Noninvasive measurement of portal venous blood flow in patients with cirrhosis

The present study aims to evaluate the usefulness of combined pulse Doppler-real-time ultrasonography as a noninvasive method for the measurement of portal blood flow in man. This measurement technique was performed on 12 healthy subjects and 20 patients with portal hypertension. Ten patients (group 1) were evaluated prior to and after ingestion of a standard meal (Ensure Plus) or placebo. In the remaining 10 patients (group 2), the effects of isosorbide dinitrate (5 mg/SL) administration or placebo were studied. In group 1, food intake caused a significant increase of portal blood flow (from 1038±539 to 1572±759 ml/min,P<0.02); this effect was due to a significant rise in mean blood velocity (from 18.5±3.7 to 23.9±3.9 cm/sec,P<0.02). In group 2, isosorbide dinitrate significantly reduced portal blood flow (from 985±491 to 625±355 ml/min,P<0.05); a significant decline of mean blood velocity (from 18.8 ±4.5 to 14.5±2.5 cm/sec,P<0.02) was observed. Placebo administration had no significant hemodynamic effects in either group. Our results suggest that Doppler measurements gave accurate noninvasive estimations of portal blood flow and that this technique may be used to monitor physiological and pharmological stimuli in patients with portal hypertension.     

硝酸异山梨酯(消心痛)皮肤喷雾剂防治心绞痛的效果

硝酸异山梨醋(消心痛)皮肤喷雾剂治疗39例稳定性心绞痛的疗效达79.5%,作HoIler监测减少心肌缺血发作有效率为73.4%,运动耐量在喷药后有改善(占79%)。本药具有使用简便、作用时间持久,副作用小、无皮肤过敏等优点。     

Blood volume and right heart haemodynamics in abrupt hypotension following sublingual isosorbide dinitrate in acute myocardial infarction

Arterial blood pressure and heart rate were measured in 43 patientswith acute myocardial infarction and a systolic blood pressure120 mmHg during sublingual administration of 5 mg of isosorbidedinitrate. In 25 of them right heart haemodynamics were alsomeasured. Severe (25%) hypotension developed in 12 patients(Group 1, systolic blood pressure 158 ± 28 to 78 ±17 mmHg, mean ± SD) but not in the remaining 31 (Group2) and was accompanied by a fall in heart rate (82 ±20 to 70 ± 22beats min^-1, P<0.05), in cardiac output(4.3 ± 0.3 to 3.2 ± 0.4l mm^-1, P<0.02, n =5) and in systemic vascular resistances (2326 ± 463 to1532 ± 442 dynes sec^-1 cm^-5, P<0.02) not present inGroup 2. The reduction in right (Group 1,8 ± 3 to 3 ±1, vs. Group 2,10 ± 3 to 6± 3 mmHg, V <0.005)and in left ventricular filling pressures (Group 1,15 ±4 to 8 ± 2, vs. Group 2,18 ± 6 to 13 ±5 mmHg, P<0.001) was more remarkable in Group 1. In thisgroup there was also a high incidence of anterior infarction(9/12, 75%). Blood volume measured in 30 patients was lowerin Group 1 but differences were not significant. A second doseof 5 mg of isosorbide dinitrate 36–48 h later producedneither symptomatic hypotension (Group 1, 147 ± 29 to129 ± 24 mmHg) nor a fall in cardiac output in any patient,whereas changes infilling pressures were comparable to thoseof the first dose. Thus, severe isosorbide dinitrate-induced hypotension in myocardialinfarction is limited to the acute phase and seems more prevalentin anterior infarction but can not be clearly predicted fromresting haemodynamic or blood volume measurements, at leastin non-hypotensive patients. Moreover, it appears to be causedby an excessive ventricular emptying due to a striking venousand arterial vasodilation, probably during a stage of a particularlydepressed ventricular compliance.     

Treatment of infarct related heart failure: Vasodilators other than ACE inhibitors

Summary Vasodilator drugs, particularly intravenously infused nitroprusside and an orally administered combination of hydralazine and isosorbide dinitrate, exert a profoundly favorable hemodynamic effect in the setting of heart failure complicating a prior myocardial infarction. Although these oral drugs also may relieve symptoms and improve exercise tolerance, the long-term benefits appear to be related to inhibition or reversal of the left ventricular dilation that results in a progressive fall in left ventricular ejection fraction. The long-term efficacy of both ACE inhibitors and hydralazine-nitrate in symptomatic heart failure makes the vasodilator combination a rational alternative to an ACE inhibitor and possibly an effective agent for cotherapy with an ACE inhibitor. Trials are needed to test the additive efficacy of this vasodilator combination and to develop other safe and effective drugs that target the progressive remodeling process in heart failure.     

Ointments and transdermal nitroglycerin patches for stable angina pectoris

Summary Nitroglycerin (NTG) ointment is used for the prophylaxis against angina pectoris, but there are no data to support its effectiveness during long-term therapy. Continuous, once-daily application of isosorbide dinitrate cream produces tolerance with complete loss of efficacy within 1 week. Nitroglycerin patches are very popular and continuous once-daily application is still claimed by some investigators to provide 24 hour antiischemic and antianginal efficacy. This claim is based on data from postmarketing studies in a very large number of patients and placebo-controlled studies in smaller groups of patients from Italy, Yugoslavia, Greece, and Germany. In contrast, studies from the United States, Canada, England, and some centers in Germany have failed to show superiority of patches over placebo during continuous therapy. This controversy was addressed by the NTG cooperative study group, in which a total of 562 patients who were responders to sublingual nitroglycerin were studied. Patients received either placebo or NTG patches delivering low (15–30 mg/24 hr), moderate (45–60 mg/ 24 hr), or large (75 and 105 mg/24 hr) amounts of NTG. Four hours after the initial application, NTG patches increased exercise duration compared to placebo, but this beneficial effect had disappeared by 24 hours. Furthermore, after 8 weeks of continuous therapy, none of the NTG patches were superior to placebo, whether patients were or were not taking concomitant beta-blockers. Therefore, current opinion is that continous therapy with NTG patches produces pharmacologic tolerance and is ineffective. Pharmacologic tolerance can be minimized when patches are applied every morning and removed after 10–12 hours at night. However, patches delivering >15 mg NTG/24 hr are required to maintain an increased exercise duration for up to hour 8 after the patch application. Intermittent therapy with patches, however, may lead to rebound nocturnal angina in some patients. Also, intermittent therapy with patches has been associated with worsening of exercise performance in the morning prior to the patch renewal, compared to therapy with placebo patches. This has been referred to as the zero-hour effect and probably represents a rebound phenomenon following nitrate withdrawal. Patients experiencing either nocturnal or early morning angina during intermittent therapy with patches should either be switched to oral long-acting nitrates or should in addition be treated with a beta-blocker, provided there are no contraindications to beta-blocker treatment.The opinions expressed here are those of the authors and should not be taken as those of FDA.     

CARDIOVASCULAR EFFECTS OF ISOSORBIDE DINITRATE INFUSED INTRAVENOUSLY INTO ANAESTHETIZED DOGS

The cardiohaemodynamic response and the development of tolerance to isosorbide dinitrate (ISDN) were examined in anaesthetized, open-chest dogs. ISDN, infused intravenously (i.v.) for 2 h at a rate of 10 or 30 micrograms/kg per min, decreased systemic blood pressure (systolic, mean and diastolic; SBP), left ventricular (LV) systolic and end-diastolic pressure, LVdP/dt max, pressure-rate product and coronary blood flow. No significant changes in heart rate (HR) and coronary vascular resistance were observed. Intravenous ISDN significantly attenuated the vasodilator effect of bolus intracoronary (i.a.) glyceryl trinitrate (GTN, 1 micrograms), and ISDN (30 micrograms), whereas that of bolus i.a. nicorandil (mononitrate, 20 micrograms) remained unaffected. Just after acute tolerance towards i.a. ISDN was provoked 1 h after starting ISDN infusion (30 micrograms/kg per min, i.v.), the combined infusion of ISDN (i.v.) and nicorandil (30 micrograms/kg per min) was instigated for a further hour. Also, 1 h after the onset of vehicle infusion (i.v.), the combined infusion of vehicle and nicorandil (30 micrograms/kg per min, i.v.) was started. There were essentially no significant differences between the corresponding values concerning the coronary vascular responses obtained from the two combined infusion groups.     

那屈肝素钙与硝酸异山梨酯或葛根素治疗不稳定性心绞痛的临床疗效

目的 :探索抗栓治疗基础上加用硝酸异山梨酯或葛根素治疗不稳定性心绞痛的临床疗效。方法 :将 5 5例不稳定性心绞痛 (UA)患者随机分为 :A组 30例 (男 2 1例 ,女 9例 ) ,年龄 (6 2 6± 12 9)a ,予那屈肝素钙 0 4～ 0 6mL ,sc,bid ,持续 7d ,硝酸异山梨酯 10mg 5 %GS 5 0 0mL ,ivgtt,qd ,持续 14d ;B组 2 5例 (男 17例 ,女 8例 ) ,年龄 (6 5 5 10 3)a ,在那屈肝素钙治疗基础上加用葛根素葡萄糖注射液 2 5 0mL ,ivgtt,qd ,持续 14d。结果 :A组临床疗效的总有效率为 90 % ,与B组疗效 (6 0 % )相比 ,P <0 0 1;A组ECG改善 80 % ,优于B组 5 6 % (P <0 0 5 )。B组治疗后凝血酶原时间 (PT)及激活型部分凝血活酶时间 (APTT)均延长 ,而纤维蛋白原 (Fg)、血小板聚集率 (PAR)和血浆黏度 (PV)均下降 ;A组治疗后PAR及PV均下降 ,而PT ,APTT和Fg无显著变化。结论 :在那屈肝素钙治疗基础上加用硝酸异山梨酯或葛根素对UA的早期治疗都有良好的抗栓及临床疗效     

Effect of sublingual isosorbide dinitrate on sputum volume and viscoelasticity in chronic obstructive lung disease

Summary The effect of isosorbide dinitrate (ISDN) on sputum volume and sputum viscoelasticity in 12 patients with chronic obstructive lung diseases (COLD) was investigated by the double-blind randomized cross-over method with matched placebo. Each patient was given either sublingual ISDN 5 mg or placebo at 9 a.m. and sputum was collected for 3 h before and after 9 a. m. The dynamic viscoelasticity of the sputum was measured using a coaxial cylinder rheometer at an angular frequency of 0.1 rad/s. ISDN significantly increased sputum volume, and it caused a significant decrease in dynamic viscosity and in dynamic elasticity compared to placebo. The findings suggest that ISDN might be useful as an expectorant in the treatment of COLD when abundant and viscous sputum is present.     

Nitroglycerin dinitrate metabolites do not affect the pharmacokinetics and pharmacodynamics of nitroglycerin in the dog: A preliminary report

Studies were carried out in conscious dogs to determine the effects of 1,2-glyceryl dinitrate (1,2-GDN) and 1,3-glyceryl dinitrate (1,3-GDN) on nitrogtycerin (GTN) pharmacokinetics and pharmacodynamics. In the first set of experiments, steady state plasma levels (Css) of either 1,2-GDN or 1,3-GDN in three dogs were rapidly achieved by giving an iv bolus (77 g/kg), followed immediately by an infusion (50 g/min) of the same GDN. A single iv bolus dose of GTN (0.025 g/kg) was given 50 min after beginning the GDN infusion and compared with plasma concentrations following a similar GTN dose in the absence of dosed GDNs. No significant differences in GTN AUC (p0.9) and CL_app (p 0.7) were found. In a second set of experiments, an infusion of nitroglycerin was begun in each of 4 dogs and continued for 160 min at an infusion rate of 100 gm/min. Steady state concentrations of GTN were achieved within 100 min, at which time the dog received, simultaneously, an iv bolus dose (5.14 mg) of one of the GDNs and an infusion dose (100 gmg/min) of the same GDN. For both dinitrate metabolites no significant differences (p 0.5) were found between control and interaction arterial and venous clearances, although venous GTN clearances tended to decrease in the presence of dosed GDNs. Steady state systolic blood pressure during GDN infusions could be further reduced when GTN doses were administered; however, the steady state systolic blood pressure decrease caused by GTN could not be further reduced by the GDN infusions. Results suggest that the GDNs do not inhibit nitroglycerin metabolism or hemodynamics at the dose levels studied here.Supported in part by National Institutes of Health Grant HL32243.     

Massive ingestion of isosorbide-5-mononitrate and nitroglycerin: suicide attempt by an adolescent girl without previous heart disease

High plasma levels of isosorbide-5-mononitrate were found ina young girl who had ingested 1.6 g of the drug plus 20mg ofnitroglycerin. These concentrations produced no disturbanceof the patient's state of consciousness and no serious haemodynamiceffects appeared except for a tachycardia in relation to peripheralvasodilatation.