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Biomedical subjects

K Rajakulasingam

Publications and source records attributed to K Rajakulasingam.

At least 37 records · Page 2Linked to original sources
PubMed1993

Skin responses to bradykinin, kallidin, and [desArg9]-bradykinin in nonatopic and atopic volunteers.

BACKGROUND: Kinins are potent vasoactive oligopeptides that may act as mediators in a variety of inflammatory diseases of the skin by interacting with specific receptors designated B1 and B2. In this study we have investigated the structure-activity relationship of intradermally injected bradykinin, kallidin (lysine-bradykinin), and [desArg9]-bradykinin in atopic (n = 8) and nonatopic (n = 8) subjects. METHODS: On two separate occasions, each separated by a week, subjects randomly underwent intradermal challenge with incremental doses (0.5, 5, and 50 nmol) of either the B1-agonist [desArg9]-bradykinin, the B2-agonists bradykinin or kallidin, or vehicle placebo. In a separate randomized double-blind study we have also examined the effect of an orally administered antihistamine, terfenadine, on kinin-induced wheal and flare responses and their repeatability in a group of nine volunteers. The skin responses were monitored objectively by measurement of wheal and flare areas. RESULTS: Both bradykinin and kallidin induced a dose-dependent increase in wheal and flare areas in all subjects studied. Although the effects of the two lowest doses (0.5 and 5 nmol) of [desArg9]-bradykinin on skin responses were indistinguishable from those of placebo, this kinin at the highest dose administered (50 nmol) caused a significant increase in wheal and flare areas in all subjects studied. No difference could be identified in the skin responses to kinins between atopic and nonatopic subjects. In addition kinin-induced cutaneous responses were not altered by pretreatment with terfenadine. CONCLUSIONS: These in vivo structure activity studies suggest that in human beings the skin responses to kinins may be compatible with the stimulation of B2 receptors, which is unrelated to histamine release from cutaneous mast cells.

Adult↗
PubMed1993

Relative potencies and time course of changes in adenosine 5'-monophosphate airway responsiveness with inhaled furosemide and bumetanide in asthma.

A randomized, double-blind, placebo-controlled study was conducted to compare the effects of two chemically unrelated "loop" diuretics, furosemide (40 mg) and bumetanide (2 mg) on the bronchoconstrictor response to inhaled adenosine 5'-monophosphate (AMP) in 12 subjects with asthma. In eight additional volunteers with asthma, we also carried out a separate randomized, double-blind study to examine in more detail the time course of change in bronchial reactivity to inhaled AMP after administration of nebulized furosemide and bumetanide. Inhaled loop diuretics significantly increased the provocative concentration of AMP causing a 20% fall in forced expiratory volume in 1 second (FEV1) from the value of 21.2 mg/ml (range, 2.5 to 96.9 mg/ml) after placebo administration to 83.4 mg/ml (range, 11.3 to 345.0 mg/ml) (p < 0.01) and 33.8 mg/ml (range, 4.7 to 120.9 mg/ml) (p < 0.05) after administration of furosemide and bumetanide, respectively. After placebo administration, the provocative concentration of AMP causing a 20% fall in FEV1 (PC20 AMP) at 10, 30, and 120 minutes did not differ significantly; their geometric mean (range) values were 57.8 mg/ml (10.9 to 341.0 mg/ml), 55.0 mg/ml (13.2 to 304.1 mg/ml), and 52.8 mg/ml (14.4 to 252.2 mg/ml), respectively. When compared with placebo, inhaled furosemide significantly reduced the airway responsiveness to AMP at all time points; the PC20 AMP values at 10, 30, and 120 minutes were 154.6 mg/ml (29.4 to 658.7 mg/ml) (p < 0.01), 142.6 mg/ml (25.5 to 639.9 mg/ml) (p < 0.01), and 103.9 mg/ml (12.5 to 605.5 mg/ml) (p < 0.05), respectively. The PC20 values for AMP after pretreatment with bumetanide were significantly increased up to 110.2 mg/ml (25.9 to 639.0 mg/ml) (p < 0.01) and to 92.0 mg/ml (21.6 to 531.7 mg/ml) (p < 0.05) at 10 and 30 minutes, respectively. At 120 minutes, inhaled bumetanide failed to affect AMP airway responsiveness; the PC20 AMP was not significantly different from that of placebo, with a value of 71.5 mg/ml (22.6 to 318.0 mg/ml). We conclude that comparable equidiuretic doses of furosemide and bumetanide are effective in attenuating the airway response to AMP, with furosemide being approximately 2.5 times more potent than bumetanide (p < 0.01). The time course of change in bronchial reactivity to AMP is similar for both drugs with a peak effect at 10 minutes. It is possible that the mechanism(s) underlying the protective effects of inhaled loop diuretics in asthma may be distinct from those responsible for their diuretic properties.

Adenosine Monophosphate↗
PubMed1993

Comparative nasal effects of bradykinin and histamine: influence on nasal airways resistance and plasma protein exudation.

BACKGROUND: Bradykinin may contribute to the pathogenesis of allergic rhinitis. Like histamine, nasal challenge with bradykinin induces rhinorrhoea, nasal blockage, and plasma protein leakage. Their comparative nasal potencies have not, however, been fully elucidated. METHODS: Three double blind, randomised, placebo controlled and cross-over studies were undertaken to compare objectively the nasal effects of bradykinin, histamine, and vehicle. RESULTS: Both bradykinin and histamine produced dose dependent increases in nasal airways resistance (NAR). There was no significant difference in the effects of bradykinin and histamine on NAR at any dose level. On a molar basis, however, bradykinin was 6.98 times more potent than histamine in inducing a 50% increase in NAR. Nasal challenge with bradykinin and histamine also induced significant rhinorrhoea compared with vehicle. The amount of rhinorrhoea induced by histamine was significantly greater than that induced by bradykinin at any dose level. Bradykinin and histamine induced dose dependent nasal pain and nasal itch respectively. When administered as single doses both bradykinin (1.9 mumol) and histamine (1.9 mumol) induced significant rhinorrhoea compared with the vehicle. The volume of rhinorrhoea secretions induced by histamine was 29% greater than that induced by bradykinin. In contrast, although NAR was increased significantly more by histamine than by the vehicle, the effect of bradykinin on NAR was significantly greater than histamine and vehicle in both magnitude and duration of effect. The incremental effect of bradykinin on lavage albumin levels was also significantly greater than both histamine and vehicle. CONCLUSIONS: This study shows that the nasal vascular effects of histamine are less prominent than its actions on rhinorrhoea, and that the greater obstructive effect of bradykinin than histamine on NAR may contribute to the relative lack of efficacy of H1 antihistamines on nasal blockage in clinical disease.

Administration, Inhalation↗
PubMed1993

Interactive effect of inhaled bradykinin with histamine and PGD2 in bronchial asthma.

Interaction among mediators such as bradykinin (BK), histamine (H), and prostaglandin (PG) D2 may contribute to reduction in airway caliber in asthma. Ten stable asthmatic subjects took part in a study to investigate possible mediator interaction. The provocative concentration of mediator required to reduce forced expiratory volume in 1 s (FEV1) by 12.5% from the starting baseline value (PC12.5) and that required to reduce the fall in FEV1 from 12.5 to 25% (PC25-12.5) of H, BK, and PGD2 were determined. On three subsequent occasions, subjects inhaled either the vehicle plus BK PC12.5 or the vehicle plus H or PGD2 PC25-12.5, and FEV1 was measured at regular time intervals up to 40 min. Predicted time course curves were calculated from these results. On two additional occasions, interactive time course studies were undertaken when the subject inhaled BK PC12.5 followed by H or PGD2 PC25-12.5. On a further three visits, the time courses of individual mediators were studied. When BK was combined with H and PGD2, the maximum fall in FEV1 and the rate of recovery after inhalation of the second mediator were not significantly different from those values of predicted time course responses for the same combination of mediator. Thus, by employing pharmacologically active concentrations of inhaled BK, H, and PGD2, which act through separate receptor mechanisms, we were unable to demonstrate any pharmacological interaction on airway caliber in asthma.

Adult↗
PubMed1993

Cross-tachyphylactic airway response to inhaled bradykinin, kallidin and [desArg9]-bradykinin in asthmatic subjects.

Kinins are oligopeptides that may act as mediators in the pathogenesis of bronchial asthma by interacting with specific cell surface receptors designated B1 and B2. When administered by inhalation to asthmatic subjects, bradykinin and kallidin, but not [desArg9]-bradykinin, provoke potent bronchoconstriction, thus suggesting a specific effect compatible with the stimulation of B2 receptors. To characterize further the receptor(s) mediating this bronchospastic response we have carried out cross-tachyphylactic studies with inhaled bradykinin, kallidin, and [desArg9]-bradykinin, administered in a randomized double-blind fashion in a group of 10 asthmatic subjects. Inhalation of bradykinin and kallidin, but not [desArg9]-bradykinin, elicited concentration-related falls in forced expiratory volume in one second (FEV1) in all the subjects studied. The geometric mean provocation concentrations of inhaled agonists reducing FEV1 by 20% of baseline (PC20) were 0.12 and 0.28 mg.ml-1 for bradykinin and kallidin, respectively. When inhaled at concentrations up to 10.62 mg.ml-1, [desArg9]-bradykinin failed to provoke any significant fall in FEV1 from baseline in any of the subjects studied. Following recovery from the second bradykinin challenge, provocation with kallidin revealed a reduced response to this agonist, the PC20 value increasing from 0.28 to 1.23 mg.ml-1. Similarly, once the airways had recovered from the second kallidin challenge, provocation with bradykinin also showed a reduced response, the PC20Bk increasing from 0.12 to 0.94 mg.ml-1. Surprisingly, despite failing to cause bronchoconstriction, repeated exposures with inhaled [desArg9]-bradykinin reduced the airway response to bradykinin, the PC20Bk increasing from 0.12 to 0.41 mg.ml-1.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗
PubMed1992

The influence of terfenadine and ipratropium bromide alone and in combination on bradykinin-induced nasal symptoms and plasma protein leakage.

Nasal instillation of bradykinin elicits many of the characteristic features of rhinitis. To assess the relevance of histamine release from metachromatic cells and the activation of cholinergic pathways, we investigated the effects of terfenadine, a histamine H1-receptor antagonist, and ipratroprium bromide, a selective antimuscarinic agent, on bradykinin induced rhinorrhoea, nasal airways resistance (NAR), nasal pain and plasma protein leakage. Oral terfenadine (120 mg) or matched placebo and nasal ipratropium bromide (80 micrograms) or matched placebo were administered at 4 hr and 30 min respectively prior to bradykinin nasal challenge in two randomized, double-blind and cross-over studies on eight non-rhinitic subjects. Thus subjects received either double-placebo, oral terfenadine and nasal placebo, oral placebo and nasal ipratopium bromide or oral terfenadine and nasal ipratropium bromide, as pretreatment. Bradykinin challenge induced mean maximal increases of 57%, 59%, 77% and 72% in NAR on the placebo, terfenadine, ipratropium bromide and terfenadine plus ipratropium bromide pretreatment days respectively. These increments were not significantly different. Similarly rhinorrhoea and nasal pain induced by bradykinin nasal challenge were not significantly different on the four challenge days. Bradykinin nasal challenge caused a mean maximal increase in albumin levels in recovered nasal lavages of 11.5, 13.0, 12.2 and 12.3 times of baseline levels on the placebo, terfenadine, ipratropium bromide and terfenadine plus ipratroprium bromide pretreatment days respectively. Similarly total protein levels achieved a mean maximal increase of 8.0, 8.2, 7.9 and 8.8 times of baseline levels on these challenge days. The increments in both albumin and total protein did not significantly differ on the 4 challenge days.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Nasal effects of bradykinin and capsaicin: influence on plasma protein leakage and role of sensory neurons.

Nasal insufflation with bradykinin induces nasal discomfort, rhinorrhea, and nasal blockage, all features of rhinitis. We recently showed these effects to be mediated by the B2-receptor subtype, which has been identified at neural and vascular sites. To investigate the relative contribution of capsaicin-sensitive sensory neural stimulation to the action(s) of bradykinin, two randomized double-blind placebo-controlled studies have been undertaken comparing the nasal effects of single-dose administrations of bradykinin (1.88 x 10(-3) M) and capsaicin (3.28 x 10(-5) M). In comparison with placebo, both bradykinin and capsaicin induced nasal pain/discomfort (P less than 0.01) and rhinorrhea (P less than 0.02). Bradykinin significantly increased nasal airways resistance (P less than 0.005) and plasma protein exudation (P less than 0.02). No such changes were identified after nasal challenge with capsaicin. These findings suggest that bradykinin-induced nasal discomfort and rhinorrhea are neurally mediated, whereas the effects on nasal airways resistance and plasma protein exudation are due to a direct vascular action. In addition, these findings question the role of capsaicin-sensitive sensory neurons in nasal vasculature responses, because no vascular effects of capsaicin could be identified in the human nasal mucosa.

Adult↗
PubMed1992

Repeated inhalation of bradykinin attenuates adenosine 5'-monophosphate (AMP) induced bronchoconstriction in asthmatic airways.

Repeated bronchial challenges with inhaled bradykinin lead to a rapid loss of the bronchoconstrictor response and this has been suggested to be due to depletion of contractile neuropeptides from sensory nerve endings. If adenosine 5'-monophosphate (AMP), another potent bronchoprovocant in asthma, and bradykinin share a common pathway in inducing bronchoconstriction in asthmatic subjects, then repeated bradykinin bronchoprovocation tests should reduce the response to subsequent inhalation of AMP. We examined this hypothesis in eight asthmatic subjects in a double-blind, randomized study. On the histamine study day, two consecutive concentration-response studies with inhaled histamine were followed by a third consecutive challenge with AMP and the provocation concentration producing a 20% fall in forced expiratory volume in one second from the post-diluent baseline value (PC20 FEV1) for this agonist was calculated. On the bradykinin study day, two consecutive bronchoprovocation tests with bradykinin were followed by a third inhalation challenge to obtain the PC20AMP value. On a further occasion, the asthmatic subjects underwent two consecutive concentration-response studies with inhaled bradykinin followed by a third consecutive challenge with histamine. On the histamine study day, the geometric mean PC20AMP value was 28.1 mg.ml-1, whilst on the bradykinin study day, the fifteenfold reduction in bradykinin responsiveness after the second bradykinin challenge was accompanied by a significant reduction of the airway responsiveness to AMP, the PC20AMP being 59.8 mg.ml-1. A similar reduction in bradykinin responsiveness failed to alter the airway response to a subsequent inhalation with histamine.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Monophosphate↗
PubMed1991

The effect of inhaled ipratropium bromide alone and in combination with oral terfenadine on bronchoconstriction provoked by adenosine 5'-monophosphate and histamine in asthma.

The aim of this study was to investigate the effect of terfenadine, an antihistamine, 180 mg orally, the anticholinergic drug, ipratropium bromide (IB), 0.5 mg nebulized aerosol, the combination of these two drugs, and placebo tablets and aerosol on histamine- and adenosine 5'-monophosphate (AMP)-induced bronchoconstriction in a randomized, double-blind fashion. Airway response was evaluated as FEV1. After placebo, the geometric mean (GM) provocative concentration causing a 20% in FEV1 from the postsaline baseline value (PC20) for histamine and AMP was 0.63 and 5 mg/ml, respectively. Terfenadine displaced the FEV1 concentration-response curves obtained with both histamine (GM PC20 values increasing to 26.92 mg/ml) and AMP (GM PC20 values increasing to 26.7 mg/ml) to the right. IB had a small, but significant, protective effect against the fall in FEV1 produced by histamine and AMP, the GM PC20 values increasing to 1.69 and to 12.6 mg/ml, respectively. Terfenadine and IB in combination produced protection against histamine and AMP that was more than the production produced by either drug alone, the GM PC20 values increasing to 54.76 and 47.7 mg/ml, respectively. There was no correlation between degree of bronchodilatation induced by active treatments and concentration ratios for AMP or histamine. These data suggest that histamine release and vagal reflexes both contribute to AMP-induced bronchoconstriction in clinical asthma in man.

Adenosine Monophosphate↗
PubMed1991

Comparative nasal effects of bradykinin, kallidin and [Des-Arg9]-bradykinin in atopic rhinitic and normal volunteers.

1. The structure-activity relationship of kinins within the nose has been investigated in atopic rhinitic (n = 7) and non-rhinitic (n = 7) subjects. On 4 separate days, each separated by a week, subjects randomly underwent nasal challenge with incremental doses of either the B1 agonist [Des-Arg9]-bradykinin, the B2 agonists kallidin or bradykinin, or vehicle placebo in a double-blind comparative study. The nasal response was monitored objectively by measurement of nasal airways resistance (NAR) by active posterior rhinomanometry and subjectively by symptom reporting of nasal blockage, rhinorrhoea, nasal itch and nasal pain. 2. The B2 agonists kallidin and bradykinin both induced a dose-dependent increase in NAR (P less than 0.001) and were associated with symptomatic reporting of nasal blockage (P less than 0.05), rhinorrhoea (P less than 0.01) and nasal discomfort (P less than 0.05) compared to placebo. In contrast the effects of the B1 agonist [Des-Arg9]-bradykinin on NAR and symptom reporting were indistinguishable from placebo. No difference could be identified in the nasal response to kallidin and bradykinin between rhinitic and non-rhinitic subjects and there was no evidence of B1 receptor upregulation in the disease state. For the whole group the provocative dose of agonist inducing a 50% increase in NAR (PD50) was 1.77 x 10(-4) mol for bradykinin and 2.86 x 10(-4) mol for kallidin (P greater than 0.05). 3. These findings identify that the nasal effects of kinins are mediated through B2 receptors and the advent of B2 receptor antagonists will permit a further evaluation of the role of kinins in rhinitis.

Adult↗
PubMed1980

Femoral-cerebral angiography in infants and children. Analysis and comparison with direct puncture/retrograde brachial technique.

The technique of femoral-cerebral catheterization in infants and children is described, and a series of 1,869 procedures is analyzed for complications. Clinical complications occurred in 12 of 678 or 1.8% of examinations while radiographic complications were discovered in 38 of 1,869 or 1.1% of procedures. The results are compared to a similar retrospective study of a large series (2,184 procedures) of direct puncture/retrograde brachial studies in a similar patient population at the same institution in which there was a 2.6% clinical complication rate and a 4.3% radiographic complication rate. Those factors which predispose to complications, clinical or radiographic, are more pronounced in the younger age groups but affect the direct puncture/retrograde brachial technique to a greater degree. The lower morbidity, greater selectivity and improved comfort make the femoral-cerebral route preferable for neuroangiographic studies in infants and children.

Brain Diseases↗
PubMed1979

Childhood moyamoya syndrome. Postradiation pathogenesis.

The development of typical clinical and radiological features of moyamoya syndrome is described in 3 children following radiation therapy for a gliomatous tumor at the base of the brain. The effect of radiation therapy on the medium-sized arteries is discussed with a review of the literature. Radiation therapy as the causative factor for the narrowing or occlusion of the carotid siphon is discussed.

Arterial Occlusive Diseases↗