Multi-phase CT-Angiography outperforms angiographic careggi collateral score and predicts functional outcome in acute ischemic stroke.

BACKGROUND: Collaterals are a strong determinant of clinical outcome in acute ischemic stroke (AIS) patients undergoing Endovascular Treatment (EVT). Careggi Collateral Score (CCS) is an angiographic score that demonstrated to be superior to the widely suggested ASITN/SIR score. Multi-phase CT-Angiography (mCTA) could be alternatively adopted for collateral assessment. We investigated whether mCTA had an equivalent predictive performance for functional outcome compared to CCS. METHODS: Consecutive AIS patients undergoing EVT for large vessel occlusion within 24 h from onset were analyzed. Receiver operating characteristic curves and multivariable logistic regression were investigated to evaluate the predictive performance of mCTA collateral score (range 0-5) and CCS (range 0-4) for good functional outcome (three-months modified Rankin Scale 0-2). RESULTS: We included 201 subjects (59.7% females, mean age 75), of whom 96 (47.7%) had good outcome at three-months. Both CCS (OR = 14.4, 95% CI = 6.3-33.8) and mCTA (OR = 23.8, 95% CI = 10.1-56.4) collateral scores were independent predictors of outcome. The AUC of CCS was 0.80 (95% CI 0.73-0.86) and the best cut-off was ≥ 3 (87% sensitivity, 71% specificity), while the AUC of mCTA collateral score was 0.84 (95% CI 0.78-0.90) with an optimal cut-off of ≥ 4 (85% sensitivity, 87% specificity). Patients with good mCTA collaterals experienced smaller (16.6 vs. 63.7 mL, p < 0.001) infarct lesion as compared to those with mCTA poor collaterals. CONCLUSION: mCTA discriminative ability for three-months 0-2 mRS was found to be comparable to CCS. mCTA appears a valid, non-invasive imaging modality for evaluating collaterals of AIS patients potentially eligible for EVT.

Thrombectomy in ischemic stroke patients with tandem occlusion in the posterior versus anterior circulation.

BACKGROUND: Mechanical thrombectomy (MT) was found to be beneficial in acute ischemic stroke patients with anterior tandem occlusion (a-TO). Instead, little is known about the effectiveness of MT in stroke patients with posterior tandem occlusion (p-TO). We aimed to compare MT within 24 h from last known well time in ischemic stroke patients with p-TO versus a-TO. METHODS: We conducted a cohort study on prospectively collected data of patients registered in the Italian Registry of Endovascular Treatment in Acute Stroke (IRETAS) who were treated with MT within 24 h from last known well time for acute ischemic stroke with p-TO (n = 275) or a-TO (n = 1853). RESULTS: After adjustment for unbalanced pre-procedure variables (year 2015-2021, age, sex, NIHSS score, ASPECTS, and time strata for puncture groin) and pre-stroke mRS score as pre-defined predictor, p-TO was significantly associated with lower probability of mRS score 0-2 (OR 0.415, 95% CI 0.268-0.644) and with higher risk of death (OR 2.813, 95% CI 2.080-3.805) at 3 months. After adjustment for unbalanced procedural and post-procedure variables (IVT, general anesthesia, TICI 3, and 24-h HT) and pre-stroke mRS score as pre-defined predictor, association between p-TO and lower probability of mRS score 0-2 (OR 0.444, 95% CI 0.304-0.649) and association between p-TO and with higher risk of death (OR 2.971, 95% CI 1.993-4.429) remained significant. CONCLUSIONS: MT within 24 h from last known well time in ischemic stroke patients with p-TO versus a-TO was associated with worse outcomes at 3 months.

Woven EndoBridge Device for Unruptured Wide-Neck Bifurcation Aneurysm: A Multicenter 5-Year Follow-up.

BACKGROUND AND OBJECTIVES: This multicenter study aimed to assess the safety and efficacy of the Woven EndoBridge (WEB) device for treating unruptured wide-neck intracranial bifurcation aneurysms (WIBAs) with short-, mid-, and long-term follow-ups (FUPs). METHODS: Consecutive patients with unruptured WIBAs treated with WEB between December 2014 and January 2018 were included. Patient, aneurysm, and device characteristics were collected and analyzed retrospectively. Morbidity and mortality rates were determined by collecting intraprocedural, periprocedural, and delayed complications. Aneurysm occlusion was assessed at 1, 3, and 5 years using a 3-grade scale: complete occlusion, neck remnant, and residual aneurysm. Complete occlusion and neck remnant were considered as adequate occlusion. Patients who received re-treatment were also evaluated. RESULTS: The study included 104 consecutive patients (55.8% female, mean age 58.6 ± 11.8 years). Aneurysm maximum size, neck, and dome-to-neck mean were, respectively, 6.9 ± 2.1 mm, 4.5 ± 1.2 mm, and 1.4 ± 0.3 mm. One-year FUP was collected for 95 patients, and 3- and 5-year FUPs were collected for 83 patients. Adequate occlusion was observed at 1-year FUP in 90.5% (86/95), 91.6% (76/83) was observed at 3-year FUP, and 92.8% (77/83) at 5-year FUP. None of the aneurysms bled after treatment. During FUP, 6/83 patients (7.2%) were re-treated for residual aneurysm. Morbidity and mortality rates closely related to aneurysm occlusion were 0% (0/104). CONCLUSION: The WEB device was safe and effective for treating unruptured WIBAs, both in short-term and long-term FUPs.

Epidemiology, organization, diagnosis and treatment of acute ischemic stroke.

The management of acute ischemic stroke is changing. Over the period of 2010-2050, the number of incident strokes is expected to be more than double. Rapid access to mechanical thrombectomy for patients with large vessel occlusion is critically associated with their functional outcome. Moreover, patients with first pass effect had a better clinical outcome, lower mortality, and fewer procedural adverse events. We discuss some advances in acute ischemic stroke regarding the organization, the diagnosis and the treatment.

Predictors for hemorrhagic transformation and cerebral edema in stroke patients with first-pass complete recanalization.

BACKGROUND: Predictors of radiological complications attributable to reperfusion injury remain unknown when baseline setting is optimal for endovascular treatment and procedural setting is the best in stroke patients with large vessel occlusion (LVO). AIMS: To identify clinical and radiological/procedural predictors for hemorrhagic transformation (HT) and cerebral edema (CED) at 24 hr in patients obtaining complete recanalization in one pass of thrombectomy for ischemic stroke ⩽ 6 h from symptom onset with intra-cranial anterior circulation LVO and ASPECTS ⩾ 6. METHODS: We conducted a cohort study on prospectively collected data from 1400 patients enrolled in the Italian Registry of Endovascular Treatment in Acute Stroke. RESULTS: HT was reported in 248 (18%) patients and early CED was reported in 260 (19.2%) patients. In the logistic regression model including predictors from a first model with clinical variables and from a second model with radiological/procedural variables, diabetes mellitus (odds ratio (OR) = 1.832, 95% confidence interval (CI) = 1.201-2.795), higher National Institutes of Health Stroke Scale (NIHSS) (OR = 1.076, 95% CI = 1.044-1.110), lower Alberta Stroke Program Early CT (ASPECTS) (OR = 0.815, 95% CI = 0.694-0.957), and longer onset-to-groin time (OR = 1.005, 95% CI = 1.002-1.007) were predictors of HT, whereas general anesthesia was inversely associated with HT (OR = 0.540, 95% CI = 0.355-0.820). Higher NIHSS (OR = 1.049, 95% CI = 1.021-1.077), lower ASPECTS (OR = 0.700, 95% CI = 0.613-0.801), intravenous thrombolysis (OR = 1.464, 95% CI = 1.061-2.020), longer onset-to-groin time (OR = 1.002, 95% CI = 1.001-1.005), and longer procedure time (OR = 1.009, 95% CI = 1.004-1.015) were predictors of early CED. After repeating a fourth logistic regression model including also good collaterals, the same variables remained predictors for HT and/or early CED, except diabetes mellitus and thrombolysis, while good collaterals were inversely associated with early CED (OR = 0.385, 95% CI = 0.248-0.599). CONCLUSIONS: Higher NIHSS, lower ASPECTS, and longer onset-to-groin time were predictors for both HT and early CED. General anesthesia and good collaterals were inversely associated with HT and early CED, respectively. Longer procedure time was predictor of early CED.

Endovascular treatment in patients with acute ischemic stroke and cancer: Systematic review and meta-analysis.

Introduction: Although stroke occurs frequently in patients with cancer, there is scarce evidence regarding the safety and efficacy of endovascular treatment (EVT) in patients with acute ischemic stroke and concurrent cancer. We performed a systematic review and meta-analysis to summarize the existing literature. Methods: We searched for English written observational studies reporting data on safety and efficacy of EVT in patients with acute ischemic stroke and concurrent cancer. Outcomes of interest were: functional independence (modified Rankin Scale (mRS) ⩽ 2); mortality at 3 months; rate of successful recanalization (modified Treatment In Cerebral Ischemia (mTICI) 2b or 3); occurrence of any hemorrhagic transformation (both symptomatic and asymptomatic). We pooled data with Maentel-Haenszel model to calculate cumulative odds ratios (ORs). Results: We included seven studies with a total of 4465 patients, of whom 262 (6%) with cancer. We observed various definitions of cancer across included studies. Patients with cancer had less likely mRS⩽2 at 3 months (24% vs 42%, OR = 0.44; 95% CI = 0.32-0.60) and increased probability of death (43% vs 19%, OR = 5.02; 95% CI = 2.90-8.69). There was no difference in successful recanalization (70% vs 75%, OR = 0.84; 95% CI = 0.49-1.44); patients with cancer had increased risk of any intracerebral hemorrhage after treatment (49% vs 34%, OR = 1.95; 95% CI = 1.28-2.96), though not for symptomatic ICH (OR 1.04; 95% CI = 0.59-1.85). Conclusion: Patients with acute ischemic stroke and cancer have similar EVT recanalization but higher probability of functional dependence, death, and any hemorrhagic transformation, though not necessarily symptomatic, compared with patients without cancer. Our results may help communication with patients and carers.

Pulsatile tinnitus due to stenosis of the supraclinoid segment of the internal carotid artery: Management with a low-profile self-expanding stent.

Atherosclerotic stenosis of the internal carotid artery is a rare cause of pulsatile tinnitus. Stenosis responsible for tinnitus is usually located in the petrous segment of the vessel or, even more uncommonly, in the extracranial segment. However, to the best of our knowledge, a stenosis of the intradural supraclinoid segment of the internal carotid had never been reported as a source of pulsatile tinnitus. We describe the case of a man with a history of previous ischaemic stroke and invalidating pulsatile tinnitus, caused by a high grade, diaphragm-like shaped, stenosis of the supraclinoid internal carotid artery. The stenosis was treated with angioplasty and stenting with a low-profile self-expanding high radial force stent (Acclino flex HRF, Acandis). Tinnitus disappeared immediately after the procedure. At the two-year follow-up no recurrence of the tinnitus and the stenosis occurred. Intradural internal carotid artery stenosis should be considered as a very rare cause of pulsatile tinnitus.

Case report: Treatment of anterior cerebral artery aneurysms with combined remodeling technique and flow diverter deployment through a dual lumen balloon catheter.

We present the technical aspects of embolization for two unruptured medium-sized aneurysms of the anterior cerebral artery treated with balloon-remodeling technique and loose coiling of the sac with the final deployment of a 0. 017-compatible flow diverter. Both procedures were performed with dual antiplatelet therapy premedication and under general anesthesia. The anatomy of the two aneurysms was similar with a wide neck and the presence of a collateral artery branching off it, which required the additional use of a compliant balloon in order to retain patency and avoid coil protrusion. After initial coiling, a nitinol flow-diverter was deployed through a coaxial dual lumen balloon microcatheter. Both these interventions encountered no complications, and the patient was discharged on day 2. At 6-month clinical and radiological follow-up, neither patient had neurological deficits, the aneurysms were both completely occluded, nor the stented arteries were patent along with their collateral branches.

Initial Experience With the Trevo NXT Stent Retriever.

Background: The application of a new coating to the delivery wire of the Trevo retriever has the potential to improve its handling. We therefore report our initial experience with this new stent retriever for mechanical thrombectomy of large and medium vessel occlusions. Methods: We pooled data of four high-volume European stroke centers over the time period from October 2020 to February 2021. Patients were included in our study if the Trevo NXT stent retriever was used as a first-line device. Primary endpoints were first-pass near-complete or complete reperfusion, defined as mTICI score of ≥2c. Secondary endpoints were final reperfusion, National Institutes of Health Stroke Scale (NIHSS) at 24 h and discharge, device malfunctions, complications during the procedure, and subjective ratings of the interventionalists regarding device functionality. Results: Eighty patients (39 women, mean age 74 ± 14 years) were eligible for our study. Median NIHSS at admission was 15 (IQR, 8-19), and median Alberta Stroke Program Early CT Score at baseline was 9 (IQR, 8-10). In 74 (93%) patients a primary combined approach was used as first-line technique. First-pass near-complete reperfusion was achieved in 43 (54%) and first-pass complete reperfusion in 34 (43%) patients. Final near-complete reperfusion was achieved in 66 (83%) patients after a median of 1.5 (1-3) passes, while final successful reperfusion was observed in 96% of our cases. We observed no device malfunctions. Median NIHSS at discharge was 2 (IQR, 0-5), and 3 patients (4%) suffered a symptomatic intracranial hemorrhage. Conclusions: Based on our initial data, we conclude that the Trevo NXT is an effective and safe tool for mechanical thrombectomy especially when used for combined approaches.

Successful endovascular treatment of a spontaneous bleeding accessory spleen: A case report.

Accessory spleens are often encountered in radiologic studies and they are not usually associated with symptoms. They could arise from autotransplantation of splenic tissue after splenic trauma or splenectomy (splenosis) [1]. In this case we describe a woman treated for splenectomy 20 years before and subsequently for adhesions, that suffered sudden left upper abdominal quadrant pain, weakness, and pale color. Contrast-enhanced computed tomography revealed free spilling in the abdomen and venous bleeding of a big accessory spleen; thus the patient underwent transcatheter arterial embolization with coils. Due to the 2 previous surgical operations in the splenic loggia, endovascular treatment compared to "open surgery" was the best choice in this case because of determined less complications, a shorter period of hospitalization, and a reduction of health cost.

Inhibitory effect of cannabichromene, a major non-psychotropic cannabinoid extracted from Cannabis sativa, on inflammation-induced hypermotility in mice.

BACKGROUND AND PURPOSE: Cannabichromene (CBC) is a major non-psychotropic phytocannabinoid that inhibits endocannabinoid inactivation and activates the transient receptor potential ankyrin-1 (TRPA1). Both endocannabinoids and TRPA1 may modulate gastrointestinal motility. Here, we investigated the effect of CBC on mouse intestinal motility in physiological and pathological states. EXPERIMENTAL APPROACH: Inflammation was induced in the mouse small intestine by croton oil. Endocannabinoid (anandamide and 2-arachidonoyl glycerol), palmitoylethanolamide and oleoylethanolamide levels were measured by liquid chromatography-mass spectrometry; TRPA1 and cannabinoid receptors were analysed by quantitative RT-PCR; upper gastrointestinal transit, colonic propulsion and whole gut transit were evaluated in vivo; contractility was evaluated in vitro by stimulating the isolated ileum, in an organ bath, with ACh or electrical field stimulation (EFS). KEY RESULTS: Croton oil administration was associated with decreased levels of anandamide (but not 2-arachidonoyl glycerol) and palmitoylethanolamide, up-regulation of TRPA1 and CB1 receptors and down-regulation of CB2 receptors. Ex vivo CBC did not change endocannabinoid levels, but it altered the mRNA expression of TRPA1 and cannabinoid receptors. In vivo, CBC did not affect motility in control mice, but normalized croton oil-induced hypermotility. In vitro, CBC reduced preferentially EFS- versus ACh-induced contractions. Both in vitro and in vivo, the inhibitory effect of CBC was not modified by cannabinoid or TRPA1 receptor antagonists. CONCLUSION AND IMPLICATIONS: CBC selectively reduces inflammation-induced hypermotility in vivo in a manner that is not dependent on cannabinoid receptors or TRPA1.

Milk thistle in liver diseases: past, present, future.

Silybum marianum or milk thistle (MT) is the most well-researched plant in the treatment of liver disease. The active complex of MT is a lipophilic extract from the seeds of the plant and is composed of three isomer flavonolignans (silybin, silydianin, and silychristin) collectively known as silymarin. Silybin is a component with the greatest degree of biological activity and makes up 50% to 70% of silymarin. Silymarin is found in the entire plant but it is concentrated in the fruit and seeds. Silymarin acts as an antioxidant by reducing free radical production and lipid peroxidation, has antifibrotic activity and may act as a toxin blockade agent by inhibiting binding of toxins to the hepatocyte cell membrane receptors. In animals, silymarin reduces liver injury caused by acetaminophen, carbon tetrachloride, radiation, iron overload, phenylhydrazine, alcohol, cold ischaemia and Amanita phalloides. Silymarin has been used to treat alcoholic liver disease, acute and chronic viral hepatitis and toxin-induced liver diseases.

Anti-proliferative effect of rhein, an anthraquinone isolated from Cassia species, on Caco-2 human adenocarcinoma cells.

In recent years, the use of anthraquinone laxatives, in particular senna, has been associated with damage to the intestinal epithelial layer and an increased risk of developing colorectal cancer. In this study, we evaluated the cytotoxicity of rhein, the active metabolite of senna, on human colon adenocarcinoma cells (Caco-2) and its effect on cell proliferation. Cytotoxicity studies were performed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), neutral red (NR) and trans-epithelial electrical resistance (TEER) assays whereas (3)H-thymidine incorporation and Western blot analysis were used to evaluate the effect of rhein on cell proliferation. Moreover, for genoprotection studies Comet assay and oxidative biomarkers measurement (malondialdehyde and reactive oxygen species) were used. Rhein (0.1-10 microg/ml) had no significant cytotoxic effect on proliferating and differentiated Caco-2 cells. Rhein (0.1 and 1 microg/ml) significantly reduced cell proliferation as well as mitogen-activated protein (MAP) kinase activation; by contrast, at high concentration (10 microg/ml) rhein significantly increased cell proliferation and extracellular-signal-related kinase (ERK) phosphorylation. Moreover, rhein (0.1-10 microg/ml): (i) did not adversely affect the integrity of tight junctions and hence epithelial barrier function; (ii) did not induce DNA damage, rather it was able to reduce H(2)O(2)-induced DNA damage and (iii) significantly inhibited the increase in malondialdehyde and reactive oxygen species (ROS) levels induced by H(2)O(2)/Fe(2+). Rhein was devoid of cytotoxic and genotoxic effects in colon adenocarcinoma cells. Moreover, at concentrations present in the colon after a human therapeutic dosage of senna, rhein inhibited cell proliferation via a mechanism that seems to involve directly the MAP kinase pathway. Finally, rhein prevents the DNA damage probably via an anti-oxidant mechanism.

Cannabidiol, a safe and non-psychotropic ingredient of the marijuana plant Cannabis sativa, is protective in a murine model of colitis.

Inflammatory bowel disease affects millions of individuals; nevertheless, pharmacological treatment is disappointingly unsatisfactory. Cannabidiol, a safe and non-psychotropic ingredient of marijuana, exerts pharmacological effects (e.g., antioxidant) and mechanisms (e.g., inhibition of endocannabinoids enzymatic degradation) potentially beneficial for the inflamed gut. Thus, we investigated the effect of cannabidiol in a murine model of colitis. Colitis was induced in mice by intracolonic administration of dinitrobenzene sulfonic acid. Inflammation was assessed both macroscopically and histologically. In the inflamed colon, cyclooxygenase-2 and inducible nitric oxide synthase (iNOS) were evaluated by Western blot, interleukin-1beta and interleukin-10 by ELISA, and endocannabinoids by isotope dilution liquid chromatography-mass spectrometry. Human colon adenocarcinoma (Caco-2) cells were used to evaluate the effect of cannabidiol on oxidative stress. Cannabidiol reduced colon injury, inducible iNOS (but not cyclooxygenase-2) expression, and interleukin-1beta, interleukin-10, and endocannabinoid changes associated with 2,4,6-dinitrobenzene sulfonic acid administration. In Caco-2 cells, cannabidiol reduced reactive oxygen species production and lipid peroxidation. In conclusion, cannabidiol, a likely safe compound, prevents experimental colitis in mice.

Silymarin BIO-C, an extract from Silybum marianum fruits, induces hyperprolactinemia in intact female rats.

Breastfeeding is widely acknowledged to have important health benefits for infants and mothers. Milk thistle (Silybum marianum fruits) has been recently proposed to be used by nursing mothers for stimulating milk production; however, the mode of action of this herbal drug is still unknown. In this paper, we have evaluated the effect of a micronized standardized extract of S. marianum (Silymarin BIO-C=Piùlatte) on the serum levels of prolactin in female rats. A 14-day treatment with Silymarin BIO-C (25-200mg/kg, given orally) increased, in a dose dependent manner, the serum prolactin levels. Moreover, after a 66-day discontinuation of Silymarin BIO-C treatment, prolactin levels were still significantly elevated although we observed a trend to decrease that was counteracted by a further 7-day treatment with Silymarin BIO-C. Bromocriptine, a dopamine D(2) receptor agonist, (1-10mg/kg, os) significantly and in a dose dependent manner, reduced the serum prolactin levels; bromocriptine, at the dose of 1mg/kg, significantly reduced the high serum prolactin levels induced by Silymarin BIO-C. In conclusion, we have shown that an extract from S. marianum fruits significantly increases circulating prolactin levels in female rats; this effect seems to involve, at least in part, dopamine D(2) receptors.

Phytotherapeutic approach to alcohol dependence: new old way?

Alcohol abuse and dependence represent a worldwide problem from both medical and social points of view. In Italy it is estimated that there are about one million alcohol-dependent subjects. The pharmacological treatment of patients with alcohol dependence plays a key role in order to achieve alcohol abstinence and prevent relapse. At present, the possible utility of the complementary medicines in the treatment of alcohol dependence is controversial. In the last years, pre-clinical and clinical data from traditional medicines suggest that novel pharmacological approaches for treatment of alcoholism and alcohol abuse may stem from natural substances. The present review summarizes the findings of the effects of phytotherapy in alcohol addiction.

Garlic: empiricism or science?

Garlic (Allium sativum L. fam. Alliaceae) is one of the best-researched, best-selling herbal remedies and is also commonly used as a food and a spice. Garlic constituents include enzymes (for example, alliinase) and sulfur-containing compounds, including alliin, and compounds produced enzymatically from alliin (for example, allicin). Traditionally, it has been employed to treat infections, wounds, diarrhea, rheumatism, heart disease, diabetes, and many other disorders. Experimentally, it has been shown to exert antilipidemic, antihypertensive, antineoplastic, antibacterial, immunostimulant and hypoglycemic actions. Clinically, garlic has been evaluated for a number of conditions, including hypertension, hypercholesterolemia, intermittent claudication, diabetes, rheumatoid arthritis, common cold, as an insect repellent, and for the prevention of arteriosclerosis and cancer. Systematic reviews are available for the possible antilipidemic, antihypertensive, antithrombotic and chemopreventive effects. However, the clinical evidence is far from compelling. Garlic appears to be generally safe although allergic reactions may occur.

Inhibitory effect of the anorexic compound oleoylethanolamide on gastric emptying in control and overweight mice.

Gastric emptying regulates food intake. Oleoylethanolamide (OEA), an endogenous acylethanolamide chemically related to the endocannabinoid anandamide, inhibits food intake, but its effect on gastric emptying is unknown. Here, we investigated the effect and the role of OEA on gastric emptying in mice fed either a standard (STD) or a high-fat diet (HFD) for 14 weeks. Gastric emptying was reduced by OEA, but not by its saturated analog, palmitoylethanolamide. The effect of OEA was unaffected by rimonabant (cannabinoid CB1 receptor antagonist), SR144528 (cannabinoid CB2 receptor antagonist), 5'-iodoresiniferatoxin (transient receptor potential vanilloid type 1 antagonist), or MK886 (peroxisome proliferator-activated receptor-alpha) antagonist. Compared to STD mice, HFD mice showed delayed gastric emptying and higher levels of gastric OEA. HFD-induced increase in OEA levels was accompanied by increased expression of the OEA-synthesizing enzyme N-acyl-phosphatidylethanolamine-selective phospholipase D and decreased expression of the OEA-degrading enzyme fatty acid amide hydrolase. These results might suggest that elevation of gastric OEA could possibly contribute to the delayed gastric emptying observed in HFD-fed animals. HFD regulates OEA levels in the stomach through an increase of its biosynthesis and a decrease of its enzymatic degradation. The inhibitory effect of OEA on gastric emptying here observed might underlie part of the anorexic effects of this compound previously reported.