Search PubMed⌕ Search

Biomedical subjects

R W Grady

Publications and source records attributed to R W Grady.

85 records · Page 5Linked to original sources
PubMed1977

Inhibition of platelet function with 2,3-dihydroxybenzoic acid.

2,3-Dihydroxybenzoic acid (2,3-DHB) inhibits the second wave of platelet aggregation release of serotonin, and malonaldehyde production. The effect is concentration dependent and reversible in vitro and in vivo. 50% inhibition of platelet aggregation induced in vitro with 70 micron adrenaline was obtained with 1.5 mM 2,3-DHB. Malonaldehyde production was inhibited by 50% with 0.4 mM 2,3-DHB. Serotonin release was 50% inhibited by 50% with 0.08 mm 2,3-DHB. Neither desferrioxamine nor various benzoic acid derivatives with iron-chelating properties showed the effect. Only benzoic acid derivatives with the potential to terminate free radical reactions through the formation of an ortho- or paraquinone structure inhibit the second wave of platelet aggregation. These studies support the concept that the second wave of platelet aggregation is mediated through free radical reactions.

Blood Platelets↗
PubMed1976

Inhibition of membrane peroxidation in thalassaemic erythrocytes by 2,3-dihydroxybenzoic acid.

Both iron and precipitated haemoglobin may catalyse the formation of free radicals, which in turn react with the polyunsaturated fatty acids of membranes leading to membrane failure and cell death. 2,3-Dihydroxybenzoic acid (2,3-DHB), a recently identified, orally effective iron-chelating drug, inhibited membrane peroxidation in vitro in H2O2-stressed erythrocytes from patients with beta-thalassaemia major, beta-thalassaemia intermedia, haemoglobin Köln disease and sickle cell disease. We present evidence suggesting that the inhibition of peroxidation is due to ability of 2,3-DHB to scavenge free radicals via quinone formation, a mechanism analogous to that proposed for vitamin E.

Cell Membrane↗
PubMed1976

Chelation studies with 2,3-dihydroxybenzoic acid in patients with beta-thalassaemia major.

2-3-Dihydroxybenzoic acid was evaluated as a potentially useful, orally effective iron-chelating drug by performing iron balance studies in patients with beta-thalassaemia major. The administration of this substance at 25 mg/kg/d to five patients for 8 d caused an average increase in iron excretion of 4.5 mg/d. When the drug was administered at 25 mg/kg q.i.d. to eight patients for 21 d, iron excretion increased to 6.5 mg/d. Chelation was highly specific for iron with changes in magnesium and calcium excretion being insignificant. The drug was well tolerated with side effects limited to gastrointestinal complaints which ameliorated when the drug was taken with food. These studies provide a rationale for further evaluation of 2,3-dihydroxybenzoic acid in patients with iron overload.

Administration, Oral↗
PubMed1976

The use of chang cells cultured in vitro to evaluate potential iron chelating drugs.

A number of iron chelating agents, consisting largely of hydroxamic acid and benzoic acid derivatives, have been studied in an in vitro Chang cell culture system to determine their effect on cellular iron uptake, ferritin synthesis and the incorporation of iron into ferritin. The results have been compared with those of a previous study in which iron balance was determined in hypertransfused rats. Both techniques appear to be of value in screening new iron chelating agents for potential therapeutic use in patients with iron overload.

Benzoates↗
PubMed1976

The effect of chelating agents on iron mobilization in Chang cell cultures.

The investigation of chelating agents with potential therapeutic value in patients with transfusional iron overload has been facilitated by the use of Chang cell cultures. These cells have been incubated with [59Fe]transferrin for 22 hr, following which most of the intracellular radioiron is found in the cytosol, distributed between a ferritin and a nonferritin form. Iron release from the cells depends on transferrin saturation in the medium, but when transferrin is 100% saturated, which normally does not allow iron release, desferrioxamine, 2,3-dihydroxybenzoic acid, rhodotorulic acid, cholythydroxamic acid, and tropolone all promote the mobilization of ferritin iron and its release from cells. They are effective to an approximately equal degree. The incubation of [59Fe]transferrin with tropolone in vitro at a molar ratio of 1:500 results in the transfer of most of the labeled iron to the chelator, reflecting the exceptionally high binding constant of this compound. How far these phenomena relate to therapeutic potentially remains to be seen.

Anemia, Hypochromic↗
PubMed1976

The development of new iron-chelating drugs.

2,3-Dihydroxybenzoic acid has been identified as a potentially useful iron-chelating drug. Accordingly, we have evaluated a series of derivatives of hydroxylated benzoic acids for their ability to induce iron excretion in the iron-overloaded rat. In addition, we have examined a number of hydroxamic acids and some other naturally occurring iron-chelating agents. Of the 26 benzoic acid derivatives studied, none appeared to be more effective than 2,3-dihydroxybenzoic acid, for reasons which are discussed. Rhodotorulic acid, a hydroxamic acid produced by and isolated from cultures of Rhodotorula pilimanae, was the most effective of all the compounds studied in inducing iron excretion. When administered parenterally, rholotorulic acid induced iron excretion via both the urinary and the fecal routes and was more than twice as potent (on a weight basis) as desferrioxamine. Two ferrous chelators, alpha, alpha-dipyridyl ad 1,10-phenanthroline, induced a moderate amount of iron excretion, suggesting that a pool of ferrous iron may be available for chelation.

Animals↗
PubMed1975

Iron metabolism, sickle cell disease, and response to cyanate.

In an attempt to understand the variability of the hematologic response to oral sodium cyanate, iron metabolism was studied in a group of 39 patients with sickel cell disease. Eleven of the 39 patients were found to have no stainable iron in the marrow despite the fact that patients with sickle cell disease are generally considered to have hemosiderosis. The mean per cent saturation and total iron-binding capacity were in the low-normal range in sickle cell patients whether or not stainable iron was present in the bone marrow aspirate. Serum ferritin concentrations, on the other hand, were found to be high in both groups (greater than 500 mu g/liter) when compared to controls (60 mu g/liter). The high serum ferritin levels denoted significant total-body iron deposition which may be unavailable for normal metabolic processes. One patient with no stainable iron in the bone marrow aspirate did respond to iron therapy alone with an increase in hemoglobin concentration. Serum ceruloplasmin levels were also found to be high in sickle cell disease patients. The ability to respond to oral cyanate therapy was correlated with the amount of stainable iron in the bone marrow aspirate. These studies emphasize the necessity of a reevaluation of iron metabolism in the pathophysiology and treatment of sickle cell disease.

Administration, Oral↗