NXY-059, a Failed Stroke Neuroprotectant, Offers No Protection to Stem Cell-Derived Human Neurons.

BACKGROUND: Developing new medicines is a complex process where understanding the reasons for both failure and success takes us forward. One gap in our understanding of most candidate stroke drugs before clinical trial is whether they have a protective effect on human tissues. NXY-059 is a spin-trap reagent hypothesized to have activity against the damaging oxidative biology which accompanies ischemic stroke. Re-examination of the preclinical in vivo dataset for this agent in the wake of the failed SAINT-II RCT highlighted the presence of a range of biases leading to overestimation of the magnitude of NXY-059's effects in laboratory animals. Therefore, NXY-059 seemed an ideal candidate to evaluate in human neural tissues to determine whether human tissue testing might improve screening efficiency. MATERIALS AND METHODS: The aim of this randomized and blinded study was to assess the effects of NXY-059 on human stem cell-derived neurons in the presence of ischemia-like injury induced by oxygen glucose deprivation or oxidative stress induced by hydrogen peroxide or sodium nitroprusside. RESULTS: In MTT assays of cell survival, lactate dehydrogenase assays of total cell death and terminal deoxynucleotidyl transferase dUTP nick end labeling staining of apoptotic-like cell death, NXY-059 at concentrations ranging from 1 µm to 1 mm was completely without activity. Conversely an antioxidant cocktail comprising 100 µm each of ascorbate, reduced glutathione, and dithiothreitol used as a positive control provided marked neuronal protection in these assays. CONCLUSION: These findings support our hypothesis that stroke drug screening in human neural tissues will be of value and provides an explanation for the failure of NXY-059 as a human stroke drug.

Alpha-ketoglutarate attenuates toxic effects of sodium nitroprusside and hydrogen peroxide in Drosophila melanogaster.

The protective effects of dietary alpha-ketoglutarate (AKG) are described that aid fruit flies, Drosophila melanogaster, to resist sodium nitroprusside (SNP) and hydrogen peroxide toxicity. Food supplementation with 10mM AKG alleviated toxic effects of 1mM SNP added to food and improved fly development. Dietary AKG also prevented the increase in levels of oxidative stress markers seen in SNP-reared adult flies. In vitro AKG did not affect the rate of SNP decomposition and did not bind iron and nitrite ions released in this process. Alpha-ketoglutarate also displayed high H2O2-scavenging activity in vitro and efficiently protected adult flies against this compound in combined treatments. Based on the observed antioxidant activity of AKG, it may be suggested that the antioxidant mode of AKG action (apart from its cyanide-binding capability) may be used to prevent the toxic effects of SNP and improve general physiological state of D. melanogaster and other animals and humans.

Protective effects of resveratrol oligomers from Vitis amurensis against sodium nitroprusside-induced neurotoxicity in human neuroblastoma SH-SY5Y cells.

Nitric oxide (NO) induces apoptosis in neuronal cells, and has been implicating in a variety of neuronal pathological process. Thus, there is much interest in identifying natural substances which have protective effects against damage induced by nitrosative stress. The roots of Vitis amurensis have been used as traditional medicine and contain structurally diverse resveratrol oligomers with various biological activities. However, there have been few studies on the protective effect of resveratrol oligomers against neurotoxic reactive nitrogen species. In this study, we evaluated the protective effects of two resveratrol oligomers from V. amurensis, vitisin A and heyneanol A, against NO-induced toxicity. Additionally, their antioxidant activities were determined by measuring NO and hydroxyl radical scavenging ability. Both vitisin A and heyneanol A reduced cell death and DNA fragmentation induced by sodium nitroprusside in SH-SY5Y cells. The present study indicates that radical scavenging activities of vitisin A and heyneanol A contribute to protecting neuronal cells against nitrosative stress.

Stereoselective reduction of 1-o-isopropyloxygenipin enhances its neuroprotective activity in neuronal cells from apoptosis induced by sodium nitroprusside.

Genipin is a Chinese herbal medicine with both neuroprotective and neuritogenic activity. Because of its unstable nature, efforts have been to develop more stable genipin derivatives with improved biological activities. Among the new compounds reported in the literature, (1R)-isopropyloxygenipin (IPRG001) is a more stable but less active compound compared with the parent, genipin. Here, two new IPRG001 derivatives generated by stereoselective reduction of the C6 =C7 double bond were synthesized. The 1R and 1S isomers of (4aS,7S,7aS)-methyl-7-(hydroxymethyl)-1-isopropoxy-1,4a,5,6,7,7a-hexahydrocyclopenta[c]pyran-4-carboxylate (CHR20 and CHR21) were shown to be very stable both in high-glucose cell culture medium and in mice serum at 37 °C. Evaluation using an MTT assay and Hoechst staining showed that CHR20 and CHR21 promote the survival of rat adrenal pheochromocytoma (PC12) and retinal neuronal (RGC-5) cells from injury induced by sodium nitroprusside (SNP). The neuroprotective effects of CHR20 and CHR21 were greater than both isomers of IPRG001, the parent compounds. These results indicate that reduction of 1-O-isopropyloxygenipin enhances its neuroprotective activity without affecting its stability.

Inhibition of key enzymes linked to type 2 diabetes and sodium nitroprusside-induced lipid peroxidation in rat pancreas by water extractable phytochemicals from some tropical spices.

CONTEXT: Spices have been used as food adjuncts and in folklore for ages. Inhibition of key enzymes (α-amylase and α-glucosidase) involved in the digestion of starch and protection against free radicals and lipid peroxidation in pancreas could be part of the therapeutic approach towards the management of hyperglycemia and dietary phenolics have shown promising potentials. OBJECTIVE: This study investigated and compared the inhibitory properties of aqueous extracts of some tropical spices: Xylopia aethiopica [Dun.] A. Rich (Annonaceae), Monodora myristica (Gaertn.) Dunal (Annonaceae), Syzygium aromaticum [L.] Merr. et Perry (Myrtaceae), Piper guineense Schumach. et Thonn (Piperaceae), Aframomum danielli K. Schum (Zingiberaceae) and Aframomum melegueta (Rosc.) K. Schum (Zingiberaceae) against α-amylase, α-glucosidase, 1,1-diphenyl-2-picrylhydrazyl (DPPH) radicals and sodium nitroprusside (SNP)-induced lipid peroxidation in rat pancreas--in vitro using different spectrophotometric method. MATERIALS AND METHODS: Aqueous extract of the spices was prepared and the ability of the spice extracts to inhibit α-amylase, α-glucosidase, DPPH radicals and SNP-induced lipid peroxidation in rat pancreas--in vitro was investigated using various spectrophotometric methods. RESULT: All the spice extracts inhibited α-amylase (IC(50) = 2.81-4.83 mg/mL), α-glucosidase (IC(50) = 2.02-3.52 mg/mL), DPPH radicals (EC(50) = 15.47-17.38 mg/mL) and SNP-induced lipid peroxidation (14.17-94.38%), with the highest α-amylase & α-glucosidase inhibitory actions and DPPH radical scavenging ability exhibited by X. aethiopica, A. danielli and S. aromaticum, respectively. Also, the spices possess high total phenol (0.88-1.3 mg/mL) and flavonoid (0.24-0.52 mg/mL) contents with A. melegueta having the highest total phenolic and flavonoid contents. DISCUSSION AND CONCLUSION: The inhibitory effects of the spice extracts on α-amylase, α-glucosidase, DPPH radicals and SNP-induced lipid peroxidation in pancreas (in vitro) could be attributed to the presence of biologically active phytochemicals such as phenolics and some non-phenolic constituents of the spices. Furthermore, these spices may exert their anti-diabetic properties through the mechanism of enzyme inhibition, free radicals scavenging ability and prevention of lipid peroxidation.

Antioxidant properties of Taraxacum officinale fruit extract are involved in the protective effect against cellular death induced by sodium nitroprusside in brain of rats.

CONTEXT: Taraxacum officinale Weber (Asteraceae), known as dandelion, is used for medicinal purposes due to its choleretic, diuretic, antitumor, antioxidant, antiinflammatory, and hepatoprotective properties. OBJECTIVE: We sought to investigate the protective activity of T. officinale fruit extract against sodium nitroprusside (SNP)-induced decreased cellular viability and increased lipid peroxidation in the cortex, hippocampus, and striatum of rats in vitro. To explain the mechanism of the extract's antioxidant activity, its putative scavenger activities against NO, DPPH·, OH·, and H(2)O(2) were determined. METHODS: Slices of cortex, hippocampus, and striatum were treated with 50 µM SNP and T. officinale fruit ethanolic extract (1-20 µg/mL) to determine cellular viability by MTT reduction assay. Lipid peroxidation was measure in cortical, hippocampal and striatal slices incubates with SNP (5 µM) and T. officinale fruit extract (1-20 µg/mL). We also determined the scavenger activities of T. officinale fruit extract against NO·, DPPH·, OH·, and H(2)O(2), as well as its iron chelating capacity. RESULTS: The extract (1, 5, 10, and 20 µg/mL) protected against SNP-induced decreases in cellular viability and increases in lipid peroxidation in the cortex, hippocampus, and striatum of rats. The extract had scavenger activity against DPPH· and NO· at low concentrations and was able to protect against H(2)O(2) and Fe(2+)-induced deoxyribose oxidation. CONCLUSION: T. officinale fruit extract has antioxidant activity and protects brain slices against SNP-induced cellular death. Possible mechanisms of action include its scavenger activities against reactive oxygen species (ROS) and reactive nitrogen species (RNS), which are attributed to the presence of phenolic compounds in the extract.

Inhibition of acetylcholinesterase activities and some pro-oxidant induced lipid peroxidation in rat brain by two varieties of ginger (Zingiber officinale).

Ginger has been reportedly used for the management or treatment of Alzheimer's disease in folklore medicine. Therefore, this study sought to investigate the inhibitory effects of water extractable phytochemicals of red and white ginger on acetylcholinesterase activities, and sodium nitroprusside (SNP) and quinolinic acid (QA)-induced lipid peroxidation in rat brain -in vitro. Both extracts inhibited acetylcholinesterase (AChE) activities in a dose-dependent manner; however, white ginger had higher acetylcholinesterase inhibitory activity than red ginger. Combination of the ginger inhibited acetylcholinesterase activities synergistically. Furthermore, SNP and QA caused a significant increase in the malondialdehyde (MDA) contents of the brain; however, the extracts significantly decrease the SNP and QA elevated brain MDA contents in a dose-dependent manner. Nevertheless, there was no significant difference (P>0.05) in the inhibition of the SNP and QA-induced lipid peroxidation by both extracts. The inhibitory effect of ginger extracts on acetylcholinesterase activities and some prooxidants induced lipid peroxidation in rat's brain could be attributed to the presence of phytochemicals such as flavonoids, tannins, alkaloids and terpenoids. Therefore, some possible mechanism by which ginger extracts exert anti-Alzheimer properties could be through the inhibition of acetylcholinesterase activities and prevention of lipid peroxidation in the brain.

The plant phenolic diterpene carnosol suppresses sodium nitroprusside-induced toxicity in c6 glial cells.

Carnosol, a naturally occurring bioactive phenolic diterpene originating from rosemary and sage, has been shown to exert antioxidant and anti-inflammatory effects. This study examined possible protective effects of carnosol on sodium nitroprusside (SNP)-induced cytotoxicity in C6 glial cells. Carnosol (1-10 microM) dose-dependently attenuated SNP (100 microM)-induced cell death and NO production. SNP-induced apoptotic characteristics, including DNA fragmentation, caspase-3 activation, and c-jun N-terminal protein kinase (JNK) phosphorylation, were significantly suppressed by carnosol (10 microM). In addition, carnosol pretreatment restored the level of reduced glutathione (GSH), which was diminished by SNP treatment. Although both SNP (100 microM) and carnosol (10 microM) stimulated the HO-1 expression time-dependently, SNP caused a temporal increase in HO-1 in early time periods (3-6 h) before cell death occurred. In contrast, carnosol induced the sustained expression of HO-1 until a late time point (24 h). The addition of 1 microM zinc protoporphyrin IX (ZnPP), a specific HO inhibitor, with SNP or carnosol further reduced cell viability. Also, the addition of ZnPP inhibited the protective effect of carnosol against SNP-induced cytotoxicity in C6 cells. These results suggest that carnosol possesses abilities to inhibit SNP-mediated glial cell death through modulation of apoptotic events and induction of HO-1 expression.

Commonly used tropical medicinal plants exhibit distinct in vitro antioxidant activities against hepatotoxins in rat liver.

Lipid peroxidation in biological systems has been considered as one of the major mechanisms of cell injury in aerobic organisms subjected to oxidation stress. Plants, among other functions, are considered to act as free radical scavengers and as antioxidants. Iron II (Fe(2+)), sodium nitroprusside (SNP) and nitropropionic acid stimulate the production of free radicals and lipid peroxidation. In this study, four commonly used tropical medicinal plants (Kigelia africana, Calotropis procera, Hibiscus sabdariffa and Alchornea cordifolia) were studied (in vitro) for their effects on the formation of thiobarbituric acid reactive substances (TBARS) induced by different pro-oxidants (10 microM FeSO(4), 5 microM -sodium SNP and 2mM 3-nitropropionic acid) in rat liver homogenate. All the pro-oxidants significantly increased (P<0.05) the formation of TBARS, which indicates increased lipid peroxidation in the rat liver (in vitro). However, all the plant extracts statistically (P<0.05) reduced the production of TBARS in a concentration-dependent manner in all the tested pro-oxidant-induced oxidative stresses. Alchornea cordifolia appeared to offer the highest protection. The results of the present study suggest that the use of these plants in the treatment of various diseases, especially liver disease, is probably due to their ability to act as antioxidants.

Characterization of transcriptional regulation of neurogranin by nitric oxide and the role of neurogranin in SNP-induced cell death: implication of neurogranin in an increased neuronal susceptibility to oxidative stress.

Neurogranin (Ng), a calmodulin (CaM)-binding protein kinase C (PKC) substrate, regulates the availability of Ca(2+)/CaM complex and modulates the homeostasis of intracellular calcium in neurons. Previous work showed Ng oxidation by NO donor induces increase in [Ca(2+)](i). The current study demonstrated that the gene transcription of Ng could be up-regulated by various nitric oxide (NO) donors via a NO-soluble guanylyl cyclase (sGC)-mediated pathway. Furthermore, ectopic expression of neuronal nitric oxide synthase (nNOS) in human embryonic kidney 293 cells (HEK 293) exhibited a nNOS-concentration-dependent biphasic regulatory effect on Ng gene transcription. One of the NO donors, sodium nitroprusside (SNP), however, induced cell death of neuroblastoma Neuro-2a cells. The potency of SNP-induced cell death was shown to be higher in Neuro-2a cells expressing recombinant Ng, as compared with Neuro-2a control cells without Ng expression in cell viability and apoptosis assays. Single-cell fluorescence imaging and site-directed mutagenesis studies suggest that Ng promotes SNP-induced cell death through an amplification of calcium-mediated signaling, which requires the interaction between CaM and IQ motif of Ng. Increased neuronal susceptibility rendered by Ng in response to pathophysiological NO production is suggested to be involved in the selective vulnerability of neurons to oxidative insults in the CNS.

Phenotype-dependent susceptibility of cholinergic neuroblastoma cells to neurotoxic inputs.

A preferential loss of brain cholinergic neurons in the course of Alzheimer's disease and other encephalopathies is accompanied by a proportional impairment of acetyl-CoA synthesizing capacity in affected brains. Particular susceptibility of cholinergic neurons to neurodegeneration might results from insufficient supply of acetyl-CoA for energy production and acetylcholine synthesis in these conditions. Exposure of SN56 cholinergic neuroblastoma cells to dibutyryl cAMP and retinoic acid for 3 days caused their morphologic differentiation along with the increase in choline acetyltransferase activity, acetylcholine content and release, calcium content, and the expression of p75 neurotrophin receptors. Acetyl-CoA content correlated inversely with choline acetyltransferase activity in different lines of SN56 cells. In differentiated cells, aluminum (1 mM), amyloid beta(25-35) (0.001 mM), and sodium nitroprusside (1 mM), caused much greater decrease of pyruvate dehydrogenase and choline acetyltransferase activities and cell viability than in nondifferentiated ones. Aluminum (1 mM) aggravated suppressory effects of amyloid beta on choline acetyltransferase and pyruvate dehydrogenase activities and viability of differentiated cells. Similar additive inhibitory effects were observed upon combined exposure of differentiated cells to sodium nitroprusside and amyloid beta(25-35). None or much smaller suppressory effects of these neurotoxins were observed in nondifferentiated cells. Increase in the fraction of nonviable differentiated cells positively correlated with losses of choline acetyltransferase, pyruvate dehydrogenase activities, and cytoplasmic cytochrome c content in different neurotoxic conditions. These data indicate that highly differentiated cholinergic neurons may be more susceptible to aluminum and other neurotoxins than the nondifferentiated ones due to relative shortage of acetyl-CoA, increased content of Ca(2+), and expression of p75 receptors, yielding increase in cytoplasmic cytochrome c and subsequently grater rate of death of the former ones.

Zinc released from metallothionein-iii may contribute to hippocampal CA1 and thalamic neuronal death following acute brain injury.

Vesicular zinc was initially considered the sole source of toxic intraneuronal zinc accumulation in response to acute brain injury, but recent evidence suggests that additional sources also exist. Because metallothioneins (MTs) can bind and release zinc, we examined the possibility that the brain-specific form, MT-III, is such a zinc source. After kainate-induced seizures, cytoplasmic zinc accumulation and neuronal death in the hippocampal CA1 region and the thalamus were substantially lower in Mt3-null mice than in wild-type mice. Furthermore, compared with zinc transporter 3 (Znt3)-null mice, Znt3/Mt3 double-null mice exhibited further reductions in neuronal death in CA1 following kainate-induced seizures. Similar reductions in zinc accumulation and neuronal death in hippocampal CA1 and the dentate gyrus in Mt3-null mice were observed in a sodium nitroprusside model of acute brain injury. In contrast to CA1, more neuronal death occurred after kainate-induced seizures in CA3 of Mt3-null mice. These results suggest that intracellular zinc release from MT-III may contribute substantially to zinc-mediated neuronal death in certain brain areas, including the hippocampal CA1 region and the thalamus.

Green tea polyphenols enhance sodium nitroprusside-induced neurotoxicity in human neuroblastoma SH-SY5Y cells.

Oxidative stress is a main mediator in nitric oxide (NO) -induced neurotoxicity and has been implicated in the pathogenesis of many neurodegenerative disorders. Green tea polyphenols are usually expected as potent chemo-preventive agents due to their ability of scavenging free radicals and chelating metal ions. However, not all the actions of green tea polyphenols are necessarily beneficial. In the present study, we demonstrated that higher-concentration green tea ployphenols significantly enhanced the neurotoxicity by treatment of sodium nitroprusside (SNP), a nitric oxide donor. SNP induced apoptosis in human neuroblastoma SH-SY5Y cells in a concentration and time-dependent manner, as estimated by cell viability assessment, FACScan analysis and DNA fragmentation assay, whereas treatment with green tea polyphenols alone had no effect on cell viability. Pre-treatment with lower-dose green tea polyphenols (50 and 100 microm) had only a slightly deleterious effect in the presence of SNP, while higher-dose green tea polyphenols (200 and 500 microm) synergistically damaged the cells severely. Further research showed that co-incubation of green tea polyphenols and SNP caused loss of mitochondrial membrane potential, depletion of intracellular GSH and accumulation of reactive oxygen species, and exacerbated NO-induced neuronal apoptosis via a Bcl-2 sensitive pathway.

Effect of seabuckthorn on sodium nitroprusside-induced cytotoxicity in murine macrophages.

The present study reports the anti-oxidant activity of alcoholic extracts of leaf and fruit of seabuckthorn (SBT) on nitric oxide (NO) induced cytotoxicity in J-774 macrophages. Sodium nitroprusside (SNP), which generates NO at the concentration of 500 microg/ml, induced cytotoxicity as revealed by decreased neutral red uptake by macrophages. The cytotoxicity of SNP was attributed to enhanced reactive oxygen species (ROS) production, which in turn resulted in decrease in anti-oxidant levels. Alcoholic leaf and fruit extracts of SBT at the concentration of 500 microg/ml were found to have a significant cytoprotective effect against SNP-induced oxidative stress. These extracts inhibited SNP-induced cytotoxicity, free radical production and maintained the anti-oxidant status identical to that of control cells. The alcoholic fruit extract of SBT was found to have significantly higher anti-oxidant activity than leaf extract against SNP-induced cytotoxicity in murine macrophages.

The Ginkgo biloba extract (EGb 761) protects and rescues hippocampal cells against nitric oxide-induced toxicity: involvement of its flavonoid constituents and protein kinase C.

An excess of the free radical nitric oxide (NO) is viewed as a deleterious factor involved in various CNS disorders. Numerous studies have shown that the Ginkgo biloba extract EGb 761 is a NO scavenger with neuroprotective properties. However, the mechanisms underlying its neuroprotective ability remain to be fully established. Thus, we investigated the effect of different constituents of EGb 761, i.e., flavonoids and terpenoids, against toxicity induced by NO generators on cells of the hippocampus, a brain area particularly susceptible to neurodegenerative damage. Exposure of rat primary mixed hippocampal cell cultures to either sodium nitroprusside (SNP; 100 microM) or 3-morpholinosydnonimine resulted in both a decrease in cell survival and an increase in free radical accumulation. These SNP-induced events were blocked by either EGb 761 (10-100 microg/ml) or its flavonoid fraction CP 205 (25 microg/ml), as well as by inhibitors of protein kinase C (PKC; chelerythrine) and L-type calcium channels (nitrendipine). In contrast, the terpenoid constituents of EGb 761, known as bilobalide and ginkgolide B, as well as inhibitors of phospholipases A [3-[(4-octadecyl)benzoyl]acrylic acid (OBAA)] and C (U-73122), failed to display any significant effects. Moreover, EGb 761 (50 microm) CP 205 (25 microg/ml), and chelerythrine were also able to rescue hippocampal cells preexposed to SNP (up to 1 mM). Finally, EGb 761 (100 microg/ml) was shown to block the activation of PKC induced by SNP (100 microM). These data suggest that the protective and rescuing abilities of EGb 761 are not only attributable to the antioxidant properties of its flavonoid constituents but also via their ability to inhibit NO-stimulated PKC activity.

Dehydroepiandrosterone (DHEA) protects hippocampal cells from oxidative stress-induced damage.

It has been postulated that decreases in plasma levels of dehydroepiandrosterone (DHEA) may contribute to the development of some age-related disorders. Along with neuroprotective and memory enhancing effects, DHEA has been shown to display antioxidant properties. Moreover, oxidative stress is known to cause lipid peroxidation and degenerative changes in the hippocampus, an area involved in memory processes and especially afflicted in Alzheimer's disease (AD). Accordingly, we investigated the antioxidant effects of DHEA in models of oxidative stress using rat primary hippocampal cells and human hippocampal tissue from AD patients and age-matched controls. A pre-treatment of rat primary mixed hippocampal cell cultures with DHEA (10-100 microM) protected against the toxicity induced by H2O2 and sodium nitroprusside. Moreover, DHEA (10-100 microM) was also able to prevent H2O2/FeSO4-stimulated lipid oxidation in both control and AD hippocampal tissues. Taken together, these data suggest that DHEA may be useful in treating age-related central nervous system diseases based on its protective effects in the hippocampus.

Aspectos terapêuticos da DHEG na Maternidade do Hospital Universitário Lauro Wanderley / Therapeutics aspects of DHEG in Lauro Wanderley University Hospital

Os autores fazem um estudo retrospectivo nos prontuários de 100 pacientes portadores de DHEG que foram internadas na Maternidade do Hospital Universitário Lauro Wanderley no período compreendido entre outubro de 1991 e março de 1993. O estudo das pacientes foi realizado levando em consideraçåo: idade, idade gestacional, pressåo arterial sistólica e distólica na admissåo, edema, proteinúria e convulsöes, tendo sido excluídas das observaçöes as pacientes portadoras de hipertensåo crônica, diabetes mellitus, cardiopatias e nefropatias. Foram analisados os resultados das drogas utilizadas em administraçåo única, no serviço, e em associaçöes, para controle da hipertensåo arterial, tendo sido a metildopa administrada com maior frequência em dosagem única, como também a mais utilizada em associaçåo com a nifedipina e fenobarbital, atingindo 46 por cento. O sulfato de magnésio foi utilizadado em 4 por cento das pacientes para controlar e prevenir crises consulvisas. Face às propriedades dos benzodiazepínicos no controle primário e na prevençåo das crises consulsivas recorrentes, foi o mesmo administrado em 4 por cento das pacientes, tendo sido utilizado o diazepan associado aos hipotensores. O nitroprussiato de sódio foi usado em 3 por cento das pacientes encaminhadas ao CTI, ocasiäo em que se pôde observar o efeito tóxico da droga para o feto, já que ocasionou óbito fetal intra-uterino em todas as pacientes que fizeram uso do medicamento

The effect of intrathecal sodium nitroprusside on severe chronic vasospasm.

The efficacy of sodium nitroprusside in resolving cerebral vasospasm was evaluated with multicisternal injections. Twelve animals received fresh, unheparinized arterial blood via three injections (15 ml total) into the cisterna magna. Selective vertebral arteriography was performed on Day 0, and blood injections were performed on the second and third days after the first injection. On the seventh day selective arteriography was performed to evaluate the diameter of the basilar artery. In the sodium nitroprusside group, intrathecal injections of the drug were started on Day 4 and continued for two days (25 micrograms/kg/day). The diameter of the basilar artery was reduced 72.98 +/- 11.07% in control experiments. For the animals treated with intrathecal sodium nitroprusside, the mean diameter of the basilar artery was reduced 29.25 +/- 4.54%. The effect of intrathecal sodium nitroprusside on intracranial pressure (ICP), blood pressure (BP) and electrocardiogram (ECG) was also evaluated in 14 animals. There were no prominent changes in ICP, BP, or ECG when sodium nitroprusside was given intrathecally, but BP decreased and ICP and heart rate increased with intravenous doses of sodium nitroprusside. These results support the hypothesis that sodium nitroprusside administered intrathecally is an effective treatment for cerebral vasospasm.