Browsing by Author "Aronson, J.K."

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Abnormal functions of pottasium channels in the platelets of patients with Alzheimer's disease
(Lancet Publishing Group, 1998) de Silva, H.A.; Aronson, J.K.; Grahame-Smith, D.G.; Jobst, K.A.; Smith, A.D.
BACKGROUND:Reports of abnormalities of potassium-channel function in various cultured cells of Alzheimer's disease patients led us to attempt to characterise the pharmacological characteristics of the abnormal channel.METHODS: We studied platelets from 14 patients with Alzheimer-type dementia and 14 non-demented controls matched for age and sex. The effects of specific inhibitors of K+ channels on the efflux of rubidium-86 ions, a radioactive analogue of K+, from the platelets were measured.FINDINGS: Normal platelets contain three types of K+ channel, sensitive to the inhibitory actions of apamin (small-conductance calcium-dependent potassium channels), charybdotoxin (of less specificity, but probably intermediate-conductance calcium-dependent K+ channels), and alpha-dendrotoxin (voltage-sensitive K+ channels). However, 8Rb+ efflux from the platelets of patients with Alzheimer-type dementia was not inhibited by either apamin or charybdotoxin. By contrast, inhibition by alpha-dendrotoxin did occur. INTERPRETATION: Our results suggest that calcium-dependent K+ channels in platelets are selectively impaired in Alzheimer's disease. A similar abnormality in neurons could contribute to the pathophysiology of the disorder.
Effects of high external concentrations of K+ on 86Rb+ efflux in human platelets: evidence for Na+/K+/2Cl- co-transport.
(Portland Press on behalf of the Medical Research Society and the Biochemical Society, 1996) de Silva, H.A.; Carver, J.G.; Aronson, J.K.
Na+/K+/2Cl- co-transport mediates a bidirectional symport of Na+, K+ and Cl-. The important properties of the co-transport system are its requirement for Na+, K+ and Cl- and its inhibition by loop diuretics such as bumetanide. This co-transporter has been described in a number of animal and human tissues. However, its presence in human platelets, although inferred, has not been demonstrated directly. 2. We have studied the efflux of 86Rb+ (a marker for K+) from Rb(+)-loaded platelets, and have defined their response to stimulation by high concentrations of external K+. 3. KCl (30-120 mmol/l) stimulated a concentration-dependent increase in 86Rb+ efflux from the platelets. This efflux was completely inhibited by bumetanide (10 mumol/l) but was insensitive to ouabain and R(+)-[(dihydroindenyl)oxy]alkanoic acid. It also required Cl- in the external medium, but did not depend on the presence of extracellular Na+. 4. These observations suggest that 86Rb+ efflux from platelets stimulated by external K+ occurs via Na+/K+/2Cl- co-transport acting in a K+/K+ (K+/Rb+) exchange mode. 5. Non-stimulated efflux of 86Rb+ from the platelets (i.e. in the presence of 5 mmol/l K+) had the characteristics of Na+/K+/2Cl- co-transport acting in normal mode.
Evidence for an R(+)-[(dihydroindenyl)oxy]alkanoic acid-sensitive K+/Cl- co-transporter in human platelets and its interaction with the Na+/K+/2Cl- co-transporter.
(Portland Press on behalf of the Medical Research Society and the Biochemical Society, 1997) de Silva, H.A.; Aronson, J.K.
The K+/Cl- co-transport system is activated by a number of interventions, such as cell swelling and stimulation with N-ethylmaleimide. It is specifically inhibited by R(+)-[(dihydroindenyl)oxy]alkanoic acid and requires the presence of K+ and Cl- on the same side of the cell membrane. This co-transporter has been studied extensively, mainly in erythrocytes of many species, in which it plays a key role in cell volume regulation. Here we present evidence that human platelets contain K+/Cl- co-transporters. 2. We have studied the efflux of 86Rb+ (a marker for K+) from 86Rb(+)-loaded human platelets, and have defined their response to stimulation by N-ethylmaleimide. 3. N-Ethylmaleimide (0.5 and 1 mmol/l) stimulated an increase in cumulative 86Rb+ efflux in a concentration-dependent manner. This efflux was inhibited by R(+)-[(dihydroindenyl)oxy]alkanoic acid (10 mumol/l) but was insensitive to bumetanide. It also required the presence of external Cl-. 4. These observations suggest that 86Rb+ efflux from the platelets stimulated by N-ethylmaleimide occurs via K+/Cl- co-transport. 5. When the K+/Cl- co-transporter was stimulated by N-ethylmaleimide we were unable to stimulate the Na+/K+/2Cl- co-transporter with a high external concentration of KCl or inhibit 86Rb+ efflux with bumetanide. Together with other evidence, this suggests that when the K+/Cl- co-transporter is stimulated with N-ethylmaleimide, the Na+/K+/2Cl- co-transporter is inhibited.
Low-dose adrenaline, promethazine and hydrocortisone, (alone and in combination) in the prevention of acute adverse reactions to antivenom following snakebite: a randomised, double blind, placebo-controlled trial
(Sri Lanka Medical Association, 2011) de Silva, H.A.; Pathmeswaran, A.; Ranasinha, C.D.; Jayamanne, S.; Samarakoon, S.B.; Hittharage, A.; Kalupahana, R.; Ratnatilaka, G.A.; Uluwatthage, W.; Aronson, J.K.; Armitage, J.M.; Lalloo, D.G.; de Silva, H.J.
INTRODUCTION AND OBJECTIVES: Envenoming from snakebites is most effectively treated by antivenom. However, the antivenom available in South Asian countries commonly causes acute allergic reactions, anaphylactic reactions being particularly serious. We have assessed whether adrenaline, promethazine, and hydrocortisone prevent such reactions in secondary referral hospitals in Sri Lanka. METHODS: We randomized 1007 patients, using a 2x2x2 factorial design, in a double-blind, placebo-controlled trial of adrenaline (0.25 mi of a 1:1000 solution subcutaneously), promethazine (25 mg intravenously), and hydrocortisone (200 mg intravenously), a!one and in all possible combinations. The interventions or matching placebo were given immediately before infusion of antivenom. Patients were monitored for mild, moderate, or severe adverse reactions for at least 96 hours. The pre-specified primary endpoints were the effects of the interventions on the incidence of severe reactions over 48 hours. Results: 752 (75%) patients had acute reactions to antivenom; 9% mild, 48% moderate, 43% severe; 89% of the reactions occurred within one hour and 40% of all patients were given rescue medication during the first hour. Compared with placebo, adrenaline significantly reduced severe reactions to antivenom by 43% at one hour (95%CI 25-67) and by 38% (26-49) over 48 hours; hydrocortisone and promethazine did not. Adding hydrocortisone negated the benefit of adrenaline. CONCLUSIONS: Pre-treatment with tow-dose adrenaline was safe and reduced the risk of acute severe reactions to snake antivenom. This may be of particular importance in countries where adverse reactions to antivenom are common, although the need to improve the quality of available antivenom cannot be overemphasized.
Low-dose adrenaline, promethazine, and hydrocortisone in the prevention of acute adverse reactions to antivenom following snakebite: a randomised, double-blind, placebo-controlled trial
(Public Library of Science, 2011) de Silva, H.A.; Pathmeswaran, A.; Ranasinha, C.D.; Jayamanne, S.; Samarakoon, S.B.; Hittarage, A.; Kalupahana, R.; Ratnatilaka, G.A.; Uluwatthage, W.; Aronson, J.K.; Armitage, J.M.; Lalloo, D.G.; de Silva, H.J.
BACKGROUND: Envenoming from snakebites is most effectively treated by antivenom. However, the antivenom available in South Asian countries commonly causes acute allergic reactions, anaphylactic reactions being particularly serious. We investigated whether adrenaline, promethazine, and hydrocortisone prevent such reactions in secondary referral hospitals in Sri Lanka by conducting a randomised, double-blind placebo-controlled trial. METHODS AND FINDINGS: In total, 1,007 patients were randomized, using a 2 × 2 × 2 factorial design, in a double-blind, placebo-controlled trial of adrenaline (0.25 ml of a 1∶1,000 solution subcutaneously), promethazine (25 mg intravenously), and hydrocortisone (200 mg intravenously), each alone and in all possible combinations. The interventions, or matching placebo, were given immediately before infusion of antivenom. Patients were monitored for mild, moderate, or severe adverse reactions for at least 96 h. The prespecified primary end point was the effect of the interventions on the incidence of severe reactions up to and including 48 h after antivenom administration. In total, 752 (75%) patients had acute reactions to antivenom: 9% mild, 48% moderate, and 43% severe; 89% of the reactions occurred within 1 h; and 40% of all patients were given rescue medication (adrenaline, promethazine, and hydrocortisone) during the first hour. Compared with placebo, adrenaline significantly reduced severe reactions to antivenom by 43% (95% CI 25-67) at 1 h and by 38% (95% CI 26-49) up to and including 48 h after antivenom administration; hydrocortisone and promethazine did not. Adding hydrocortisone negated the benefit of adrenaline. CONCLUSIONS: Pretreatment with low-dose adrenaline was safe and reduced the risk of acute severe reactions to snake antivenom. This may be of particular importance in countries where adverse reactions to antivenom are common, although the need to improve the quality of available antivenom cannot be overemphasized.
Management of yellow oleander poisoning (YOP) with multiple-dose activated charcoal: a randomized placebo controlled trial
(Sri Lanka Medical Association, 2003) de Silva, H.A.; Fonseka, M.M.D.; Pathmeswaran, A.; Alahakone, D.G.S.; Ratnatilake, G.A.; Gunatilake, S.B.; Ranasinha, C.D.; Lalloo, D.G.; Aronson, J.K.; de Silva, H.J.
Abstract Available
Multi-dose activated charcoal for yellow oleander poisoning
(Lancet Publishing Group, 2003) de Silva, H.A.; Aronson, J.K.; Ranasinha, C.D.; Gunatilake, S.B.; de Silva, H.J.
Author Reply to: Juurlink DN, Sivilotti ML. Lancet. 2003; 362(9383):581 No Abstract Available
Multiple-dose activated charcoal for treatment of yellow oleander poisoning : a single-blind randomized placebo controlled trial
(Lancet Publishing Group, 2003) de Silva, H.A.; Fonseka, M.M.D.; Pathmeswaran, A.; Alahakoon, D.G.S.; Ratnatilaka, G.A.; Gunatilake, S.B.; Ranasinha, C.D.; Lalloo, D.G.; Aronson, J.K.; de Silva, H.J.
BACKGROUND: Deliberate self-poisoning with yellow oleander seeds is common in Sri Lanka and is associated with severe cardiac toxicity and a mortality rate of about 10%. Specialised treatment with antidigoxin Fab fragments and temporary cardiac pacing is expensive and not widely available. Multiple-dose activated charcoal binds cardiac glycosides in the gut lumen and promotes their elimination. We aimed to assess the efficacy of multiple-dose activated charcoal in the treatment of patients with yellow-oleander poisoning. METHODS: On admission, participants received one dose of activated charcoal and were then randomly assigned either 50 g of activated charcoal every 6 h for 3 days or sterile water as placebo. A standard treatment protocol was used in all patients. We monitored cardiac rhythm and did 12-lead electocardiographs as needed. Death was the primary endpoint, and secondary endpoints were life-threatening cardiac arrhythmias, dose of atropine used, need for cardiac pacing, admission to intensive care, and number of days in hospital. Analysis was by intention to treat. FINDINGS: 201 patients received multiple-dose activated charcoal and 200 placebo. There were fewer deaths in the treatment group (five [2.5%] vs 16 [8%]; percentage difference 5.5%; 95% CI 0.6-10.3; p=0.025), and we noted difference in favour of the treatment group for all secondary endpoints, apart from number of days in hospital. The drug was safe and well tolerated. INTERPRETATION: Multiple-dose activated charcoal is effective in reducing deaths and life-threatening cardiac arrhythmias after yellow oleander poisoning and should be considered in all patients. Use of activated charcoal could reduce the cost of treatment.
Multiple-dose activated charcoal in yellow oleander poisoning
(Lancet Publishing Group, 2008) de Silva, H.A.; Pathmeswaran, A.; Lalloo, D.G.; de Silva, H.J.; Aronson, J.K.
Comment on : Michael Eddleston and colleagues (Lancet. 2008 Feb 16;371(9612):579-87)study. No Abstract Available
Pharmacological evidence of calcium activated and voltage-gated potassium channels in the platelets
(Portland Press on behalf of the Medical Research Society and the Biochemical Society, 1997) de Silva, H.A.; Aronson, J.K.
Previous electrophysiological studies have suggested the presence of KCa and Kv channels in human platelets. However, the pharmacology of these channels has not been defined.We have studied potassium channels in human platelets by measuring the efflux of 86Rb+ (a marker for K+) from 86Rb+-loaded cells, and have defined their responses to stimulation by the platelet agonist thrombin and the calcium ionophore ionomycin. Thrombin (0.1–0.6 i.u./ml) stimulated an increase in 86Rb+ efflux from the platelets in a concentration-dependent manner. This efflux was significantly inhibited by apamin (100 nmol/l), charybdotoxin (300 nmol/l) and α-dendrotoxin (100–200 nmol/l), blockers of SKCa channels, KCh channels and Kv channels respectively. Iberiotoxin (300 nmol/l), a specific inhibitor of BKCachannels, had no effect on the thrombin-stimulated 86Rb+ efflux. Although glibenclamide, an inhibitor of KATP channels, inhibited the thrombin-stimulated efflux, it did so only in a high concentration (20 μmol/l). Ionomycin (1–5 μmol/l) stimulated an increase in 86Rb+ efflux from the platelets in a concentration-dependent manner. This efflux was significantly inhibited by apamin (100 nmol/l) and charybdotoxin (300 nmol/l). However, iberiotoxin (300 nmol/l) had no effect on the ionomycin-stimulated 86Rb+ efflux. These findings suggest that 86Rb+ efflux from platelets stimulated by thrombin and ionomycin occurs via two types of KCachannel: SKCa and KCh channels. Thrombin also stimulated efflux via Kv channels.
Prevention of acute adverse reactions to snake antivenom after snakebite: multi-centre, randomized, controlled clinical trial
(Sri Lanka Medical Association, 2009) de Silva, H.A.; Ranasinha, C.D.; Pathmeswaran, A.; Jayamanne, S.; Kalupahana, R.; Ratnathilake, G.A.; Ariyasena, H.; Uluwatte, W.; Lalloo, D.; Armitage, J.; Aronson, J.K.; de Silva, H.J.
BACKGROUND: Antivenom is the most effective treatment for snakebite envenoming. Acute adverse reactions to the polyvalent antivenom (PAV) are common; anaphylactk reactions are particularly serious. OBJECTIVE: To determine whether promethazine, hydrocortisone, and low-dose adrenaline, alone and in all possible combinations, prevent reactions to antivenom. METHODS: The study was conducted in 3 hospitals in Sri Lanka from March 2005 to April 2008. It required 1000 patients to detect a 25% reduction in reactions at p<0.01 with 80% power. After informed consent, patients were randomized in a 2x2x2 factorial blinded design to receive each active intervention versus matching placebo immediately before administration of PAV. They were monitored for adverse reactions categorized as mild, moderate, severe, for at least 96 hours. The pre-specified primary analyses were of effects of each intervention on the incidence of severe reactions over 48 hours. Results: Of 1007 randomized subjects 776 (77.2%) were males, mean (sd) age 36.5 (13.6) yrs. Median time between snakebite and PAV administration was 4.25 hours. 752 (75%) patients developed acute reactions to PAV; 9% mild, 48% moderate and 43% severe. None of the drugs significantly reduced severe reactions to PAV at any time point. However, there was an 18% reduction in the rate of severe reactions at 1 hour with adrenaline (p-0.052) and a 33-3% reduction in signs of allergy (pruritus, urticaria, facial oedema, bronchospasm) with promethazine at 1 and 24 hours (p<0.001). CONCLUSIONS: Pre-treatment with promethazine, hydrocortisone, and low-dose adrenaline alone and in different combinations do not significantly reduce acute reactions to PAV.