Also High Dose of Aspirin Prolongs Bleeding Time, But Later After Ingestion

1979 ◽  
Author(s):  
E. Waiter ◽  
R. Siess ◽  
R. Zimmermann ◽  
E. Weber
Keyword(s):  
Low Dose ◽  
Bleeding Time ◽  
Dose Range ◽  
Blood Levels ◽  
High Dose ◽  
Antithrombotic Agent ◽  
Double Blind ◽  
Significant Prolongation ◽  
Small Doses ◽  
Induced Aggregation

O’Grady and Moncada (Lancet, 1978, ii, 780) found after ingestion of 0.3 g but not after 3.9g of aspirin a significant prolongation of the bleeding time, measured 2h after ingestion. This confirmed their unpublished findings in cats and rabbits, and also their suggestion, that aspirin as an antithrombotic agent should be used in small doses. We decided to test a intermediate dose of 1.5g in comparison to 0.3 and 4.0. Young healthy volunteers received in a double blind trial at random with 14 days interval the three doses. Bleeding time was measured and blood taken for collagen induced aggregation and blood levels of ASA and SA before, 2, 4 and 5.5 after ingestion of ASA. Bleeding time increased significantly 2 h after 0.3g ASA from 213 to 380 sec.(n=8,p <0.01), and from 181 to 408 after 1. g. The high dose of 4g led to a smaller prolongation from 224 to 342 after 2 h, but reached the low dose range after 4 h, 440 sec. (p < 0.01). Collagen-induced aggregation (1 μg/m 1 and 5 μg/ml) was independent from the digese of ASA reduced, beginning after two hours. Our findings do not confirm the result of O’Grady and Moncada. The slower increase of bleeding time after the high dose of ASA must be discussed in relation to ASA and SA blood-levels and reversible inhibition of cyclooxygenase in endothelial cells

Benefit/Risk Profile of Combined Antiplatelet Therapy with Ticlopidine and Aspirin

1991 ◽  
Vol 65 (05) ◽  
pp. 504-510 ◽  
Author(s):  
Raffaele De Caterina ◽  
Rosa Sicari ◽  
Walter Bernini ◽  
Guido Lazzerini ◽  
Giuliana Buti Strata ◽  
...  
Keyword(s):  
Platelet Function ◽  
Low Dose ◽  
Bleeding Time ◽  
Ex Vivo ◽  
Stable Coronary Artery Disease ◽  
High Dose ◽  
Single Drug ◽  
Before And After ◽  
Serum Thromboxane ◽  
Artery Disease

SummaryTiclopidine (T) and aspirin (ASA) are two antiplatelet drugs both capable of prolonging bleeding time (BT), with a different mechanism of action. A synergism in BT prolongation has been reported and is currently considered an argument for not recommending their combination. However, a profound suppression of platelet function might be a desirable counterpart of a marked prolongation of BT, with a possible use in selected clinical situations. We therefore studied ex vivo platelet function (aggregation by ADP 0.5-1-2.5 μM; adrenaline 0.75-2.5 μM; collagen 1.5-150 μg/ml; arachidonic acid 1 mM; PAF 1 μM; adrenaline 0.17 μM + ADP 0.62 μM; serum thromboxane ([TX]B2 generation) and BT (Mielke) in 6 patients with stable coronary artery disease receiving such combination. Patients underwent sequential laboratory evaluations at baseline, after 7 days of T 250 mg b.i.d., before and after the intravenous administration of ASA 500 mg, respectively, and, finally, after a minimum of 7 days of sole ASA oral administration (50 mg/day). The experimental design, therefore, allowed a comparison of T and ASA effects (2nd and 4th evaluation), and an assessment of the combination effect (3rd evaluation). Platelet aggregation in response to all doses of ADP was depressed more by T than by ASA. Conversely, responses to adrenaline, and arachidonate were affected more by ASA than by T. For all other agents, differences were not significant. T + ASA combination was more effective (p <0.05) than either treatment alone in depressing responses to high-dose collagen (% over control, mean ± SEM: T: 95 ± 3; ASA: 96 ± 5; T + ASA: 89 ± 4). Serum TXB2 (basal, ng/ml: 380 ± 54) did not change with T (372 ± 36), dropped to <1 ng/ml on ASA injection and slightly re-increased to 9.1 ± 3.1 ng/ml on oral low-dose ASA. BT (basal 7.4 ± 0.6 min) was affected similarly by T (9.2 ± 0.8) or ASA (9.7 ± 0.9) alone, but increased to 15.0 ± 0.7 min on combination treatment (106% increase over control). Thus, the strong synergism in BT prolongation by ASA-T combination has a counterpart in the inhibition of platelet function in response to strong stimuli such as high-dose collagen, not otherwise affected significantly by single-drug treatment. This effect is a possible rationale for the clinical evaluation of T + ASA combination.

scholarly journals Skin regeneration is accelerated by a lower dose of multipotent mesenchymal stromal/stem cells—a paradigm change

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Gertraud Eylert ◽  
Reinhard Dolp ◽  
Alexandra Parousis ◽  
Richard Cheng ◽  
Christopher Auger ◽  
...  
Keyword(s):  
Stem Cells ◽  
Wound Healing ◽  
Low Dose ◽  
Dose Range ◽  
High Dose ◽  
Full Thickness ◽  
Burn Wound ◽  
Dermal Regeneration Template ◽  
Yorkshire Pigs ◽  
Stromal Stem Cells

Abstract Background Multipotent mesenchymal stromal/stem cell (MSC) therapy is under investigation in promising (pre-)clinical trials for wound healing, which is crucial for survival; however, the optimal cell dosage remains unknown. The aim was to investigate the efficacy of different low-to-high MSC dosages incorporated in a biodegradable collagen-based dermal regeneration template (DRT) Integra®. Methods We conducted a porcine study (N = 8 Yorkshire pigs) and seeded between 200 and 2,000,000 cells/cm2 of umbilical cord mesenchymal stromal/stem cells on the DRT and grafted it onto full-thickness burn excised wounds. On day 28, comparisons were made between the different low-to-high cell dose groups, the acellular control, a burn wound, and healthy skin. Result We found that the low dose range between 200 and 40,000 cells/cm2 regenerates the full-thickness burn excised wounds most efficaciously, followed by the middle dose range of 200,000–400,000 cells/cm2 and a high dose of 2,000,000 cells/cm2. The low dose of 40,000 cells/cm2 accelerated reepithelialization, reduced scarring, regenerated epidermal thickness superiorly, enhanced neovascularization, reduced fibrosis, and reduced type 1 and type 2 macrophages compared to other cell dosages and the acellular control. Conclusion This regenerative cell therapy study using MSCs shows efficacy toward a low dose, which changes the paradigm that more cells lead to better wound healing outcome.

PREVENTING VENOUS THROMBOSIS (VT) WITH HEPARIN ALONE OR WITH HEPARIN/DIHYDROERGOTAMINE AFTER ELECTIVE HIP REPLACEMENT, A DOUBLE-BLIND, RANDOMISED, VENOGRAM END-POINT COMPARISON

1987 ◽  
Author(s):  
J F Cade ◽  
K W Mills ◽  
A S Gallus ◽  
W Murphy
Keyword(s):  
Venous Thrombosis ◽  
General Surgery ◽  
Hip Replacement ◽  
Low Dose ◽  
Double Blind ◽  
Randomised Study ◽  
Sodium Heparin ◽  
End Point ◽  
Small Doses

Dihydro-ergotaraine (DHE) appears to be synergistic with small doses of hepari when used to prevent VT after general surgery. However, doubt remains whether DHEhas this effect in patients with elective hip replacement (THR). We have therefore compared the results of VT prophylaxis using sub-cutaneous (sc) low-dose heparinalone or sc heparin plus sc DHE in a double-blind, randomised, study of 126 patientshaving elective THR, 98 at centre (1)and 28 at centre (2).All received 5000 iu sodium heparin, hourly for 7 days, starting 2 hours before surgery at centre (1), or immediately after surgery at centre (2). Patients alsoreceived a separate 0.5 ml (0.5 mg) DHEorplacebo injection each time they receivedheparin. Patients had bilateral ascendingvenography on the 7th postoperativeday, and venograms were read before the treatment code was broken.These results do not support the presence of synergism between heparin and DHE in this situation.

Responses to Methylphenidate and Varied Doses of Caffeine in Children with Attention Deficit Disorder

1981 ◽  
Vol 26 (6) ◽  
pp. 395-401 ◽  
Author(s):  
D. Garfinkel Barry ◽  
D. Webster Christopher ◽  
Leon Sloman
Keyword(s):  
Attention Deficit ◽  
Attention Deficit Disorder ◽  
Low Dose ◽  
Stimulant Medication ◽  
High Dose ◽  
Day Hospital ◽  
Double Blind ◽  
Treatment Conditions ◽  
Hospital Patients ◽  
Low Dosage

Six children with the diagnosis of Attention Deficit Disorder were treated as day hospital patients, using different stimulant medication. They were studied in a double-blind crossover experiment in which they received caffeine in low dose or in a high dose. Methylphenidate was added to both dosages, as well as administered alone. Results indicated that caffeine in low dosage when added to methylphenidate was superior to all other treatment conditions. Caffeine in low dosage could not be differentiated from 10 mg of methylphenidate. High dosage caffeine was not different from placebo or no-drug conditions. This study offers evidence to support a curvilinear pattern of dose-response for caffeine, in attenuating the behavioural manifestations of this syndrome.

Comparative Effects of Staphylokinase and Alteplase in Rabbit Bleeding Time Models

1996 ◽  
Vol 75 (05) ◽  
pp. 816-819 ◽  
Author(s):  
Steven Vanderschueren ◽  
Désiré Collen
Keyword(s):  
Thrombolytic Therapy ◽  
Low Dose ◽  
Bleeding Time ◽  
Tissue Type ◽  
High Dose ◽  
Time Model ◽  
Spontaneous Bleeding ◽  
Tissue Type Plasminogen Activator ◽  
Type Plasminogen Activator ◽  
Combined Administration

Summary Background: The pathogenesis of bleeding associated with thrombolytic therapy remains largely unknown, although spontaneous bleeding appears to correlate with bleeding time prolongation. Here, the comparative effects on cuticle bleeding times (CBT) and ear puncture bleeding times (EBT) of recombinant staphylokinase (Sak) and alteplase (recombinant tissue-type plasminogen activator, rt-PA) at equivalent doses, alone and in combination with aspirin and heparin, were studied in rabbits. Methods and Results: Groups of 4 to 9 rabbits were allocated to one of the 8 following intravenous infusions: saline; aspirin 15 mg/kg and heparin - 100 IU/kg bolus and 10 IU/kg infusion over one hour; 1.5 mg/kg rt-PA; 1.5 mg/kg rt-PA plus aspirin and heparin; 4.5 mg/kg rt-PA; 0.5 mg/kg Sak; 0.5 mg/kg Sak plus aspirin and heparin and 1.5 mg/kg Sak. Bleeding times were determined 30 and 15 min before and 5,15,30 and 60 min after the administration over one min of saline, rt-PA or Sak, by simultaneously severing a nail cuticle (CBT) and by puncturing the ear (EBT). Bleeding times were unaffected by saline and by both doses of Sak in monotherapy. Heparin-aspirin and low dose rt-PA significantly lengthened EBT but not CBT. Both CBT and EBT were significantly prolonged (to a mean of >4 times pretreatment at 5 min) after high-dose rt-PA and after the combined administration of heparin and aspirin with either Sak or rt-PA. rt-PA provoked significantly longer bleeding than Sak in the CBT (p = 0.001; mean estimated difference = 23 min), but not in the EBT. rt-PA but not Sak degraded plasma fibrinogen dose-dependently. CBT correlated inversely with fibrinogen (r = −0.66, p = 0.001) but EBT did not. Conclusions: At equivalent doses Sak displays a significantly higher fibrin specificity and prolongs bleeding time less than rt-PA, particularly in the nail cuticle bleeding time model in which larger vessels are injured that require fibrinogen for hemostasis.

A study of the effect of X-rays on the electrical properties of mammalian nerve and muscle

1963 ◽  
Vol 157 (969) ◽  
pp. 536-561 ◽  
Keyword(s):  
Dose Rate ◽  
Action Potentials ◽  
Time Course ◽  
Low Dose ◽  
High Dose ◽  
X Rays ◽  
Low Dose Rate ◽  
End Plate ◽  
Small Doses ◽  
Motor End Plate

Resting potentials, action potentials, and miniature end-plate potentials have been re­corded from isolated phrenic-diaphragm preparations of the rat during and after irradiation with X-rays. Relatively small doses of a few thousand roentgens have no obvious effect on the preparation for many hours but larger doses, of the order of 70 to 150 kr irreversibly block neuromuscular transmission. The block is not accompanied by any change in the size of action potentials, resting potentials, membrane constants or miniature potentials recorded in the muscle with intracellular electrodes, or in the size of action potentials recorded in the nerve. Records made at the motor end-plate show that the cause of the block is a ‘pre-synaptic ’ failure of impulse propagation in the intramuscular part of the nerve. The time course of the failure depends largely on the rate at which X-rays are delivered to the pre­paration: at a high dose-rate (70kr/min) the block develops rapidly and is accompanied by an increase in the frequency of miniature potentials; at a low dose-rate (7 kr/min) larger doses are required, the latency is longer and the miniature potentials continue at a normal frequency. The sequence in which different parts of the muscle become blocked, the abrupt nature of the failure at an individual motor end-plate, and the increase in frequency of the miniature potentials together suggest that the action of X-rays is to block conduction in the nerve near its terminals, possibly by depolarizing points where the axons branch and the safety factor for the propagation of impulses is low. The results reported in this paper do not support the hypotheses that small doses of X-rays at a high or a low dose-rate lead to an initial 'enhancement' of function or that they produce immediate and reversible changes in the permeability of excitable membranes to ions.

scholarly journals SUN-042 Low Dose Cyproterone Acetate for the Treatment of Transgender Women - a Retrospective Study

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Naomi Even-Zohar ◽  
Yael Sofer ◽  
Iris Yaish ◽  
Merav Serebro ◽  
Karen Tordjman ◽  
...  
Keyword(s):  
Cyproterone Acetate ◽  
Dose Group ◽  
Low Dose ◽  
Dose Range ◽  
Hormonal Treatment ◽  
Transgender Women ◽  
High Dose ◽  
Historical Cohort ◽  
Treatment Groups ◽  
First Time

Abstract Introduction : Transgender women with intact gonads receive lifelong hormonal treatment in order to suppress physiologic androgen production. Cyproterone acetate (CA) is the most comon antiandrogenic drug prescribed for this indication in Europe, with a dose range between 25-100 mg/day. Aim: To assess the effectiveness and safety of low dose (&lt;20 mg/day), compared with high dose (&gt;50 mg/day) CA treatment. Methods: Historical cohort study of transgender women treated in our department between January 2000 and October 2018. Results: There were 42 transgender women in the low dose group (LDG) and 32 in the high dose group (HDG). Age (27.9 ± 1.6 vs.28.9 ± 1.7 years) and follow up time (16.2 ± 2.2 vs. 20.1 ± 2.1 months) were similar in the LDG and HDG, respectively. At the last available visit, testosterone levels were effectively and similarly suppressed in both treatment groups (0.6 ± 0.1 vs 0.8 ± 0.3 nmol/l; p=0.37, for LDG and HDG respectively). Prolactin (659 ± 64 vs 486 ± 42 mIU/ml, p=0.02), LDL cholesterol (96.1 ± 5 vs 78.5 ± 4 mg/dl, p= 0.02) and triglycerides (93.3 ± 9 vs 69 ± 5 mg/dl; p=0.02) were higher in the HDG compared with LDG respectively. Side effects were common in the HDG (four cases of increased liver enzymes, one case of pulmonary embolism and one case of sudden death). Conclusion: We show for the first time that anti-androgenic treatment of transgender women with low dose CA is as effective as high dose treatment, but safer. We suggest incorporation of this observation in future guidelines.

scholarly journals Carbidopa for Afferent Baroreflex Failure in Familial Dysautonomia

Hypertension ◽  
2020 ◽  
Vol 76 (3) ◽  
pp. 724-731
Author(s):  
Lucy Norcliffe-Kaufmann ◽  
Jose-Alberto Palma ◽  
Jose Martinez ◽  
Horacio Kaufmann
Keyword(s):  
Blood Pressure ◽  
Blood Pressure Variability ◽  
Low Dose ◽  
Familial Dysautonomia ◽  
Reduce Blood Pressure ◽  
Catecholamine Release ◽  
High Dose ◽  
Double Blind ◽  
Adequate Treatment ◽  
Baroreflex Failure

Afferent lesions of the arterial baroreflex occur in familial dysautonomia. This leads to excessive blood pressure variability with falls and frequent surges that damage the organs. These hypertensive surges are the result of excess peripheral catecholamine release and have no adequate treatment. Carbidopa is a selective DOPA-decarboxylase inhibitor that suppresses catecholamines production outside the brain. To learn whether carbidopa can inhibit catecholamine-induced hypertensive surges in patients with severe afferent baroreflex failure, we conducted a double-blind randomized crossover trial in which patients with familial dysautonomia received high dose carbidopa (600 mg/day), low-dose carbidopa (300 mg/day), or matching placebo in 3 4-week treatment periods. Among the 22 patients enrolled (13 females/8 males), the median age was 26 (range, 12–59 years). At enrollment, patients had hypertensive peaks to 164/116 (range, 144/92 to 213/150 mm Hg). Twenty-four hour urinary norepinephrine excretion, a marker of peripheral catecholamine release, was significantly suppressed on both high dose and low dose carbidopa, compared with placebo ( P =0.0075). The 2 co-primary end points of the trial were met. The SD of systolic BP variability was reduced at both carbidopa doses (low dose: 17±4; high dose: 18±5 mm Hg) compared with placebo (23±7 mm Hg; P =0.0013), and there was a significant reduction in the systolic BP peaks on active treatment ( P =0.0015). High- and low-dose carbidopa were similarly effective and well tolerated. This study provides class Ib evidence that carbidopa can reduce blood pressure variability in patients with congenital afferent baroreflex failure. Similar beneficial effects are observed in patients with acquired baroreflex lesions.

INITIAL STUDIES IN MAN WITH A NOVEL THROMBOXANE RECEPTOR BLOCKING DRUG GR32191

1987 ◽  
Author(s):  
M Thomas ◽  
P Lumley ◽  
P Ballard ◽  
J R O'Brien
Keyword(s):  
Platelet Aggregation ◽  
Bleeding Time ◽  
Ex Vivo ◽  
Plasma Concentrations ◽  
Blocking Drug ◽  
Double Blind ◽  
Receptor Blocking ◽  
Thromboxane Receptor ◽  
Pre Treatment ◽  
Induced Aggregation

In-vitro GR32191 is a potent and specific thromboxane receptor blocking drug on platelets, and vascular and airways smooth muscle (Lumley et al this meeting). We have undertaken studies in healthy male subjects (n) to examine the effects of oral GR32191 upon platelet aggregation ex-vivo and template bleeding time. Platelet aggregation was monitored in whole blood by counting platelets electronically. Concentration-effect curves to U-46619 and ADP were constructed prior to and following drug or placebo. The degree of rightward displacement of a curve due to treatment was expressed as a concentration-ratio (CR) which was calculated at the 50% aggregation level (ECso post-treatment ECso pre-treatment). Plasma concentrations of GR32191 were determined by h.p.l.c. After single doses of GR32191 mean peak CR's of 8 and 80 were achieved with 0.125 and 0.25mg/kg (n=4) and values of 74 and 234 with 0.5 and lmg/kg (n=4). Peak effects were seen within 2 hours of dosing while activity was still present between 8 and 24 hours. ADP-induced aggregation was unaffected by drug (CR<2) and placebo was without significant effect upon the sensitivity to either aggregating agent (CR<2). GR32191 was rapidly absorbed and the plasma elimination half-life was about 2 hours. GR32191 17.5mg 12-hourly for 10 days (n=6) produced a progressive antagonism of U-46619 induced aggregation which resulted in a large continuous blockade in all subjects (range of 12htrough CR's 85 to 287). However, plasma concentrations of GR32191 did not accumulate on repeated administration. In a double-blind, placebo-controlled, cross-over study (n=16), a statistically significant (p= 0.002) increase in bleeding time was seen following treatment with GR32191 40mg twice daily for 7 days (pre-treatment mean 3.79 min, post-placebo mean 3.47 min, post-GR32191 mean 5.42 min). Rectal bleeding (n=l) has occurred with GR32191 but otherwise tolerability has been good. No drug related changes have been seen in routine laboratory safety screens. Clinical studies are in progress.

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