Pulmonary haemodynamics during exercise after low and high doses of acetylsalicylic acid in sheep

Despite comparable increases in cardiac output there is a greater reduction in pulmonary vascular resistance (PVR) in sheep during exercise than in dog or man. The mechanism for this marked reduction in PVR in sheep is unknown. To assess the role of arachidonic acid metabolites in producing this low PVR we measured the effect of intravenous acetylsalicylic acid (ASA, 10 mg/kg) on PVR at rest and during exercise in sheep. ASA caused a slight rise in resting PVR (p less than 0.05), but did not affect the exercise-induced decrease in PVR. High-dose ASA (100 mg/kg), presumably sufficient to block the lipoxygenase pathway produced the same responses as low-dose ASA which should only block the cyclo-oxygenase pathway. Products of the cyclo-oxygenase and lipoxygenase pathways which include vasodilator prostaglandins, have only a minor role in maintaining low pulmonary vascular resistance at rest and have no demonstrable role in the reduced PVR that occurs during exercise in sheep.     

The effects of different doses of some acetylsalicylic acid formulations on platelet function and bleeding times in healthy subjects

In an attempt to find the most appropriate dose and formulation(s) of acetylsalicylic acid (ASA) for thrombosis prophylaxis, healthy volunteers were given doses of ASA for 1 wk daily ranging from 50 to 3900 mg as either Aspro-Clear (soluble), Astrix (enteric coated pellets) or Ecotrin (enteric coated tablets). Platelet function and bleeding times were monitored. All doses of ASA significantly inhibited platelet function (p less than 0.05) and increased bleeding times (p less than 0.05) relative to control values. Irrespective of the formulation, maximum increases in bleeding time and platelet dysfunction were obtained with daily doses of about 100 mg, and no further changes were observed with higher doses.     

不同剂量阿司匹林抗血小板治疗老年冠心病的临床研究

目的 研究老年冠心病患者不同时间间隔,服用不同剂量阿司匹林抗血小板的疗效和安全性.方法 120例老年冠心病患者随机分成6组:阿司匹林75 mg,每天一次(75 mg/qd)组,阿司匹林100 mg,隔天一次(100 mg/qod) 组,阿司匹林100 mg,每天一次(100 mg/qd)组,阿司匹林150 mg,隔天一次(150 mg/qod) 组,阿司匹林150 mg,每天一次(150 mg/qd)组,对照组.服药7 d后,观察服药前后各组血小板聚集率、白细胞、血小板数目、止凝血指标的变化.结果 与对照组比较,各组对血小板聚集有显著的抑制作用.组间比较,阿司匹林75 mg/qd和阿司匹林100 mg/qod;阿司匹林100 mg/qd和阿司匹林150 mg/doq比较,服药前后血小板聚集率的差值无显著差异(P＞0.05).各组服药前、7 d后白细胞、血小板数目、止凝血指标无显著变化(P＞0.05).阿司匹林75 mg/qd组与阿司匹林150 mg/qd组比较,服药7 d后血小板聚集率差异显著(P＜0.05).结论 老年冠心病患者服用阿司匹林75 mg/qd和阿司匹林100 mg/qod能起到同样抗血小板作用;同样阿司匹林100 mg/qd和阿司匹林150 mg/qod抗血小板的疗效相同,且较安全.     

Immune reconstitution after haematopoietic transplantation with two different doses of pre-graft antithymocyte globulin

Antithymocyte globulin is widely used before haematopoietic transplantation with HLA-matched unrelated donors or mismatched relatives to prevent rejection and graft-versus-host disease (GVHD). However, optimal dosage is still under debate. Thirty-one consecutive children, mainly with haematological malignancies, were transplanted in a single institution with such donors, selected by HLA-A -B compatibility by serology and DRB1* by DNA typing. Antithymocyte globulin (Thymoglobuline; Sangstat) was infused at days -3, -2, -1. Total dosage varied: 16 patients received a median of 7.5 mg/kg (2.5 to 10.5: low-dose group), and 15 a median of 15.5 mg/kg (14.4 to 19.4: high-dose group). Post-transplant GVHD prophylaxis consisted of cyclosporine, short-course methotrexate and steroids. CD3(+), CD4(+) and CD19(+) cell reconstitution was slower in the high-dose group. Median time to reach 100 CD4(+) cells was 8 months vs 4 months (P = 0.03). Median time to normal CD19(+) cells was 16 months vs 8 months (P = 0.01). CD16(+)CD56(+) and CD8(+) cell reconstitution was similar. Nine patients in the high-dose group and two in the low-dose group experienced life-threatening opportunistic infections (P = 0.009). Although obtained from a limited number of patients, our data suggest that a higher pre-graft dose of antithymocyte globulin may negatively influence immune reconstitution.     

Oral nitroglycerin in angina pectoris—Evaluation of effect by computerized exercise testing using two different doses

Summary The antianginal effects of sustained-released oral nitroglycerin were evaluated in patients with chronic stable angina using a double-blind randomized protocol. Nineteen patients were inducted into the trial and 17 of these completed the study. Two doses of oral nitroglycerin were used; 2.6 mg and 6.5 mg given three times daily for a period of 2 weeks, the patients crossing over to the alternative dose at the end of each period. Evaluation of effect was carried out 2 hours after the morning dose using graded treadmill exercise testing with on-line computer analysis of the electrocardiogram (EKG) (CASE, Marquette Electronics, Inc.). Various exercise parameters were measured and the results compared to placebo values and between the two dosages. The aim was to demonstrate an antianginal effect and to look for a dose-response relationship and for attenuation of effect if any on continued administration. The mean±SEM exercise time on placebo was 6.7±0.6 min, increasing to 8.6±8 min (p<0.02) with 2.6 mg tds dosage and 8.4±0.7 min (p<0.01) with 6.5 mg tds of oral nitroglycerin. None of the other exercise-derived indices were altered significantly by oral nitroglycerin. Two patients were withdrawn because of severe headaches and both were receiving the higher dose. The data did not demonstrate and dose-response relationship but confirmed the anti-anginal efficacy of sustained action oral nitroglycerin. This efficacy did not show any significant attenuation of effect on continued administration, indicating a possible lack of development of tolerance.     

The effect of acetylsalicylic acid resistance on prognosis of patients who have developed acute coronary syndrome during acetylsalicylic acid therapy

AIM: The relationships between clinical events and acetylsalicylic acid resistance (AR), as well as its frequency, have been established in stable patients with coronary artery disease (CAD). Although acute coronary syndrome (ACS) patients taking acetylsalicylic acid have been accepted as a high-risk population, the role of AR has not been investigated in these patient groups. Thus, in the present study, the impact of AR was investigated in patients with ACS who were taking acetylsalicylic acid. METHODS: Between January 2001 and February 2003, 140 ACS patients were included in the present prospective study. All patients had ACS while taking acetylsalicylic acid. Coronary angiographic scores for severity and extent of CAD were determined for all patients. The effect of acetylsalicylic acid on platelet function was assessed by the platelet function analyzer PFA-100 (Dade Behring, USA). The primary end point was the composite of death, myocardial infarction, cerebrovascular accident and revascularization. The mean follow-up period was 20 months. RESULTS: Patients with AR were older than patients without AR (63.8+/-10.8 years versus 58.3+/-11.2 years; P=0.005). Moreover, myocardial damage was higher in patients with AR according to cardiac troponin T values (1.11+/-1.3 mug/L versus 0.41+/-0.5 mug/L; P=0.01). The composite end point of death, myocardial infarction, cerebrovascular accident or revascularization was present in 16 of 45 patients (35%) with AR and in 13 of 79 patients (16%) without AR (hazard ratio 2.46, 95% CI 1.18 to 5.13; P=0.016). After adjustment for age, platelet count, cardiac troponin T value and CAD severity score, AR remained an independent predictor for long-term adverse events (hazard ratio 3.03, 95% CI 1.06 to 8.62; P=0.038). CONCLUSIONS: The clinical event rate was found to be higher in ACS patients with AR than in those without AR. Thus, it may be concluded that there is a strong correlation between a worse prognosis and AR in these patients.     

Platelet function during cardiopulmonary bypass not changed by two different doses of aprotinin

BACKGROUND AND OBJECTIVE: Bleeding is one of the major complications of cardiopulmonary bypass (CBP) during cardiac surgery. A platelet function defect seems to be the main cause of the hemostatic problems associated with CBP. Controversial results have been reported concerning the possible protective mechanism of action of aprotinin on platelets. DESIGN AND METHODS: In this study we investigated the effect of two different dosages of aprotinin (high and pump-prime-only dose) on platelet reactivity in vitro and adhesion, activation and aggregation receptors on the platelet surface. RESULTS: The results obtained from 53 patients undergoing CBP showed a significantly deficient platelet aggregation in response to agonist in all groups without differences between aprotinin treated or not treated patients. No changes in platelet surface expression of glycoprotein (GP) IIb-IIIa, GPIb, GPIV and P-selectin, were observed during CBP between patients treated with aprotinin or not. INTERPRETATION AND CONCLUSIONS: These data suggest that inadequate platelet function induced by CBP is not a defect intrinsic to the platelet. We conclude that the hemostatic effect of aprotinin, regardless of the dose employed, is not mediated by protection of platelet function.     

Plasma, erythrocyte and urine concentrations of chlorproguanil and two metabolites in man after different doses

Failures in the prophylactic effect of the antimalarial biguanide chlorproguanil (Lapudrine) may be caused by insufficient levels of its active metabolite chlorcycloguanil. Concentrations of chlorproguanil, chlorcycloguanil and a second metabolite, dichlorophenylbiguanide, in plasma, erythrocytes and urine, were followed in 13 volunteers, using a HPLC assay. In an initial study the basic kinetics were investigated after an oral dose of 2 mg kg-1. In the main study, the concentration-time curves were followed for 1 week after an oral dose of 20 or 80 mg chlorproguanil, respectively, after either a single dose or one weekly dose for 5 weeks. Higher concentrations of all three compounds were found in erythrocytes than in plasma. The active substance, chlorcycloguanil, was below the probably effective concentration in erythrocytes 24 h after 20 mg chlorproguanil and 72 h after 80 mg. The urinary recovery was about 45% of the dose and t1/2 31-44 h, both higher than previously reported. The apparent clearance was 0.52-0.82 l h-1 kg-1, which is lower than previously found. It is suggested that improved dose regimens, e.g. a higher dose given once a week, should be clinically tested on basis of these kinetic results.     

Serum bile acid determination after different doses of orally ingested chenodeoxycholic acid. Evaluation of a simplified enzymatic method

A simplified enzymatic method for determination of serum 3 alpha-hydroxy bile acids (3 alpha-HBA) has been evaluated. Analytical precision was low in the normal range but satisfactory for elevated values. The fasting upper reference value was 8.0 mumol/l. In 12 healthy subjects serum 3 alpha-HBA levels were measured after oral loads (125, 250, 500, and 1000 mg) of unconjugated chenodeoxycholic acid (CDA). After the 125-mg CDA loading dose no significant increase in serum 3 alpha-HBA was observed, but with the 250 mg CDA loading dose serum 3 alpha-HBA levels were elevated at 30, 60, and 120 min. The loading doses of 500 mg and 1000 mg CDA produced significant increases in serum 3 alpha-HBA levels throughout the observation period (3 h). When sera with increased serum bile acids were analyzed by radioimmunoassay for CDA, the results correlated well with those obtained enzymatically. The usefulness of the simplified method is evident in this situation, and we also find it useful for serum bile acid determination after an oral bile acid loading test with CDA. The method is easy to perform and requires only standard laboratory equipment.     

Protection after two doses of measles vaccine is independent of interval between doses.

The protection provided by one or two doses of measles vaccine was compared, as was the effect of the timing of delivery of the doses on the protection provided. A total of 5542 measles cases occurred in Ontario, Canada, between January 1990 and December 1996. Three controls per case were matched for age and residence. Children who received a single dose at age 15 months and older were 5 times more likely to contract measles than were children who received two doses of vaccine after their first birthday. Among children given two doses of vaccines, the risk of measles was 3 times greater in those who had their first vaccination at age 11 months compared with children who first received vaccine after age 1 year, but the protection was independent of the interval between doses. Delaying the second dose >6 months after the first does not increase protection.     

Treatment of GH-deficient children with two different GH doses: effect on final height and cost-benefit implications

OBJECTIVE: Treatment of GH-deficient (GHD) children with higher doses of recombinant human GH (rhGH) than conventional ones has been reported to result in higher growth velocity and increased final height. These findings, however, were observed by comparing large but heterogeneous groups of children. We wanted to verify whether the same results could be obtained in two groups of appropriately well-matched children with isolated GHD treated with high vs conventional doses of rhGH. METHODS: Out of two cohorts of GHD children, cohort A (on a weekly rhGH dose of 0.3 mg/kg body weight) and cohort B (on a weekly rhGH dose of 0.15 mg/kg body weight), we selected two groups, each including 13 patients, who before treatment were matched for age, sex and height standard deviation score (SDS). They were followed up until final height. RESULTS: Final height SDS was significantly higher in group A (-0.45+/-0.36 (s.d.) vs -1.07+/-0.7; P=0.008), as well as height gain SDS (1.81+/-0.58 vs 1.23+/-0.62; P=0.002). The difference between final height SDS and target height SDS was positive only in group A and significantly higher in group A than in group B (0.33+/-0.51 vs -0.46+/-0.7; P=0.01). Glucose tolerance was always normal in the group treated with higher doses. CONCLUSION: The final height of children treated with higher doses of rhGH is increased, also in relation to their genetic target. The economical burden of this choice of treatment, however, has to be taken into account when evaluating the results.     

Clinical effects of different protamine doses after cardiopulmonary bypass

The optimal dose of protamine needed to reverse the anticoagulant effect of heparin after cardiopulmonary bypass is still not known. In this retrospective cohort study, we investigated 3 different dose regimes in 300 patients undergoing coronary artery bypass grafting. Group A patients (n = 100) were given protamine in the ratio of 1.3 mg to 1 mg heparin, group B patients (n = 100) were given 0.75 mg protamine to 1 mg heparin, and group C patients (n = 100) were given protamine in fractionated doses of 1 mg + 0.15 mg + 0.15 mg to 1 mg heparin. The groups were comparable in all major clinical and operative variables. The heparin dose was almost identical in the groups. The rate of red cell transfusion was significantly higher in group B than in the other groups. A similar but nonsignificant trend was observed in the incidence of resternotomy for postoperative bleeding, mediastinal drainage, and postoperative hemoglobin loss. The study demonstrates that a single bolus dose of 1.3 mg protamine to 1 mg heparin is safe and efficient for neutralizing heparin after cardiopulmonary bypass.     

The bentiromide test using plasma p-aminobenzoic acid for diagnosing pancreatic insufficiency in young children. The effect of two different doses and a liquid meal

The bentiromide test was evaluated using plasma p-aminobenzoic acid as an indirect test of pancreatic insufficiency in young children between 2 months and 4 years of age. To determine the optimal test method, the following were examined: (a) the best dose of bentiromide (15 mg/kg or 30 mg/kg); (b) the optimal sampling time for plasma p-aminobenzoic acid; and (c) the effect of coadministration of a liquid meal. Sixty-nine children 91.6 +/- 1.0 years) were studied, including 34 controls with normal fat absorption and 35 patients (34 with cystic fibrosis) with fat maldigestion due to pancreatic insufficiency. Control and pancreatic insufficient subjects were studied in three age-matched groups: (a) low-dose bentiromide (15 mg/kg) with clear fluids; (b) high-dose bentiromide (30 mg/kg) with clear fluids; and (c) high-dose bentiromide with a liquid meal. Plasma p-aminobenzoic acid was determined at 0, 30, 60, and 90 minutes then hourly for 6 hours. The dose effect of bentiromide with clear liquids was evaluated. High-dose bentiromide best discriminated control and pancreatic insufficient subjects, due to a higher peak plasma p-aminobenzoic acid level in controls, but poor sensitivity and specificity remained. High-dose bentiromide with a liquid meal produced a delayed increase in plasma p-aminobenzoic acid in the control subjects probably caused by retarded gastric emptying. However, in the pancreatic insufficient subjects, use of a liquid meal resulted in significantly lower plasma p-aminobenzoic acid levels at all time points; plasma p-aminobenzoic acid at 2 and 3 hours completely discriminated between control and pancreatic insufficient patients. Evaluation of the data by area under the time-concentration curve failed to improve test results. In conclusion, the bentiromide test is a simple, clinically useful means of detecting pancreatic insufficiency in young children, but a higher dose administered with a liquid meal is recommended.