of the isoprenaline-induced injury was assessed by a morphometric analysis. The isoprenaline-induced injury was dramatically increased in the magnesium-deficient animals. The addition of vitamin E reduced the severity of the injury by 81% in these animals, indicating that the injury process was primarily due to an oxidative mechanism. These data show that magnesium deficiency increases the susceptibility of the cardiovascular system to oxidative stress.

Captopril protects against myocardial injury induced by magnesium deficiency.

We have previously reported that antioxidant drug intervention protects against magnesium deficiency-induced myocardial lesions. In the present study, Golden Syrian male hamsters were fed either a magnesium-deficient diet or a magnesium-supplemented diet. Animals from each group received sulfhydryl-containing angiotensin converting enzyme inhibitors: captopril, epi-captopril (a stereoisomer of captopril), and zofenopril* (arginine blend of zofenopril containing a free SH group); another group of animals received the non-sulfhydryl-containing angiotensin converting enzyme inhibitor enalaprilat. The animals were killed after 14 days, and their hearts were isolated for morphological and morphometric analyses. Hematoxylin and eosin-stained sections were examined by a computer image analysis system for a morphometric determination of the severity of myocardial injury. Captopril reduced both the density of lesions, from 0.32 to 0.08 lesions/(mm2) (p less than 0.01), and the area fraction of lesions, from 7.42 x 10(-4) to 2.03 x 10(-4) lesion area/(mm2) (p less than 0.01), as well as the degree of inflammatory infiltration around the blood vessels. Epi-captopril and zofenopril* were virtually equipotent to captopril, but enalaprilat afforded only slight (nonsignificant) protection. These results indicate that a significant component of the protective effect of captopril in this model was attributable to its sulfhydryl moiety, rather than solely due to the inhibition of the angiotensin converting enzyme. These data further support our previous findings of possible free radical participation in cardiomyopathy due to magnesium deficiency.

Propranolol reduces cardiomyopathic injury induced by magnesium deficiency.

We have previously established a link between magnesium-deficiency-induced cardiomyopathy and free radical injury. In the present study, golden Syrian male hamsters were placed on either magnesium-deficient or magnesium-supplemented diets. Animals from each group received either d,l-propranolol or d-propranolol (the non-beta-blocking form). After 14 days, the animals were sacrificed and their hearts isolated for morphological and morphometric analyses. Hematoxylin/eosin-stained sections were examined by a computer image analysis system for a morphometric determination of the severity of myocardial injury. Propranolol reduced both the density of lesions, from 0.32 to 0.06 lesions/mm2 (p < 0.01), and the area fraction of lesions, from 9.8 x 10(-4) to 2.5 x 10(-4) lesion area/mm2 (p < 0.01). In addition, d-propranolol was virtually equipotent to d,l-propranolol, indicating that part of the protective effect of propranolol, in this model, was attributable to its antioxidant properties.

Magnesium deficiency-induced cardiomyopathy: protection by vitamin E.

Syrian male hamsters weighing 80-100g were placed on either a magnesium deficient diet (MgD) or an identical diet supplemented with 100 mmols/Kg MgCl. Animals from each group received vitamin E 10, 15, and 25mg three-week slow release pellets, as subcutaneous implants. The animals were sacrificed after 14 days and their hearts isolated for morphological analysis. H&E stained sections were examined by a computer image analysis system for a morphometric determination of the severity of myocardial injury. Vitamin E significantly (p less than 0.01) reduced both the numerical density and the area fraction of MgD lesions. These data indicate possible free radical participation in the mechanism of injury.

Lymphoscintigraphy as a guide to treatment in malignant melanoma.

Regional node dissection is practiced as a measure of prophylaxis in patients with stage I and II malignant melanoma. Although the drainage pattern of the extremities is obvious, in the head and neck and trunk it may be ambiguous. We have used lymphoscintigraphy to assist in delineating the lymphatic drainage in 22 patients with primary malignant melanoma. Fourteen patients had melanoma in the head and neck region, and eight had melanoma in the trunk region. Based on Clark's classification there were ten level III melanomas, eight level IV melanomas, and two level V melanomas; the levels of the remaining two melanomas were unspecified. Seven melanomas were between 0.76 and 1.5-mm thick, eleven were between 1.51 and 4.0-mm thick, and two were over 4.0-mm thick (the remaining two were unspecified). Regional nodes were clinically negative in 18 patients. The scan distribution was unexpected in 13 patients (59%), and it influenced the surgical procedure in 11 patients (50%). No patient incurred an adverse effect from the scan. We conclude that lymphoscintigraphy may be of value in guiding prophylactic lymph node dissection in melanoma patients.

The histological effects on the guinea pig external ear of several constituents of commonly used aural preparations.

Medicament contact dermatitis can be troublesome in external ear disease. In this work the effects on the guinea pig external ear of instillation twice daily for 3 weeks of benzalkonium chloride, Cerumol, gentamicin, the pharmaceutical base for Gentisone HC, hydrocortisone and propylene glycol were studied using light microscopy, thickness measurements of tympanic membrane and meatal epidermis, and the mitotic index of meatal epidermis. Benzalkonium chloride induced severe inflammatory changes and markedly increased the thickness measurements and meatal mitotic index. Cerumol also increased the thickness measurements and the mitotic index; there was additionally low grade chronic inflammation in the dermis. Prophylene glycol increased the mitotic index and thickness measurements though no signs of inflammation were seen. Other compounds did not produce significant changes except that hydrocortisone reduced the mitotic index. Contact dermatitis to benzalkonium chloride may be important in persistent ear disease. Cerumenolytic agents ought not to be used for prolonged periods or as prophylaxis.

Detection of wheat gliadin contamination of gluten-free foods by a monoclonal antibody dot immunobinding assay.

Unfractionated wheat gliadin was used to produce murine monoclonal antibodies to gliadin. A dot immunobinding assay, using these antibodies, was developed to detect possible gliadin contamination of nominally gluten-free flour, using dilute ethanol extracts spotted onto nitrocellulose membranes. The sensitivity of the assay was less than 10 micrograms/ml of unfractionated gliadin which permitted the detection of trace amounts of gliadin present in certain wheat starch based 'gluten-free' products. The assay detected not only wheat gliadin, but also prolamine extracts of rye, barley and oats; maize, soya and potato extracts as well as the control proteins casein and ovalbumin, gave negative results. The assay is of value as a simple and rapid method of screening foods for their suitability for consumption by patients with coeliac disease.

Prevention of cyclophosphamide cystitis with 2-mercaptoethane sodium sulfonate: a histologic study.

The ability of 2-mercaptoethane sodium sulfonate to prevent histologic damage to the bladder from cyclophosphamide was studied. Male rats receiving 2-mercaptoethane sodium sulfonate in conjunction with cyclophosphamide had a statistically significant decrease in ulceration, inflammation and edema of the bladder compared to those treated with cyclophosphamide alone. Most bladders of animals given prophylactic 2-mercaptoethane sodium sulfonate with a dose of cyclophosphamide were histologically indistinguishable from controls receiving neither drug. The relevance of these findings to the short and long-term effects of cyclophosphamide on the urothelium is discussed.

A small animal model study of perlite and fir bark dust on guinea pig lungs.

Fir bark (Abies) and perlite (noncrystalline silicate) dusts have been reported to cause pulmonary disease in humans. Guinea pigs were exposed to either fir bark or perlite dust in a special chamber. Severe pathologic changes occurred in the lungs, consisting of lymphoid aggregated and a perivascular inflammatory response. Both dusts caused similar changes although one was vegetable (fir bark) and the other mineral (perlite). Fir bark and perlite dust appeared to be more than just nuisance dusts.

Methotrexate megadosage followed by folate rescue. I. A study in clearance patterns.

Plasma clearance rates of methotrexate (MTX) have been determined in five patients given an infusion of 3,000 mg of MTX over six hours, followed by folate rescue 24 hours after the commencement of infusion. Results presented indicate that maintenance of high MTX concentrations and potential toxicity could not be related to age, body weight or surface area.

Methotrexate megadose followed by folate rescue. II. Clearance patterns in patients receiving sequential megadose infusions.

In some patients receiving megadose infusions of methotrexate (MTX), the rate of drug clearance decreases with each subsequent infusion. This can be modified by administration of fluids as outlined in the Recommended Protocol. Monitoring of each treatment is needed to assess requirements of fluids since these cannot be adequately predicted from data of previous infusions.

Chronic hashish use and mental disorder.

The authors compared 47 long-term users of hashish with a control group of 40 subjects matched for age, ethnic origin, education, etc., in order to determine whether they differed significantly on psychiatric, physical health, and demographic variables. There was a significantly higher incidence of personality disorders, unemployment, and prison sentences in the group of chronic users. However, in contrast to the findings of other researchers, the hashish users did not have organic psychoses, nor did they differ from control subjects in neurologic signs or EEG and echo encephalogram patterns.