Cerebral Arterial Spasm Research Articles

Treatment of cerebral vasospasm with intra-arterial papaverine.

Cerebral vasospasm continues to be the leading treatable cause of morbidity and mortality following aneurysmal subarachnoid hemorrhage. In this preliminary anecdotal series of 12 patients who were candidates for balloon angioplasty, vasospasm was treated instead with intra-arterial papaverine. Eight patients had marked angiographic reversal of the arterial narrowing following papaverine infusion, four of whom showed dramatic reversal of profound neurological deficits. Two patients deteriorated clinically 5 days after the initially successful papaverine infusions. In both, repeat angiography demonstrated severe recurrent vasospasm, which was partially reversed with a second intra-arterial papaverine treatment. Two patients developed focal neurological deficits during papaverine infusion, which resolved spontaneously over several hours after cessation of the intra-arterial infusion. Arterial narrowing in the posterior circulation and middle cerebral artery distribution appeared to be more responsive to papaverine infusion than was spasm in the anterior cerebral arteries. The infusion of 300 mg of papaverine over 1 hour seemed to be an adequate and safe dose to effect these angiographic and clinical improvements.

Posttraumatic cerebral arterial spasm: transcranial Doppler ultrasound, cerebral blood flow, and angiographic findings

Thirty patients admitted after suffering closed head injuries, with Glasgow Coma Scale scores ranging from 3 to 15, were evaluated with transcranial Doppler ultrasound monitoring. Blood flow velocity was determined in the middle cerebral artery (MCA) and the intracranial portion of the internal carotid artery (ICA) in all patients. Because proximal flow in the extracranial ICA declines in velocity when arterial narrowing becomes hemodynamically significant, the extracranial ICA velocity was concurrently monitored in 19 patients. To assess cerebral perfusion, cerebral blood flow (CBF) measurements obtained with the intravenous 133Xe technique were completed in 16 patients. Vasospasm, designated as MCA velocity exceeding 120 cm/sec, was found in eight patients (26.7%). Severe vasospasm, defined as MCA velocity greater than 200 cm/sec, occurred in three patients, and was confirmed by angiography in all three. Subarachnoid hemorrhage (SAH) was documented by computerized tomography in five (62.5%) of the eight patients with vasospasm. All cases of severe vasospasm were associated with subarachnoid blood. The time course of vasospasm in patients with traumatic SAH was similar to that found in patients with aneurysmal SAH; in contrast, arterial spasm not associated with SAH demonstrated an uncharacteristically short duration (mean 1.25 days), suggesting that this may be a different type of spasm. A significant correlation (p less than 0.05) was identified between the lowest CBF and highest MCA velocity in patients during the period of vasospasm, indicating that arterial narrowing can lead to impaired CBF. Ischemic brain damage was found in one patient who had evidence of cerebral infarction in the territories supplied by the arteries affected by spasm. These findings demonstrate that delayed cerebral arterial spasm is a frequent complication of closed head injury and that the severity of spasm is, in some cases, comparable to that seen in aneurysmal SAH. This experience suggests that vasospasm is an important secondary posttraumatic insult that is potentially treatable.

Transcranial Doppler ultrasound in internal carotid artery and middle cerebral artery disease

Using noninvasive transcranial Doppler sonography, we studied cerebral collateral patterns in 30 patients with stenosis and/or occlusion of the extracranial internal carotid artery (ICA). All patients with unilateral ICA stenosis less than or equal to 80% had normal transcranial Doppler findings. 80% of patients with unilateral and 50% of patients with bilateral ICA stenosis of more than 80% including those with occlusion showed a collateralization via the ipsilateral anterior and/or posterior cerebral artery. 20% of patients with unilateral and 50% of patients with bilateral ICA stenoses of more than 80% (including occlusion) had two or three collateral pathways, including the ophthalmic artery. Another ten patients with stenosis or spasm of the middle cerebral artery (MCA) showed increased flow velocities with turbulence in the narrow segment. In four patients with severe MCA disease with a systolic peak velocity of more than 200 cm/s, the Doppler waveform distal to the lesion was damped. Decreased regional cerebral blood flow (rCBF) measured by 99mTc-HMPAO-SPECT was found in two patients with severe MCA stenosis. Another patient with moderate MCA stenosis with a systolic peak velocity of 140 cm/s showed a normal cerebral perfusion pattern.

The Quantitative Description of Action Disorganisation after Brain Damage: A Case Study

Abstract This paper outlines a theoretical approach to the study of action in simple, routine activities, along with a coding system for describing and analysing performance. The approach is exemplified through a single case study involving a patient who developed a profound action disorder following rupture of a pericallosal artery aneurysm and concomitant anterior cerebral artery spasm. The Action Coding System provides a detailed, quantitative picture of this patient's action disorder as it was manifested in two routine tasks and as it recovered over time. Discussion focuses on the cognitive organisation and processing of simple, everyday tasks and suggests how disruption of performance may ensue when intentional control of action is compromised.

Cerebral artery spasm and migraine

Cerebral artery spasm and migraine

Relaxant effect of calcitonin gene-related peptide on cerebral arterial spasm induced by experimental subarachnoid hemorrhage in dogs

This study examines the relaxant effect of calcitonin gene-related peptide (CGRP), a 37-amino acid peptide with a potent vasodilator action, on cerebral arterial spasm after subarachnoid hemorrhage (SAH). The spasm was induced by injecting autologous arterial blood percutaneously into the cisterna magna in adult mongrel dogs. The single-injection model of SAH was produced by injection of 1.0 ml/kg body weight of blood (on Day 0), and the double-injection model involved two successive injections of 0.5 ml/kg body weight of blood made 48 hours apart (on Day 0 and Day 2). On vertebral angiograms, arterial narrowing of the major cerebral arteries was most prominent on Day 3 after SAH in the single-injection model and on Day 7 in the double-injection model. When 10(-10) mol/kg of CGRP was administered intracisternally in the single-injection model on Day 3, the diameter of the spastic cerebral arteries, as determined by angiography, recovered to normal. After intracisternal administration of 10(-11) to 2 X 10(-10) mol/kg of CGRP on Day 7 in double-injection models, spastic cerebral arteries dilated in a dose-dependent manner. The dilatory effect of CGRP continued for a few hours after administration. The results suggest that CGRP injected intracisternally may reverse cerebral arterial spasm after SAH.

Transluminal angioplasty of intracerebral vessels for cerebral arterial spasm

We used intracerebral transluminal angioplasty to treat two episodes of symptomatic vasospasm in a patient recovering from an aneurysmal subarachnoid hemorrhage. The procedures were performed after medical therapies, intravascular volume expansion, and induced arterial hypertension failed to alleviate the patient's neurological condition. The first angioplasty, confined to the right middle cerebral and distal internal carotid arteries, took place more than 30 hours after the onset of left hemiplegia. Despite the subsequent discovery of a small parietal lobe infarct, it brought about a marked improvement in left motor function and may have also limited the spread of necrotic damage. The second angioplasty was necessitated when stenotic segments of the basilar and posterior cerebral arteries caused a 24-hour decline in the patient's mental status. Although delayed in relation to the onset of symptoms, it successfully reversed the patient's comatose state. The use of transluminal angioplasty for vasospasm is generally limited to cases where it can be performed shortly after the onset of neurological symptoms; delaying the procedure increases the risk of hemorrhage from reperfused areas of infarction. Our experience with this patient demonstrates that delayed angioplasty can improve vascular flow to ischemic territory, even after infarction, without complications and with resultant improvement in neurological function.

Transluminal Angioplasty of Intracerebral Vessels for Cerebral Arterial Spasm: Reversal of Neurological Deficits after Delayed Treatment

Abstract We used intracerebral transluminal angioplasty to treat two episodes of symptomatic vasospasm in a patient recovering from an aneurysmal subarachnoid hemorrhage. The procedures were performed after medical therapies, intravascular volume expansion, and induced arterial hypertension failed to alleviate the patient's neurological condition. The first angioplasty, confined to the right middle cerebral and distal internal carotid arteries, took place more than 30 hours after the onset of left hemiplegia. Despite the subsequent discovery of a small parietal lobe infarct, it brought about a marked improvement in left motor function and may have also limited the spread of necrotic damage. The second angioplasty was necessitated when stenotic segments of the basilar and posterior cerebral arteries caused a 24-hour decline in the patient's mental status. Although delayed in relation to the onset of symptoms, it successfully reversed the patient's comatose state. The use of transluminal angioplasty for vasospasm is generally limited to cases where it can be performed shortly after the onset of neurological symptoms; delaying the procedure increases the risk of hemorrhage from reperfused areas of infarction. Our experience with this patient demonstrates that delayed angioplasty can improve vascular flow to ischemic territory, even after infarction, without complications and with resultant improvement in neurological function.

Risk factors in intracranial saccular aneurysms. Aspects on the formation and rupture of aneurysms, and development of cerebral vasospasm.

Intracranial saccular aneurysms have been a well-known clinical and pathological entity for over two centuries. The pathophysiological events that lead to aneurysm formation and rupture are, however, poorly understood. Besides an HLA-associated genetic factor, the most widely accepted risk factors are arterial hypertension, female gender, and increasing age. Some aneurysm patients have a deficient formation of Type III collagen. This seems to interfere with the mechanical integrity of the cerebral arterial wall encouraging aneurysm formation. While some of the risk factors may be involved in the process of aneurysm formation, others may be of importance in the actual aneurysm rupture. Medical and surgical developments have only had a slight impact on mortality rates from aneurysm rupture. The principal cause of death and disability is cerebral arterial spasm. Considerable effort has been expended in investigating the etiology of this phenomenon. Previous studies have failed to yield conclusive evidence of the causative agent(s) or the nature of cerebral artery narrowing. The time course of vasospasm after the onset of subarachnoid hemorrhage is consistent with an immune-mediated response, and more recent observations suggest that immunological processes including activation of the complement system may be involved. Missed minor bleeding episodes may thus be a risk factor for aneurysm patients in respect to the development of cerebral vasospasm.

Nimodipine in the treatment of subarachnoid hemorrhage.

Nimodipine, a calcium-channel antagonist with a relatively selective vasodilatory effect on cerebral blood vessels, has recently been approved for improvement of neurologic deficits due to spasm following subarachnoid hemorrhage. Nimodipine has low oral bioavailability (2.7-27.9 percent), a short half-life (2 h), is highly protein bound (98-99 percent), and is hepatically metabolized. Clinical studies have evaluated topical, intravenous, and oral administration of nimodipine for the treatment of cerebral artery spasm associated with subarachnoid hemorrhage. These studies document some benefit of the drug in reducing the occurrence of severe neurologic deficit, although this effect is not universal. Few adverse effects have been noted. Further studies are necessary to evaluate the pharmacologic and pharmacokinetic characteristics, the appropriate dose and route of administration, adverse effects, drug interactions, and the therapeutic efficacy of nimodipine before routine use can be recommended.

Cerebral vasospasm diagnosis by means of angiography and blood velocity measurements.

We investigated 76 patients with known subarachnoid haemorrhage (SAH) in order to compare the results of angiography and non-invasive Doppler recordings of cerebral artery blood velocity in the diagnosis of cerebral vasospasm. One radiologist and one neurovascular surgeon assessed angiographic spasm visually on a four-level scale. The radiologist's ratings were the term of reference for the study. When there was angiographic spasm of the middle cerebral artery (MCA), the MCA blood velocity was higher and the blood velocity in the distal extracranical internal carotid artery (ICA) was lower than when MCA spasm was scored as absent. Analysis by Kappa statistics, a measure for the agreement between two independent judges with correction for random coincidence, revealed moderate agreement between angiographic spasm and the absolute MCA blood velocity (Kappa = 0.47). However, there was substantial agreement (Kappa = 0.64) between angiographic spasm and the index calculated from dividing the blood velocity in the MCA (VMCA) by the blood velocity in the ipsilateral ICA (VICA). The results indicate that this VMCA/VICA index gives more appropriate information on MCA spasm. Congenitally asymmetric circles of Willis with one wide dominant ACA showed normal blood velocities. In asymmetry induced by vasospasm, the diameter of the major ACA was normal or even reduced, and the blood velocity was significantly elevated. Hence, the agreement between blood velocity recordings and angiographic findings was substantial (Kappa = 0.64) when considering together the findings from both sides of the anterior circle of Willis.(ABSTRACT TRUNCATED AT 250 WORDS)

CSF leukotriene C4 following subarachnoid hemorrhage.

Leukotrienes derive from arachidonic acid metabolism via the lipoxygenase pathway and modulate several cellular events. In the central nervous system, leukotrienes are mainly synthesized in the gray matter and in vascular tissues. Their production is enhanced in ischemic conditions and in experimental subarachnoid hemorrhage (SAH). Previous studies have indicated the ability of the leukotrienes C4 and D4 to constrict arterial vessels in vivo and in vitro and have suggested their involvement in the pathogenesis of cerebral arterial spasm. In the present study, the authors measured lumbar and cisternal cerebrospinal fluid (CSF) levels of leukotriene C4 in 48 patients who had suffered aneurysmal SAH. In 12 of the cases, symptomatic and radiological spasm was evident. The mean lumbar CSF level of immunoreactive-like activity of leukotriene C4 (i-LTC4) was significantly higher (p less than 0.005) than in control cases, while the cisternal CSF level was higher than the lumbar mean concentration (p less than 0.005). Patients presenting with vasospasm had significantly higher levels of i-LTC4 compared to patients without symptomatic vasospasm. This is the first report concerning monitoring of i-LTC4 levels in the CSF after SAH. The results of this study suggest that: 1) metabolism of arachidonic acid via the lipoxygenase pathway is enhanced after SAH; 2) the higher cisternal CSF levels of i-LTC4 may be part of the biological response in the perianeurysmal subarachnoid cisterns after the hemorrhage; and 3) the higher CSF levels of i-LTC4 in patients presenting with vasospasm suggest that a relationship exists between this compound and arterial spasm and/or reflect the development of cerebral ischemic damage.

Experimental vasospasm in cultured arterial smooth-muscle cells. Part 1: Contractile and ultrastructural changes caused by oxyhemoglobin.

Smooth-muscle cells were cultured from rat aortic media, then oxyhemoglobin and other agents including serotonin, norepinephrine, and angiotensin II were added separately to the medium. Contractile and ultrastructural changes of the cells were examined with electron microscopy during the first 2 weeks of incubation. Oxyhemoglobin not only produced progressive contraction of the arterial smooth-muscle cells, but it also caused ultrastructural changes that resembled myonecrosis. In contrast, there was no evidence of progressive contraction or ultrastructural changes either in control cultures or in cultures with the other vasoactive agents. Although washout of oxyhemoglobin 3 hours after administration prevented continued contraction of the cells, washout 24 hours or longer after administration had no preventive effect. Judging from these results and from the fact that the culture medium was changed every 2 days, it is unlikely that accumulation of exogenous vasoactive agents caused these changes. The contraction and suggestive myonecrosis of the arterial smooth-muscle cells are probably caused by some intrinsic process initiated by oxyhemoglobin. The culture of cerebral arterial smooth-muscle cells requires further technical improvement; nevertheless, these results obtained with the smooth-muscle cells of rat aortic media indicate that arterial smooth-muscle cells in culture provide a promising new experimental model for chronic in vitro study of cerebral arterial spasm. It is suggested from these results that cerebral arteries are particularly prone to vasospasm because of structural differences as compared to noncerebral arteries.

Pathophysiology of delayed ischaemic dysfunction after subarachnoid haemorrhage: experimental and clinical data.

Cerebral arterial spasm from subarachnoid haemorrhage (SAH) may be associated with the clinical syndrome of delayed cerebral ischaemic dysfunction, but the two conditions are by no means synonymous. Patients in good clinical condition may be seen with severe vasospasm and vice versa. A variety of mechanisms may be responsible for the neurological dysfunction: current evidence indicates that most of these mechanisms produce a reduction in cerebral blood flow (CBF). In the early stages after SAH, there is a loss of autoregulation so that reduction in cerebral perfusion pressure (CPP) may produce ischaemia. This fall in CPP may be due to elevated intracranial pressure (ICP) or reduced mean arterial blood pressure (MABP). Delayed cerebral ischaemic dysfunction following SAH is a clinical syndrome which may also be caused by re-bleeding, hydrocephalus, dehydration, reduced cardiac output and/or blood pressure, hyperglycemia or epilepsy. Experimental evidence has indicated that at the time of an intracranial haemorrhage there is a profound and extensive focal ischaemic insult. The severity of the ischaemia depends upon the nature, size and rapidity of onset of haemorrhage. The focal ischaemic lesion around an intracerebral haemorrhage becomes smaller with the passage of time and is the result of two interacting phenomena: a) The physical properties of the haemorrhage result in increased local tissue pressure around the lesion. This produces squeezing of the microcirculation and focal ischaemia. b) Vasoconstrictor elements in blood produce spasm which may further reduce CBF, sometimes even remotely from the lesion. Treatment of delayed ischaemia therefore depends upon its cause.

Calcium Channel Blockers

The calcium channel blockers initially were approved for the treatment of classical and variant angina pectoris. Recent studies indicate that these agents also are useful in such diverse conditions as pulmonary and systemic hypertension, hypertrophic cardiomyopathy, arrhythmias, asthma, Raynaud's syndrome, esophageal spasm, myometrial hyperactivity, cerebral arterial spasm, and migraine.

'Second generation' dihydropyridine calcium antagonists. Greater vascular selectivity and some unique applications.

The newer dihydropyridine calcium antagonists are structurally related to nifedipine, but may provide greater vascular selectivity and wider clinical utility. Five new dihydropyridines-nisoldipine, nicardipine, nimodipine, felodipine and nitrendipine-are reviewed with regard to their preclinical pharmacology, haemodynamic effects and clinical indications. Nisoldipine is a potent arterial vasodilator with minimal electrophysiological and negative inotropic effects. Although data are still preliminary, the drug has shown some efficacy in both exertional angina and essential hypertension. The dosing interval is not yet clearly established, but may be twice daily. Utility in congestive heart failure awaits confirmation, but preliminary studies are promising. Nicardipine is an especially potent peripheral, cerebral and coronary arterial vasodilator that causes 10-fold less myocardial depression in animals than nifedipine, and may provide important cardioprotective effects during ischaemia. Human haemodynamic studies have confirmed nicardipine's lack of negative inotropism, its ability to reduce coronary and peripheral vascular resistance, and its lack of effect on cardiac conduction. Several controlled trials have documented its efficacy in exertional angina, vasospastic angina, and essential hypertension. Nicardipine's potential as an antiatherosclerotic agent is currently under investigation. Nimodipine is undergoing a unique clinical development programme aimed at cerebrovascular disorders. In almost all species, nimodipine selectively increases cerebral blood flow and reverses cerebral artery spasm without altering cerebral oxidative metabolism or systemic blood pressure. In humans, a large, double-blind, placebo-controlled trial in subarachnoid haemorrhage showed that nimodipine significantly reduced the severity of neurological deficits associated with delayed cerebral vasospasm. Several uncontrolled trials with larger numbers of patients support these results. Nimodipine has also proved useful in reducing cerebral artery spasm during intracranial surgery, and in the prophylactic treatment of migraine headaches. A preliminary study of nimodipine in acute stroke showed promising results in limiting neurological disability. Felodipine is a very potent systemic arterial vasodilator with negligible myocardial depressant activity. It is also a renal artery vasodilator. Unlike the other new dihydropyridines, felodipine prolongs the A-H interval on electrophysiological testing, but only to about 50% of that observed with verapamil. Felodipine is undergoing clinical trials in essential hypertension.(ABSTRACT TRUNCATED AT 400 WORDS)

Cerebral arterial vasospasm following severe head injury: a transcranial Doppler study.

Transcranial Doppler ultrasound was used to determine the natural history of cerebral arterial vascular spasm following severe head injury. Doppler Flow Velocity (DFV) was measured in the anterior cerebral, middle cerebral and terminal carotid arteries. High DFVs consistent with vasospasm were identified in 68% of the 25 patients studied. They came on from between 12 h and 4 days and lasted from 12 h to 14 days. No relationship could be determined between presumed vasospasm and blood pressure, intracranial pressure or outcome. Rises in the maximum DFV value (to above 100 cm s-1) were associated with neurological deterioration in 12 instances (in 11 of these the DFV remained elevated for more than 12 h). Deterioration occurred in three instances without change in DFV. DFV rose to above 100 cm s-1 on 10 occasions without neurological change (but remained elevated for more than 12 h in only four of these). Vasospasm has been found to be more common following head injury and may be a more significant cause of deterioration than previously thought.

Provocation of coronary spasm by dopamine in patients with active variant angina pectoris.

The effects of dopamine on arteries are different depending on the dose, route of administration, and receptor population. Its administration can cause vasodilation by stimulation of dopaminergic receptors, vasoconstriction by stimulation of alpha-adrenergic and serotonergic receptors, and even spasm of cerebral arteries when given intracisternally in dogs. The ability of dopamine to provoke coronary spasm was assessed in 18 patients with active vasospastic angina in whom this amine was infused at rates of 5, 10, and 15 micrograms/kg/min for periods of 5 min each. The 12-lead electrocardiogram and blood pressure (cuff) were monitored throughout the whole test. In nine patients dopamine caused angina and ischemic electrocardiographic changes suggestive of coronary spasm: ST segment elevation in six patients and ST segment depression in the absence of important coronary stenoses in the remaining three. Infusion of dopamine was repeated during coronary angiography in three patients with positive test results: this provoked occlusive coronary spasm with ST segment elevation in two patients and nonocclusive spasm with ST segment depression in the remainder. In conclusion, infusion of dopamine provokes coronary spasm in a sizeable proportion of patients with active vasospastic angina. Its administration may be detrimental in patients susceptible to coronary spasm, such as those with acute myocardial infarction.

Arachidonate metabolites and vasospasm after subarachnoid haemorrhage.

A wide literature exists about the pathogenesis of cerebral arterial spasm following subarachnoid haemorrhage: several compounds have been identified in human cerebrospinal fluid as possible vasoactive agents involved in the biochemical mechanism of vasospasm onset. Many experimental evidences exist for a major involvement of arachidonate metabolites. The present work represents a review of experimental data supporting the hypothesis of cerebral arterial spasm as a result of an imbalanced vascular regulatory mechanism involving arachidonate metabolites. The authors have also monitored, in 25 cases of aneurysmal subarachnoid haemorrhage, lumbar and cisternal CSF levels of prostacyclin and PGD2, as representative of vasodilating and, respectively, vasoconstrictor compounds. In all cases CSF arachidonate metabolite levels after SAH were significantly higher than in control cases. Ten patients presented with symptomatic vasospasm: lumbar CSF PGD2 levels show fluctuations with superimposed peaks related to the neurological deterioration due to vasospasm, while lumbar CSF prostacyclin concentration-trend suggest a decreasing synthesis. In 15 patients presenting without vasospasm, lumbar CSF concentration of arachidonate metabolites are in a 'steady-state'. These data confirm the existence of an imbalanced biochemical situation promoting vasospasm, markedly in cisterns near to the ruptured aneurysmal wall. The evaluation of cisternal CSF levels of arachidonate metabolites supports the hypothesis of the clotting phenomenon around the ruptured aneurysm as an important predictive pattern of vasospasm, as shown in CT findings.

Prostaglandin D2 monitoring in human CSF after subarachnoid hemorrhage: the possible role of prostaglandin D2 in the genesis of cerebral vasospasm.

Experimental and clinical studies indicate that cerebral vasospasm following subarachnoid hemorrhage (SAH) may be caused by changed biochemical properties of the endothelium and vascular smooth muscle cell exposed to vasoactive substances synthetized by cerebral arteries and released in clotted blood. Many compounds have been identified in CSF from SAH patients: Thromboxanes A2 and B2, Prostaglandins F2 alpha, E2 and D2 are the major prostanoids incriminated in the causation of cerebral arterial spasm. We have monitored the CSF PGD2 concentrations with serial lumbar punctures at different intervals from the hemorrhage in 16 patients admitted for SAH: PGD2 was measured with radioimmunoassay as its 9-methoxy derivative. The lumbar CSF PGD2 concentration ranges from 0.11 to 1.53 ng/ml. In 7 cases vasospasm was angiographically demonstrated. 9 patients presented no clinical or radiological evidence of vasospasm. In 5 cases cisternal CSF samples were available at the operation by cisternal punctures. There was no correlation between CSF PGD2 concentration and clinical course. In the 7 cases with evidence of vasospasm a significant increase of CSF PGD2 corresponded to neurological deterioration. In all 9 cases without evidence of vasospasm CSF PGD2 concentration trend was in a steady-state. The cisternal CSF PGD2 concentration was higher than lumbar CSF concentration in cases with arterial spasm. This suggests the importance of the clotting phenomenon in vasospasm onset after SAH. PGD2 is one of the most important spasmogens in clotted blood. Although its role in the genesis of vasospasm onset remains to be defined, its vasospastic action, in addition to that of other analogous compounds, seems to be relevant.