Lack of tolerance of headache and radial artery diameter during a 7 hour intravenous infusion of nitroglycerin

Summary Nitroglycerin-(NTG)-induced headache and dilatation of the radial artery were followed in a double blind, randomized, placebo-controlled, cross-over study in 6 healthy volunteers. NTG 0.5 g · kg^–1 · min^–1 or saline were infused IV for 7 h, and subsequently the infusion rate was doubled for 10 min. The radial artery diameter was measured repeatedly with high frequency ultrasound and pain was scored using a 10 point verbal scale.After 5 min of NTG infusion both headache and the arterial diameter differed significantly from baseline, and no further significant change occurred. The intensity of the headache was mild to medium (median headache score 3, range 1–7). The mean dilatation of the radial artery was 36%. The dilatation in each individual, was stable over time, both during NTG and placebo, and it did not change with the double infusion rate. The headache score in each individual was more fluctuan.No tolerance either to the NTG-induced headache or arterial dilatation was observed.     

应用超声测量婴幼儿双侧桡、尺动脉的对比研究

目的 应用超声测量并分析婴幼儿双侧桡、尺动脉的内径及深度以探讨婴幼儿在超声引导下行桡、尺动 脉穿刺置管的差异性。方法 选取择期行全麻手术的婴幼儿120例,应用超声对患儿双侧桡、尺动脉进行检查测量, 记录双侧桡、尺动脉3个标志点的深度、内径及解剖变异情况,同时记录患儿的身高、体质量、禁饮禁食时间以及每个 测量时刻的平均动脉压（MAP）、心率（HR）和体温。结果 超声测得的患儿左、右前臂间桡动脉和尺动脉深度、内径 差异无统计学意义;双侧桡动脉均较尺动脉表浅（P＜0.05）。桡、尺动脉第2测量标志点深度较第1测量标志点深,第 3测量标志点较第2测量标志点深（P＜0.05）;桡、尺动脉内径在各个测量标志点间的比较差异无统计学意义。双侧 桡、尺动脉深度与年龄、身高、体质量、MAP均呈负相关,与HR呈正相关（P＜0.01）;双侧桡、尺动脉内径与年龄、身 高、体质量、MAP均呈正相关,与HR均呈负相关（P＜0.01）。结论 超声测得婴幼儿桡、尺动脉内径相当;在超声引 导下行婴幼儿桡、尺动脉穿刺置管均具有选择性价值。     

Role of endothelium-derived hyperpolarizing factor in the regulation of radial artery basal diameter and endothelium-dependent dilatation in vivo

1. The role of the balance between nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF), synthesized by cytochrome epoxygenase and acting through calcium-activated potassium channels, in the regulation of basal diameter and endothelium-dependent flow-mediated dilatation of conduit arteries has been poorly assessed in humans. 2. Radial artery diameter and flow (echotracking coupled to Doppler) were measured in healthy volunteers under basal conditions and during flow-mediated dilatation induced by hand skin heating, in the presence of saline and inhibitors of NO-synthase, N(G)-monomethyl-L-arginine (L-NMMA), calcium-activated potassium channels, tetraethylammonium (TEA) and cytochrome epoxygenases, fluconazole, infused alone and in combination. Mean wall shear stress, the flow-mediated dilatation stimulus, was calculated and taken as cofactor into statistical analysis. 3. Under basal conditions, the radial artery diameter was not affected by L-NMMA and fluconazole infused alone but was decreased by TEA, the combinations of L-NMMA + fluconazole and, to a greater extent, L-NMMA + TEA. During heating, radial artery diameter increased with temperature in all cases. This increase in diameter, compared with saline, was reduced by L-NMMA, TEA, fluconazole and to a greater extent, by L-NMMA + TEA and L-NMMA + fluconazole. 4. These data show that EDHF is involved in balance with NO in the regulation of basal diameter and endothelium-dependent dilatation of human peripheral conduit arteries. The alteration of this balance could play a major role in the physiopathology of the endothelial dysfunction, in particular during essential hypertension.     

Plasma concentrations of isosorbide dinitrate and its metabolites after chronic high oral dosage in man

1 We have previously reported that vasodilator headache due to isosorbide dinitrate (ISDN) can be circumvented by using small 'priming' doses for an induction period of 1-2 weeks, after which it is possible to increase to dose rapidly to 360-720 mg, daily without recurrence of headache and without toxicity. The present study corroborates this earlier finding. 2. Chronic oral administration of doses of ISDN of this order of magnitude results in prolonged high plasma concentrations of the parent compound, as well as higher levels of the metabolites 2-ISMN and 5-ISMN. 3. It is our thesis that chronic high oral dosage of ISDN saturates the intrahepatic biotransformation process, and allows high concentrations of ISDN and its metabolites to enter the systemic circulation.     

Increased cardiovascular risk without generalized arterial dilating diathesis in persons who do not have abdominal aortic aneurysm but who are first‐degree relatives of abdominal aortic aneurysm patients

There is a strong genetic predisposition towards abdominal aortic aneurysm (AAA), but it is unknown whether persons without AAA but with first‐degree relatives who are AAA patients have a generalized dilating diathesis, defect arterial wall mechanics, or increased cardiovascular risk. The aim of the study was to investigate arterial diameters and wall mechanics at multiple arterial sites in these subjects and compare them with controls without a family history of AAA. This study included 118 first‐degree relatives of patients with AAA and 66 controls (age: 40–80 years). The abdominal aorta, common carotid artery, common femoral artery, and popliteal artery were investigated by echo‐tracking ultrasound. The relatives had no arterial dilatation, but they did tend to have smaller diameters than controls. Relatives had a higher heart rate, diastolic blood pressure, and mean arterial pressure than controls. The distensibility coefficient and the compliance coefficient were decreased in all arteries in male relatives, adjusted for age and smoking; these coefficients were normalized after adjustment for mean arterial pressure and heart rate. Female relatives had a lower compliance coefficient in the abdominal aorta, adjusted for age and smoking. After adjustment for mean arterial pressure and heart rate, the difference disappeared. No general arterial dilatation in relatives without AAA was found, supporting the hypothesis that the dilating diathesis is linked to the aneurysmal manifestation in the abdominal aorta. Although the threat of aneurysmal dilatation and rupture seems to be lacking in these subjects, heart rate, blood pressure, and arterial wall stiffness were all increased, which may indicate a higher risk of developing cardiovascular morbidity and mortality.     

Differential vasoactive effects of sildenafil and tadalafil on cerebral arteries

Phosphodiesterase 5 (PDE5) is associated with migraine pathophysiology, stroke recovery and vasospasm treatment. The potential vascular interplay of PDE5 inhibitors sildenafil, tadalafil and UK-114,542 was studied by intra- versus extra-luminal administration in rat middle cerebral arteries in vitro and on middle meningeal arteries in vivo. By Western blot PDE5 was detected in both cerebral and meningeal arteries, though with minor variations in band intensity between vascular beds. Rat middle cerebral artery diameter was investigated using pressurised arteriography, applying UK-114,542, sildenafil, and tadalafil intra- or extra-luminally. Effects on the dural middle meningeal artery were studied in the in vivo closed cranial window model. At high concentrations, abluminal sildenafil and UK-114,542, but not tadalafil, induced dilatation of the middle cerebral artery. Luminal application elicited a contraction of 4% (sildenafil, P=0.03) and 10% (tadalafil, P=0.02). In vivo, sildenafil, but not tadalafil, dose-dependently dilated middle meningeal artery concomitant to blood pressure reduction (1-3mg/kg);1mg/kg sildenafil inducing 60 ± 14% (P=0.04) and vehicle (DMSO) 13 ± 6% dilatation. In conclusion, PDE5 inhibitors applied luminally had minor contractile effect, whereas abluminal sildenafil induced middle cerebral artery dilatation above therapeutic levels. In vivo, sildenafil dilated middle meningeal artery concomitant with a reduction in blood pressure. Tadalafil had no dilatory effects. PDE5 inhibitors show differential vascular activity in cerebral arteries from healthy animals; arterial dilatation is seen primarily above therapeutic levels. Such findings support clinical studies showing no vasodilator effects of sildenafil on cerebral arteries in healthy subjects.     

THE EFFECT OF HYPERTENSION AND ACE INHIBITION ON ARTERIAL STRUCTURE AND COMPLIANCE

1. Large artery dilatation may be produced by angiotensin-converting enzyme inhibition in hypertensive subjects independently of blood pressure reduction. The resulting increase in arterial compliance may be due to both blood pressure reduction and to arterial smooth muscle relaxation.
2. In healthy volunteers and in hypertensive subjects, dosages producing large artery dilatation seem to be even higher than those causing arteriole dilatation with the resulting blood pressure reduction.
3. It may be important to consider such findings for the remodelling of the cardiovascular system produced by angiotensin-converting enzyme inhibition.     

Interaction of a potential antimigraine drug (Org GC 94) with the vasomotor action of serotonin

The interaction of a potential anti-migraine drug (Org GC 94) with the vasomotor action of 5-HT in vitro in feline, canine and human intra- and extracranial arteries, as well as in vivo in the canine nasal vascular bed has been investigated. In the two in vitro preparations, i.e. using superfusion or bath techniques, the intracranial vessels were more sensitive to 5-HT vasoconstriction than the extracranial ones. As both the maximum contraction and the slope of the dose-response curves were reduced by increasing concentrations of Org GC 94, the antagonism of 5-HT did not involve competitive blockade of 5-HT receptors. The dilator response was tested in arteries brought to a higher tone with prostaglandin F₂. 5-HT produced a dose-dependent dilatation which, like the vasoconstriction, was antagonized in a non-competitive manner by Org GC 94. Intra-arterial injections of 5-HT provoked nasal vasoconstriction and this response was clearly potentiated by Org GC 94 in low doses while higher doses inhibited the vascular response to 5-HT. The specific effect of Org GC 94 in vivo may be the potentiation of 5-HT-induced vasoconstriction. The hypothesis is discussed that the so-called anti-5-HT agents act in migraine patients as partial agonist of 5-HT, mimicking rather than antagonizing 5-HT.     

N-acetylcysteine modifies the acute effects of isosorbide-5-mononitrate in angina pectoris patients evaluated by exercise testing

Nitrates are well established in the treatment of angina pectoris and the presence of sulfhydryl groups seems to be fundamental to nitrate-induced vasodilatation. The present study was performed to elucidate if large oral doses of N-acetylcysteine (NAC, 2,400 mg X 2), a donor of sulfhydryl groups, given together with a single oral dose of the long-acting nitrate, isosorbide-5-mononitrate (5-ISMN, 60 mg), would modify the nitrate effect evaluated by exercise testing before and after additional sublingual doses of nitroglycerin (NTG). Ten patients with angina pectoris and angiographically proven significant coronary artery disease were included. All patients received a baseline therapy with beta blockers. None of the patients had developed nitrate tolerance at inclusion. NAC/5-ISMN treatment significantly prolonged the total exercise time as compared with placebo/5-ISMN (7.7 +/- 2.1 min vs. 6.8 +/- 1.7 min, p less than 0.05). This increase was of such magnitude that no further effect was obtained after additional NTG doses. This study demonstrated that increased availability of sulfhydryl groups can increase the exercise capacity in angina pectoris patients treated with 5-ISMN without nitrate tolerance.     

Investigation of the vasoconstrictor action of subarachnoid haemoglobin in the pig cerebral circulation in vivo.

1. Angiographic techniques have been used to study the influence of intracisternally injected haemoglobin on the diameters of the main intrathecal and representative extrathecal (ascending pharyngeal and facial) cranial arteries of the anaesthetized pig. 2. Intracisternal injection of haemoglobin caused concentration-dependent decreases in the diameters of intra- but not extrathecal arteries suggesting that haemoglobin possesses local vasoconstrictor activity. 3. When infused into one ascending pharyngeal artery, acetylcholine (ACh) caused slight dilatation of the intrathecal arteries but no change in the diameters of the ascending pharyngeal and facial arteries. The dilator response induced by ACh in the intrathecal arteries was converted into frank constriction after intracisternal injection of haemoglobin (cerebrospinal fluid concentration approximately 2 x 10(-5) M). 4. These findings are consistent with the hypothesis that subarachnoid haemoglobin can induce cerebral artery constriction by acting as an extraluminal 'sink' for intimally released endothelium-derived relaxing factor (EDRF) and may be relevant to the pathogenesis of vasospasm after subarachnoid haemorrhage in man.     

Phosphodiesterase 5 and effects of sildenafil on cerebral arteries of man and guinea pig

Sildenafil (Viagra), a selective inhibitor of phosphodiesterase 5 (PDE5), induces headache and migraine. Although previously supposed to be a "vascular" headache, no significant cerebral artery dilatation was found in vivo. Thus, we hypothesised that PDE5 may not be present or that sildenafil is less effective on the cGMP hydrolysis in cerebral arteries, and that sildenafil may not be an effective dilator of cerebral arteries under baseline conditions. We evaluated the presence of PDE5 mRNA and protein in human arteries. Furthermore, the effects of two selective PDE5 inhibitors, sildenafil and UK-114,542, and a PDE1 inhibitor UK-90,234 on cGMP hydrolysis were investigated in human and guinea pig cerebral arteries. The vasoactive responses of the compounds were evaluated in guinea pig basilar arteries in vitro, with concomitant measurements of cAMP and cGMP. PDE5 was found in human middle cerebral arteries. Sildenafil and UK-114,542 inhibited cGMP hydrolysis concentration-dependently in both species. In guinea pig arteries, sildenafil induced an endothelium-dependent vasodilatation only at concentrations above 10 nM, which was augmented by sodium nitroprusside and attenuated by reduction of cGMP, but was cGMP independent at high concentrations. UK-114,542 was more and UK-90,234 was less potent than sildenafil. In conclusion, PDE5 is present in human and guinea pig cerebral arteries, and is inhibited by sildenafil at micromolar levels. Sildenafil in vitro is a poor dilator of guinea pig cerebral arteries unless a nitric oxide donor is co-administered, corresponding to the previous findings in vivo.     

Effect of TRPA1 activator allyl isothiocyanate (AITC) on rat dural and pial arteries

BackgroundTransient receptor potential ankyrin 1 (TRPA1) channels may have a role in migraine as some substances known to cause headache activate the channel. In the craniovascular system such activation causes a calcitonin gene-related peptide (CGRP)-dependent increase in meningeal blood flow. TRPA1 channels in the endothelium of cerebral arteries cause vasodilation when activated. The headache preventive substance feverfew inhibits activation of TRPA1 channels. In this study we aim to compare and characterize the effect of the TRPA1 agonist allyl isothiocyanate (AITC) on the diameter of rat dural and pial arteries in vivo.MethodsThe genuine closed-cranial window technique in rats was used to examine changes in dural and pial artery diameter and mean arterial blood pressure (MABP) after intracarotid infusion of AITC. Blockade experiments were performed by intravenous infusion of olcegepant, HC-030031, sumatriptan or capsazepine immediately after infusion of AITC, in four different groups of rats.ResultsAITC caused a significant dilation of dural arteries, which was inhibited by HC-030031, olcegepant and sumatriptan, but not by capsazepine.In pial arteries AITC caused a significant dilation, which was not inhibited by any of the pre-treatments, suggesting a poor penetration of the blood-brain barrier or autoregulation due to dimethyl sulfoxide (DMSO) mediated decrease in MABP during HC-030031 infusion.AITC did not cause a significant change in MABP.ConclusionAITC causes dilation of dural arteries via a mechanism dependent on CGRP and TRPA1 that is sensitive to sumatriptan. AITC causes a small but significant dilation of pial arteries.     

The actions of calcitonin gene related peptide and vasoactive intestinal peptide as vasodilators in man in vivo and in vitro.

1 The two peptides calcitonin gene related peptide (CGRP) and vasoactive intestinal peptide (VIP) produced marked dilatation of the forearm vascular bed when infused via the brachial artery. 2 CGRP relaxed preconstricted segments of human radial, coronary, gastric and cerebral arteries in an endothelium dependent manner. 3 VIP relaxed human gastric and transverse cervical arteries in an endothelium dependent manner, but relaxation of the human pulmonary artery was not dependent on endothelium. 4 The characteristics of the endothelium dependent relaxation of these medium-sized muscular arteries indicated involvement of the endothelium derived relaxing factor in vitro. 5 Caution is expressed in drawing comparisons between the mechanisms involved in the in vivo and in vitro vascular responses.     

Increased external carotid artery blood flow in headache patients induced by cilostazol. Preliminary communication

Cilostazol (6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2 (1H)-quinolinone, OPC-13013) is an anti-platelet aggregating and vasodilating drug. But cilostazol is known to have a tendency to cause headache, which is thought to be due to the dilatation of the external carotid artery. In the present study the effect of cilostazol on the blood flow in the carotid arteries was established by the Doppler ultrasound technique. Twelve patients with cerebral infarction (mean age 66.3 years) were divided into two groups consisting of 9 patients (Group 1) who did not have headache during treatment with cilostazol and 3 patients (Group II) who complained of headache. The systolic peak frequency (PEAK) of the common and external carotid arteries was measured using a Doppler ultrasound device. The PEAK of the common and external carotid arteries were examined before and 4 weeks after oral administration of 200 mg/d, 100 mg twice a day, cilostazol. In Group I, the PEAK in bilateral common carotid arteries increased significantly after treatment with cilostazol, but the PEAK in bilateral external carotid arteries showed no significant change. In Group II, the PEAK in both common carotid arteries showed no significant change after treatment with cilostazol, but the PEAK in the right external carotid artery increased significantly.     

Histamine-1 receptor blockade does not prevent nitroglycerin induced migraine

It has previously been shown that in migraine sufferers infusion of glyceryl trinitrate (GTN) and histamine causes an immediate headache during the infusion and a genuine migraine attack one to several hours after the infusion. This identical time profile indicates a common mechanism of action. To evaluate whether GTN causes headache via liberation of histamine, we studied the effect of GTN 0.5 g · kg^–1·min^–1 for 20 min in seven migraine sufferers, once after pretreatment with the histamine-1(H₁)-receptor blocker mepyramine (0.5 mg · kg^–1) and once without pretreatment. This mepyramine dose is known to completely abolish histamine-induced headache. After pretreatment with mepyramine five patients experienced migraine, and without pretreatment six patients did so. The median peak headache score was 7 on a 0–10 scale with and without mepyramine pretreatment. The arterial responses, evaluated with transcranial Doppler, were also unaffected by the mepyramine pretreatment. Our results demonstrate that neither headache nor arterial dilatation due to GTN infusion is caused by histamine release. In all likelihood the common mediator of migraine induction by GTN and histamine is nitric oxide.     

Nitroglycerin for ergotism. Experimental studies in vitro and in migraine patients and treatment of an overt case

Summary Ergotamine was used to induce arterial contraction in vitro (measurement of isometric tension in segments from 3 human temporal arteries) and in vivo (peripheral systolic blood pressure measured by strain gauge plethysmography in 5 migrainous patients). In both these models of ergotism, the directly acting vasodilator nitroglycerine (NTG) effectively relieved the ergotamine-induced arterial contractions. A case of ergotism treated succesfully with NTG infusion is reported. The diagnosis was based on history and measurement of peripheral systolic blood pressure by strain gauge plethysmography. The latter technique was also used to monitor the response to treatment for 20 h. Blood levels of ergotamine during ergotism were in the therapeutic range. Possible explanations for this finding are discussed.     

Investigation of a possible pharmacokinetic interaction between ibopamine and isosorbide-5-mononitrate

Summary The possibility of a pharmacokinetic interaction between isosorbide-5-mononitrate (5-ISMN) and epinine, the active metabolite of ibopamine, has been investigated in 8 healthy male subjects given single doses of 200 mg ibopamine and 20 mg 5-ISMN, separately and together.The plasma 5-ISMN concentration-time profile was the same whether 5-ISMN was administered concomitantly with ibopamine or alone [AUC(o-t): 2.24 g·ml^–1·h after 5-ISMN alone, 2.16 g·ml^–1·h after 5-ISMN + ibopamine]. The plasma concentrations of total and free epinine and the urinary recovery of total epinine, homovanillic acid and dihydroxyphenylacetic acid, too, were not different when ibopamine was administered alone or concomitantly with 5-ISMN. The intake of ibopamine did not change the blood pressure and heart rate. The decrease in diastolic blood pressure induced by 5-ISMN was not influenced by concomitant intake of ibopamine.The observations suggest that in healthy volunteers there is no pharmacokinetic interaction between 5-ISMN and ibopamine.     

双上肢肱动脉变异1例

双上肢肱动脉变异是临床上比较少见的上肢动脉变异类型,目前偶有个案报道,本研究就1例男性大体标本解剖时发现双上肢肱动脉变异进行报道,为临床诊治提供参考。在本例中,肱动脉于腋动脉第1段即发出肱动脉浅、深两干,二者沿着臂部及前臂部向下走行,最终分别延续为桡动脉和尺动脉。在下行过程中,二者分别发出胸上动脉、胸肩峰动脉、尺侧上副动脉以及肱深动脉、肩胛下动脉、胸外侧动脉、尺侧下副动脉、旋肱前动脉、旋肱后动脉。在临床实践中,已发现由于肱动脉的变异而导致治疗过程中出现意外的事例,所以,我们应该注意这种变异的存在以避免治疗过程中意外的发生。     

INVOLVEMENT OF NITRIC OXIDE IN CORONARY VASCULAR RESPONSES TO 5-HYDROXYTRYPTAMINE IN THE ANAESTHETIZED GREYHOUND

1. The effect of the intracoronary (i.c.) injection of 5-hydroxytryptamine (5-HT; 0.1–1.0 μFg/ kg) was examined before and after inhibition of nitric oxide (NO) synthesis with N-nitro-l-arginine (NOLA; 5 mg/ kg i.c.) in nine anaesthetized greyhounds. Before administration of NOLA, 5-HT increased coronary blood flow (CBF) but decreased large coronary artery diameter indicating simultaneous dilatation of resistance vessels and constriction of large arteries. 2. The administration of NOLA significantly decreased large coronary artery diameter and increased systemic arterial pressure. There was no significant effect on coronary vascular resistance or heart rate. In the presence of NOLA, the 5-HT-induced constriction of the large coronary artery was enhanced and the dilatation of the resistance vessels was reduced. In addition there was a secondary reduction in CBF, a response that was not observed before NOLA treatment. 3. The response to NOLA suggests that a basal release of NO is important in the regulation of coronary and systemic vascular tone. Nitric oxide is an important mediator of coronary vasodilator responses to 5-HT, and in addition the release of NO modulates 5HT-induced constriction of large coronary arteries.     

Hepatoprotective effects of the nitric oxide donor isosorbide-5-mononitrate alone and in combination with the natural hepatoprotectant, silymarin, on carbon tetrachloride-induced hepatic injury in rats

The aim of this study was to investigate the effect of the nitric oxide donor isosorbide-5-mononitrate (5-ISMN) alone or in combination with the natural hepatoprotectant with anti-oxidant activity silymarin on the carbon tetrachloride (CCl₄)-induced hepatic injury in rats. 5-ISMN (1.8, 3.6 or 7.2 mg/kg), silymarin (25 mg/kg) or 5-ISMN (1.8, 3.6 or 7.2 mg/kg) combined with silymarin was given once daily orally simultaneously with CCl₄ and for 15 days thereafter. Liver damage was assessed by determining serum enzyme activities and hepatic histopathology. 5-ISMN given at the above doses conferred significant protection against the hepatotoxic actions of CCl₄ in rats, reducing serum alanine aminotransferase (ALT) levels by 31.2, 39.3 and 61.6%, respectively, when compared with controls. Serum aspartate aminotransferase (AST) levels decreased by 19.8, 22.7 and 59.4%, respectively, while alkaline phosphatase (ALP) decreased by 26.1 and 32.6% by the drug at 3.6 and 7.2 mg/kg, respectively. When silymarin was added to 5-ISMN (1.8, 3.6 or 7.2 mg/kg), ALT decreased by 32.8, 59.6, 70.2% and AST by 28.7, 50.3, 60%, when compared with CCl₄ control group levels. Silymarin in combination with 3.6 or 7.2 mg/kg 5-ISMN resulted in 37.5 and 39.2% reductions in ALP when compared with CCl₄ control group. Meanwhile, silymarin alone reduced ALT, AST and ALP levels by 65.9, 52 and 62.3%, respectively. Blood levels of reduced glutathione were markedly decreased in CCl₄-treated rats. Reduced glutathione levels were increased by the administration of 5-ISMN and restored to near normal values by silymarin treatment. Histopathological alterations by CCl₄ were markedly reduced after treatment with 5-ISMN alone or in combination with silymarin. Histopathologic examination of the livers of CCl₄-treated rats administered 5-ISMN at 7.2 mg/kg showed marked restoration of the normal architecture of the liver tissue and minimal fibrosis. Silymarin co-administered with 5-ISMN resulted in further improvement of the histologic picture. These results indicates that treatment with 5-ISMN protects against hepatocellular necrosis induced by CCl₄. The study suggests a potential therapeutic use for 5-ISMN in combination with silymarin in liver injury.