Transdermal nitroglycerin in angina pectoris

Stress is sometimes involved in cardiac patients when a number of different drugs are necessary for treatment that are taken in a variety of dose regimes. Any new method for drug delivery that can relieve some of this stress is therefore of interest. Such a preparation is glyceryl trinitrate (GTN) in the form of a skin patch (Transiderm-Nitro) and this was compared to placebo in a double-blind cross-over trial. Following a one-week control period, patients were randomly allocated to three weeks treatment with placebo followed by three weeks with Transiderm-Nitro (1–15 mg in 24 h) or vice versa. Analysis was performed on 77 cases, 37 in the placebo first group (group A) and 40 in the Transiderm-Nitro first group (group B). Irrespective of treatment order, mean weekly anginal attack rates and GTN requirements were significantly less on the active patch than on placebo. Thus, there was a 21 per cent reduction in anginal attacks on placebo but 53 per cent reduction on Transiderm-Nitro (p<O.OOl); while the mean GTN requirement was reduced by 29 per cent on placebo but 56 per cent on Transiderm-Nitro (p<O.OOl). There were no significant changes in pulse rate or recumbent or upright blood pressure. Patients' preferences (blind) were in favour of Transiderm-Nitro (p<O.OOl). The most frequent side-effect was headache, which occurred in 22 per cent of patient; on Transiderm-Nitro but in only 3 per cent on placebo (p<O.Ol). Skin rashes occurred in 5 per cent on Transiderm-Nitro and 4 per cent on placebo (NS). This short-term trial demonstrated highly significant effects from the transdermal GTN preparation in comparison to placebo.     

INHIBITION OF NITRIC OXIDE SYNTHASE SPECIFICALLY ENHANCES ADRENERGIC VASOCONSTRICTION IN RABBITS

1. The effect of inhibition of nitric oxide biosynthesis using N-nitro-L-arginine (NOLA) was examined in conscious rabbits and rabbit isolated aortae. 2. In autonomically blocked conscious rabbits intravenous infusion of NOLA (15 mg/kg) significantly increased arterial pressure and hindlimb vascular resistance but did not affect heart rate. Depressor and hindlimb vasodilator responses to acetylcholine (3-12 micrograms/kg per min) were significantly attenuated in the presence of NOLA. In contrast, NOLA significantly enhanced responses to intravenous infusion of glyceryl trinitrate (10-40 micrograms/kg per min) in vivo. 3. Infusion of noradrenaline (1-4 micrograms/kg per min) or the release of neuronal noradrenaline in response to the infusion of tyramine (80-320 micrograms/kg per min) increased arterial pressure and hindlimb vascular resistance in autonomically blocked conscious rabbits. After the administration of NOLA, the vasoconstrictor responses to both noradrenaline and tyramine were significantly enhanced. 4. In isolated rabbit aortae, NOLA (10 mumol/L) significantly impaired relaxant responses to acetylcholine but did not affect responses to glyceryl trinitrate. NOLA enhanced contractile responses to the adrenoceptor agonists noradrenaline and phenylephrine but did not affect the contractile responses to the thromboxane-mimetic U46619. 5. These data indicate that in autonomically blocked conscious rabbits, NOLA causes systemic vasoconstriction, impairs dilator responses to acetylcholine and enhances dilator responses to glyceryl trinitrate. In addition, NOLA enhances constrictor responses to both exogenous and neuronally-released noradrenaline. These results suggest that nitric oxide is important in the regulation of normal vascular tone and in the modulation of vascular responses to vasodilator and vasoconstrictor agents.     

Sex-related difference in the metabolism of isosorbide dinitrate following incubation in human blood

Isosorbide dinitrate (ISDN) (at a concentration of 100 ng/ml) was incubated aerobically at 37° in whole blood from five male and five female normal volunteers. Following incubation of the blood samples for 0, 30, 60, 120, 240 and 360 min, the samples were centrifuged and the plasma was assayed for ISDN. A linear relationship was observed between the logarithm of the concentration of ISDN remaining and incubation time, and there was a significant difference between the $\text{T}{}_{\mathrm{<mtext>1</mtext><mtext>2</mtext>}}$ of ISDN in blood from males (90.6 min) and females (161.4 min). Very little ISDN metabolism was observed when ISDN was incubated with plasma rather than whole blood. When erythrocytes, resuspended in saline, were incubated with ISDN, there was a time-dependent loss of ISDN from the saline incubation medium. Investigation of the soluble fraction obtained after hemolysis of these erythrocytes also showed a time-dependent loss of ISDN. The saline incubation medium contained sufficient concentrations of the two major ISDN metabolites (isosorbide 2- and 5-mononitrate) to account for the observed disappearance of ISDN. The results indicate that ISDN is metabolized in the cellular compartment of blood and that the metabolic rate in males is greater than that in females.     

DOES THE BARORECEPTOR-HEART RATE REFLEX INDICATE THE CAPACITY OF THE ARTERIAL BARORECEPTORS TO CONTROL BLOOD PRESSURE?

1. We have examined the question asked in the title by studying: the carotid baroreceptor reflex in man with a variable-pressure neck chamber; the carotid baroreceptor reflex in conscious rabbits with a variable-pressure capsule around the carotid bifurcation; and the baroreceptor-heart rate reflex. 2. At rest, the association between the sensitivities of the carotid barorecep-tor-blood pressure and -heart rate reflexes, and of these with the baroreceptor-heart rate reflex, is weak. Exercise causes dissociation between control of blood pressure and heart rate. In hypertension, depression of the baroreceptor-heart rate reflex does not reflect the altered characteristics of the carotid sinus-blood pressure reflex.     

Blockade of coronary reactions to arachidonic acid by glyceryl trinitrate and tranylcypromine

Isolated perfused hearts of rats or guinea pigs reacted to bolus doses of arachidonic acid (AA) with a coronary constriction followed by a protracted vasodilatation phase. Glyceryl trinitrate (GTN; 55–95 μM) produced coronary dilatation during which the AA-induced constriction remained unaltered, or even enhanced. After ‘acute tolerance’ developed by sustained GTN infusion, the constrictor phase of AA was inhibited while the vasodilation continued unaltered or slightly enhanced. Nitroprusside (Np; 5–56 μM) determined a coronary vasodilatation that persisted throughout its administration and appeared to be associated with an inhibition of the AA-induced coronary constriction. While withdrawal of Np resulted in an immediate recovery of coronary flow levels and of the reactions to AA, the blockade of AA-coronary constriction continued after GTN withdrawal. Tranylcypromine (TRC) infusion did not alter the basal coronary flow, but it produced a specific inhibition of the AA-induced coronary vasodilatation. We postulated that the blockade of the coronary constriction exerted during GTN acute tolerance would result from an inhibition of the synthesis of a constrictor metaboline (thromboxane-like substance?) formed in the coronaries through the cyclooxygenase metabolic pathway of AA.     

NF—κB上调偏头痛大鼠脑膜ICAM-1蛋白表达

目的:探讨核转录因子-κB(nuclear factor-kappa B,NF-κB)在偏头痛脑膜炎症反应中的作用及细胞间黏附分子-1(intercellular adhesion molecules-1,ICAM-1)表达的调控机制。方法采用静脉注射(iv)硝酸甘油(glyceryl trinitrate,GTN)法建立大鼠偏头痛模型,分为对照组、模型组、溶剂对照组、吡咯烷二硫氨基甲酸(pyrrolidine dithiocarbamate,PDTC)组。各组分别包括0.9%生理盐水或GTN iv后1.5,4h两个实验小组。应用Western印迹法分别观察PDTC对GTN iv后1.5h大鼠脑膜NF-κB蛋白表达水平与GTN iv后4h ICAM-1蛋白表达水平的影响。结果:PDTC50,100,200mg.kg-1各剂量组GTN iv后1.5h大鼠脑膜NF-κB蛋白表达量较模型组分别降低30%(P<0.05)、52%(P<0.01)和65%(P<0.01),呈剂量依赖性;PDTC50,100,200mg.kg-1各剂量组GTNiv后4h大鼠脑膜ICAM-1蛋白表达量较模型组分别降低36%(P<0.05)、71%(P<0.01)和51%(P<0.01),无剂量依赖关系。结论:NF-κB参与偏头痛时脑膜ICAM-1的蛋白合成调控,在偏头痛的脑膜炎症机制中起着重要作用。     

Efficacy and Safety of Dorocontin? versus Sustac? in the Treatment of Stable Angina Pectoris: A Randomized,Double-Blind Comparative Trial

Background: Development of generic drugs has numerous benefits in terms of cost-efficiency and availability. Slow-release nitroglycerin is a vasodilator drug commonly prescribed for patients with angina pectoris. Objective: The objective of this study was to compare the efficacy and safety of generic slow-release nitroglycerin (Dorocontin^®) with that of the innovator brand (Sustac^®) in patients with stable angina pectoris. Methods: In this randomized, double-blind comparative trial, 110 patients were allocated to Dorocontin^® (n=67) or Sustac^® (n=43) at a dose of 6.4 mg TID, for a total period of two months. Maximum endurable MET (metabolic equivalent of task), MPI (myocardial perfusion imaging), along with changes in the ECG and biomarkers of renal (serum creatinine, BUN) and hepatic (AST, ALT, and ALP) function, lipid profile (total cholesterol, LDL-C, HDL-C, VLDL-C, and triglycerides), electrolytes (Na⁺ and K⁺), CBC-diff (RBC, WBC, Plt, Hb, Hct, MCV, MCH, MCHC, and RDW), and FBS were assessed at the baseline and at the end of the trial. The frequency of adverse events during the course of the trial was also recorded. Results: Apart from a significantly greater reduction in maximum ST depression in the Sustac^® versus the Dorocontin^® group (p=0.03), none of the functional (MET, MPI, and ECG) and paraclinical (renal function, hepatic function, lipid profile, electrolytes, and FBS) parameters significantly differed between the study groups. The mean Hb (p=0.035), Hct (p=0.045), and MCH (p=0.032) were decreased by the end of the trial in the Sustac^®, but not in the Dorocontin^® group, whilst there was no change in other CBC-diff parameters. Reported adverse events were not serious and included headache, vertigo, gastrointestinal upset, and orthostatic hypotension. The frequency of these adverse events was comparable between the study groups. Conclusion: The findings of the present trial showed comparable efficacy and safety of the generic and innovator products of slow-release nitroglycerin in the management of stable angina pectoris.     

Angina pectoris and cold

Summary

Ten patients with angina pectoris and a history of cold intolerance performed symptom limited work tests at +18d`C and at-17d`C. At -17d`C the work capacity was found to be 20% lower than at+18d`C. In nine of the patients the work load necessary to elicit anginal pain was lower in the cold. Nitroglycerine given before cycling increased the work capacity in the cold to levels obtained in room temperature, mainly due to a decrease in the systolic blood pressure.

Résumé

10 sujets souffrant d'angine de poitrine et présentant une intolérance connue au froid ont effectué un travail à +18d`C et à -17d`C dont l'intensité ne devait pas encore occasionner des symptômes cliniques. A la température de -17d`C, la capacité de travail était de 20% inférieure à celle constatt´e à +18d`C. Dans l'ambiance froide, 9 sujets ont développt´ de l'angor en effectuant un effort normalement bien supportt. L'administration de nitroglycérine avant l'épreuve angomk´trique en chambre froide ríhausse la tolérance à l'effort jusqu'à un niveau enregistre auparavant à température normale. Ceci paraiˇt ětre dû à une baisse de la tension artérielle systolique.

Zusammenfassung

Zehn Patienten mit Angina pectoris und einer Anamnese von Kälteunvertraglichkeit führten symptombegrenzte Arbeits-teste bei Temperaturen von +18d`C und -17d`C aus. Die bei der Temperatur von -17d`C gefundene Arbeitskapazität war 20% niedriger als diejenige bei +18d`C. Bei neun der untersuchten Patienten war die fir die Auslösung eines anginösen Schmerzes notwendige Arbeitsbelastung niedriger in der Kälte als in der Wärme. Nitroglyzerin erhöhte die Arbeitskapazität in der Kälte auf die bei Raumtemperatur registrierten Werte, wenn es vor der Arbeit auf dem Standfahrrad gegeben wurde. Dieser giinstige Effekt beruhte hauptsachlich auf einer Senkung des systolischen Blutdrucks.

Resumen

Diez pacientes con angina de pecho y una historia de intolerancia a1 frio realizaron pruebas de trabajo limitado a los sintomas a +18d`C y a -17d`C. A esta ultima temperatura, se encontró que su capacidad de trabajo era un 20% menor que a la de +18d`C. En nueve casos, la carga de trabajo necesaria para provocar dolor anginoso fue menor con el frio. La nitroglicerina administrada antes del ejercicio en bicicleta aumento la capacidad para el esfuerzo en condiciones frías, a los niveles obtenidos en la temperatura ambiente, principalmente debido a la disminución de la tensión arterial sistólica.     

山嵛酸甘油酯在药剂学中的应用

山嵛酸甘油酯是一类多用途的长链脂肪酸甘油酯,具有优良的生物相容性,广泛应用于食品、药品和化妆品领域。本文以Gattefosse的产品Compritol 888 ATO为例,从口服给药、注射给药和局部给药三个方面综述山嵛酸甘油酯在药剂学中的应用和研究进展。