Suicide of an adolescent girl with sodium nitrite ordered on the internet.

Nitrites are commonly used in the chemical, pharmaceutical, and food industries. Recently, they have been identified in cases of voluntary intoxication. We report the case of a 13-year-old girl who was found lifeless on her bed next to a glass containing a white powder and a bottle containing a white powder with a moistened appearance. External examination and autopsy revealed a nonspecific asphyxia syndrome, which was confirmed by the pathological analysis. Analysis of the samples revealed metoclopramide in the peripheral blood at a concentration of 0.402 mg/L (LC-HRMS). An analysis of the gastric contents was carried out after sodium nitrite was detected in the powders found near the body (Raman spectrometry). Nitrites were found in the gastric fluid at a concentration of 30.9 mg/L. Death occurred secondary to anoxia, following ingestion of nitrites; suicide kits are available on the web and nitrites are relatively easy to source and inexpensive. Nitrites are delivered in powder form to be dissolved in liquid, which may then be consumed with metoclopramide (or an alternative anti-emetic drug) to maximize absorption and reduce emesis. The toxic effect of nitrites lies in their oxidizing power, causing the transformation of hemoglobin into methemoglobin, which, when it accumulates, induces tissue anoxia resulting in death. There has been an alarming increase in the number of cases linked to suicide using nitrites or a nitrite suicide kit. The fact that nitrites are readily available online underscores the importance of establishing effective preventive measures such as limiting the access and use of this chemical.

Liquid Chromatography-High-Resolution Mass Spectrometry (LC-HRMS) Analysis Following Voluntary Carvedilol Poisoning in a Subject with Cirrhosis: A Case Report.

Accidental or intentional carvedilol poisoning is rarely reported. Here, we describe a case of attempted suicide with a large quantity of immediate-release carvedilol (75 mg) and alcohol. In order to determine the kinetics, liquid chromatography-high-resolution mass spectrometry analyses were performed. The results for the plasma concentration of carvedilol were 906 µg/L 3 h after ingestion, 288 µg/L 12 h after ingestion and 103 µg/L 24 h after ingestion. A one-compartment model with linear and first order best described the elimination of the carvedilol, and the estimated half-life was 5.8 h. The result 3 h after ingestion represented the highest concentration ever observed for this drug. However, the patient was cirrhotic, and liver function was impaired with decreased Factor V (45%) and prothrombin ratio (61%). These conditions may explain the high concentrations of carvedilol. The patient was treated with glucagon and discharged from the hospital the following day.

"Clandestine" home delivery with mifepristone.

Denial of pregnancy is a rare psychic process associated with an increased risk of infant death. Forensic examinations to determine viability at birth can heavily influence the legal proceedings in cases of clandestine deliveries that result in the death of the infant. A 32-year-old woman who experienced a denial of pregnancy up to 30 weeks of amenorrhea reported giving birth at home at an estimated term of 35 weeks of amenorrhea. No one witnessed the delivery. She claimed the infant was stillborn. Forensic examinations revealed characteristic features of a live born infant. The mother tested positive for mifepristone. Mifepristone is an anti-progestin drug used for early abortion and to induce labor in cases of in-utero fetal death in later pregnancy. Even if mifepristone crosses the placenta, it has no direct toxic effect on the fetus. Our observations suggest premature live birth caused by mifepristone, followed by asphyxia due to meconium inhalation syndrome associated with lung immaturity especially since the birth occurred at home and no medical care was provided after the birth. The tragic outcome of this clinical case calls for vigilance and global management, including the psychiatric care of parturients in the context of late discovery of pregnancy. In France, this situation showed a legal gap between the consideration of the fetus and laws concerning abortion. To our knowledge, in France, this case has allowed the court to set a legal precedent as a similar case had never been reported elsewhere.

Lack of everolimus diffusion in pleural fluid during pleural progression of breast cancer: A case report.

BACKGROUND: We report here a case where no everolimus pleural diffusion was evidenced at the same time of pleural progression of a metastatic breast cancer treated with everolimus and exemestane. CASE DESCRIPTION: A 69-year-old woman was diagnosed in October 2006 with stage III invasive ductal breast adenocarcinoma. After nine months of everolimus and exemestane treatment, she presented with a pleural progression. Everolimus concentration was measured in blood and in pleural fluid. Residual blood concentration was at 9.1 ng/mL, while no everolimus was observed in the pleural fluid. MANAGEMENT AND OUTCOME: Due to inefficacy of everolimus in this patient, she was switched to palbociclib and fulvestrant. CONCLUSION: Everolimus seems to have a poor diffusion in the pleural fluid.

Sudden Death by Spontaneous Epiglottic Hematoma Secondary to High Blood Levels of Warfarin.

A 67-year-old man was found dead, at his home. On external examination, we found a voluminous purplish black ecchymosis of the anterior neck area. On internal examination, we found a voluminous epiglottis hematoma completely obstructing the upper airway. It was associated with other sites of intra-abdominal hemorrhage. Toxicological studies revealed the presence of warfarin at a concentration of 8.4 mg/L in peripheral blood, which supposes an INR well above 4.5. To conclude, we supposed death was due to asphyxia secondary to a spontaneous epiglottic hematoma caused by a high blood concentration of warfarin. Hemorrhage in the epiglottis is very rare. To our knowledge, our patient is the only case of "sudden death" reported with spontaneous epiglottic hematoma due to high blood concentration of warfarin. In forensic practice, an anterior neck ecchymosis, without trauma, may suggest hemorrhage into soft airway tissues. Pathology findings make it possible to exclude exogenous trauma.

Accuracy in obtaining 100 µg from 10 mg of morphine for spinal anesthesia.

STUDY OBJECTIVE: Dilution is often required to obtain appropriate concentrations of intrathecal morphine for analgesia. We compared techniques of diluting by measuring the quantity of morphine actually obtained in the final solution. DESIGN: This is an experimental study by 3 experienced anesthesiologists. SETTING: The setting is at a university teaching hospital. PATIENTS: There are no patients. INTERVENTIONS: There are no interventions. MEASUREMENTS: Five techniques for obtaining 100 µg from 10 mg/mL were compared: technique 1 (T1) = extraction up to 0.1 graduation on a 1-mL syringe, followed by simple dilution (SD). Technique 2 (T2) = As for T1 but syringe was shaken to mix solution. Technique 3 (T3): SD with 10-mL syringe. Technique 4 (T4): Double dilution with 10-mL syringe. Technique 5 (T5): Extraction up to the 0.1 graduation of a 1-mL syringe, then SD, then shake solution by hand. Three tests using high-performance liquid chromatography with ultraviolet were performed on each syringe prepared 3 consecutive times, namely, at the first (beginning, B), fifth (middle, M) and last (end, E) milliliter or 0.1 mL (depending on syringe type). MAIN RESULTS: Average overall concentrations were 208 ±19, 199 ±24, 120 ±13, 136 ±9, and 119 ±16 µg/0.1 mL, T1-T5, respectively. By Kruskal-Wallis test, we classified the techniques according to the magnitude of the difference between the observed concentration of morphine and the desired (theoretical) concentration of 100 µg/0.1 mL. In ascending order, techniques ranked as follows: T5 (smallest difference), T3, T4, T2, and T1 (greatest difference) (P = .0001). CONCLUSIONS: There is significant variability in the concentration of morphine actually contained in final solutions after dilution. Morphine presented in different premixed concentrations increases the risk of error. We advocate technique 5 as described above, whereas technique 1 should be prohibited.

In vivo efficacy of ceftaroline fosamil in a methicillin-resistant panton-valentine leukocidin-producing Staphylococcus aureus rabbit pneumonia model.

Ceftaroline, the active metabolite of the prodrug ceftaroline fosamil, is a cephalosporin with broad-spectrum in vitro activity against Gram-positive organisms, including methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant Streptococcus pneumoniae (MDRSP), and common Gram-negative pathogens. This study investigated the in vivo activity of ceftaroline fosamil compared with clindamycin, linezolid, and vancomycin in a severe pneumonia model due to MRSA-producing Panton-Valentine leukocidin (PVL). A USA300 PVL-positive clone was used to induce pneumonia in rabbits. Infected rabbits were randomly assigned to no treatment or simulated human-equivalent dosing with ceftaroline fosamil, clindamycin, linezolid, or vancomycin. Residual bacterial concentrations in the lungs and spleen were assessed after 48 h of treatment. PVL expression was measured using a specific enzyme-linked immunosorbent assay (ELISA). Ceftaroline, clindamycin, and linezolid considerably reduced mortality rates compared with the control, whereas vancomycin did not. Pulmonary and splenic bacterial titers and PVL concentrations were greatly reduced by ceftaroline, clindamycin, and linezolid. Ceftaroline, clindamycin, and linezolid were associated with reduced pulmonary tissue damage based on significantly lower macroscopic scores. Ceftaroline fosamil, clindamycin, and, to a lesser extent, linezolid were efficient in reducing bacterial titers in both the lungs and spleen and decreasing macroscopic scores and PVL production compared with the control.

Celecoxib but not the combination of celecoxib+atorvastatin prevents the development of monocrotaline-induced pulmonary hypertension in the rat.

The present study aimed to assess the effects of a COX-2 inhibitor, celecoxib, a HMG-CoA reductase inhibitor, atorvastatin, and the association of both on monocrotaline (MC)-induced pulmonary hypertension in rats. Celecoxib (Cib, 25 mg kg(-1) day(-1)), atorvastatin (AS, 10 mg kg(-1) day(-1)) or vehicle, were given orally, separately or in combination, for 26 days to Wistar male rats injected or not with MC (60 mg/kg intraperitoneally). At 4 weeks, MC-injected rats developed a severe pulmonary hypertension, with an increase in lung to body weight ratio (L/BW), right ventricular pressure (RVP in mmHg, 31 +/- 3 and 14 +/- 1 for MC and control groups, respectively, P < 0.05) and right ventricle/left ventricle + septum weight ratio (RV/LV+S) associated with a decrease in acetylcholine- and sodium-nitroprusside-induced pulmonary artery vasodilation in vitro. Hypertensive pulmonary arteries exhibited an increase in wall thickness (wall thickness to external diameter ratio, 0.42 +/- 0.01 vs 0.24 +/- 0.01 for MC and control groups, respectively, P < 0.001). Whole lung eNOS expression was decreased, and an increase in apoptosis, evaluated by cleaved caspase-3 expression, was evidenced by Western blotting. Cib (RVP in mmHg, 19 +/- 3 and 31 +/- 3 for MC+Cib and MC groups, respectively, P < 0.05), but neither AS nor AS+Cib significantly limited the development of pulmonary hypertension (P < 0.05), although the three treatments exhibited protective effects against MC-induced lung and right ventricle hypertrophy evaluated by L/BW and RV/(LV+S) ratios, respectively (P < 0.05). AS, Cib and AS+Cib treatments reduced MC-induced thickening of small intrapulmonary artery wall (0.42 +/- 0.01, 0.24 +/- 0.01, 0.26 +/- 0.01 and 0.28 +/- 0.01 for MC, MC+AS, MC+Cib and MC+AS+Cib groups, respectively, P < 0.001). In control rats, Cib reduced acetylcholine-induced pulmonary artery vasorelaxation. Treatment of MC rats by either Cib or AS did not modify acetylcholine-induced pulmonary artery relaxation, whereas combination of both drugs significantly worsened it (P < 0.05). AS, but neither Cib nor the combination of both, prevented apoptosis (AS, P < 0.05) and partially restored eNOS expression (AS, P < 0.05) in whole lung of MC rats. In conclusion, celecoxib exhibited beneficial effects against the development of monocrotaline-induced pulmonary artery hypertension and right ventricular hypertrophy. These beneficial effects of celecoxib might be, at least partly, explained by its effects on pulmonary artery thickening and pulmonary hypertrophy, even if it did not show any effect on pulmonary artery vasorelaxation and whole lung eNOS expression or apoptosis. The combination of celecoxib and atorvastatin was unable to prevent MC-induced pulmonary hypertension, decreased endothelium-dependent vasorelaxation and showed a trend toward an increased in RVP that deserves further studies.

The protective effect of HMG-CoA reductase inhibitors against monocrotaline-induced pulmonary hypertension in the rat might not be a class effect: comparison of pravastatin and atorvastatin.

Hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, so called statins, improve endothelial function and exert antiproliferative effects on vascular smooth muscle cells of systemic vessels. This study aimed at comparing the protective effects of two statins, pravastatin and atorvastatin, against monocrotaline (MC)-induced pulmonary hypertension in rats. Pravastatin or atorvastatin (PS or AS, 10 mg/kg per day) or vehicle were given orally for 28 days to Wistar male rats injected or not with MC (60 mg/kg intraperitoneally). At 4 weeks, MC-injected rats developed severe pulmonary hypertension, with an increase in right ventricular pressure (RVP) and right ventricle/left ventricle + septum weight ratio associated with a decrease in acetylcholine- or sodium-nitroprusside-induced pulmonary artery dilation observed in vitro. Hypertensive pulmonary arteries exhibited an increase in medial thickness and endothelial cell apoptosis and a decrease of endothelial nitric oxide synthase (eNOS) expression. MC-rat lungs showed a significant decrease of eNOS (P < 0.01) and increase of cleaved caspase-3 (P < 0.05) expression determined by Western blotting. PS (P = 0.02) but not AS (P = 0.30) significantly limited the development of pulmonary hypertension (RVP in mmHg: 30 +/- 3, 36 +/- 4 vs. 45 +/- 4 and 14 +/- 1 for MC + PS, MC + AS, MC, and control groups, respectively). Both statins significantly reduced MC-induced right ventricle hypertrophy [RV/left ventricular (LV) + S, in mg/g: 0.46 +/- 0.04, 0.39 +/- 0.03, 0.62 +/- 0.05 and 0.29 +/- 0.01 for MC + PS, MC + AS, MC, and control groups, respectively; P < 0.05),and reduced MC-induced thickening (61 +/- 6 microm, 82 +/- 5 microm, 154 +/- 4 microm, and 59 +/- 2 microm for MC + PS, MC + AS, MC, and control groups, respectively; P = 0.01) of small intrapulmonary artery medial wall, with MC + AS still being different from the control group. PS but not AS partially restored acetylcholine-induced pulmonary artery vasodilation in MC rats (E(max)=65 +/- 5%, 49 +/- 6%, 46 +/- 3%, and 76 +/- 4% for MC + PS, MC + AS, MC, and control groups, respectively; P < 0.05 for MC + PS vs. other groups). Both statins prevented apoptosis and restored eNOS expression of pulmonary artery endothelial cells as well as in the whole lung with a more pronounced effect with PS compared with AS. In conclusion, despite its effects on eNOS expression, apoptosis, and medial wall thickening, AS was unable to significantly reduce pulmonary hypertension and to restore endothelium-dependent relaxation, suggesting intermolecular differences between the two HMG-CoA reductase inhibitors in the protection against MC-induced hypertension.

The HMG-CoA reductase inhibitor, pravastatin, prevents the development of monocrotaline-induced pulmonary hypertension in the rat through reduction of endothelial cell apoptosis and overexpression of eNOS.

HMG-CoA reductase inhibitors improve endothelial function and exert antiproliferative effects on vascular smooth muscle cells of systemic vessels. This study was aimed to assess the protective effects of pravastatin (an HMG-CoA reductase inhibitor) against monocrotaline-induced pulmonary hypertension in rats. Pravastatin (PS, 10 mg/kg/day) or vehicle were given orally for 28 days to Wistar male rats injected or not with monocrotaline (MC, 60 mg/kg intraperitonealy) and treated or not by N(omega)-nitro-L-arginine methyl ester (L-NAME) 15 mg/kg/day. At 4 weeks, monocrotaline-injected rats developed severe pulmonary hypertension, with an increase in right ventricular pressure (RVP) and right ventricle/left ventricle+septum weight ratio (RV/LV+S), associated with a decrease in pulmonary artery dilation induced either by acetylcholine or sodium nitroprusside. Hypertensive pulmonary arteries exhibited an increase in medial thickness, medial wall area, endothelial cell apoptosis, and a decrease of endothelial nitric oxide synthase (eNOS) expression. Monocrotaline-rat lungs showed a significant decrease of eNOS expression (4080+/-27 vs 12189+/-761 arbitrary density units [ADU] for MC and control groups respectively, P<0.01) and a significant increase of cleaved caspase-3 expression by western blotting (Control=11628+/-2395 vs MC=2326+/-2243 ADU, P<0.05). A non-significant trend toward a reduced mortality was observed with pravastatin (relative risk of death = 0.33; 95% confidence interval [0.08-1.30], P= 0.12 for MC+PS vs MC groups). Pravastatine induced a protection against the development of the pulmonary hypertension (RVP in mmHg: 30+/-3 vs 45+/-4 and RV/LV+S: 0.46+/-0.04 vs 0.62+/-0.05 for MC+PS and MC groups respectively, P<0.05) and was associated with a significant reduction of MC-induced thickening (61+/-6 mum vs 81+/-3 mum for MC+PS and MC groups respectively, P= 0.01) of the medial wall of the small intrapulmonary arteries. Pravastatin partially restored acetylcholine-induced pulmonary artery vasodilation in MC rats (Emax=65+/-5% and 46+/-3% for MC+PS and MC group respectively, P<0.05) but had no effect on acetylcholine-induced pulmonary artery vasodilation in MC+L-NAME rats. It also prevented apoptosis and restored eNOS expression of pulmonary artery endothelial cells, as well as in the whole lung. Pravastatin reduces the development of monocrotaline-induced pulmonary hypertension and improves endothelium-dependent pulmonary artery relaxation, probably through a reduced apoptosis and a restored eNOS expression of endothelial cells.

Arachidonic acid relaxes human pulmonary arteries through K+ channels and nitric oxide pathways.

We aimed to investigate the role of K(+) channels and nitric oxide (NO) on the relaxant effects of arachidonic acid in the human intralobar pulmonary arteries. Arachidonic acid produced a concentration-dependent relaxation (E(max)=93+/-3% of maximal relaxation induced by papaverine 0.1 mM;-log EC(30)=7.03+/-0.09) that was antagonized by the cyclooxygenase inhibitor indomethacin (1 microM), by the combination of cyclooxygenase blockade and cytochrome P450 (CYP) blockade with 17-octadecynoic acid (17-ODYA, 10 microM), by the combination of cyclooxygenase inhibition and NO synthase (NOS) inhibition with N(omega)-nitro-l-arginine (l-NOARG, 100 microM), by the simultaneous inhibition of CYP and NOS and by the simultaneous blockade of cyclooxygenase, CYP and NOS. Arachidonic acid-induced relaxation was significantly inhibited by glibenclamide (1 microM, ATP-dependent K(+) channel (K(ATP)) blocker), apamin and charybdotoxin (0.3 microM small (SK(Ca)) and 0.1 microM big (BK(Ca)) conductance Ca(2+)-sensitive K(+) channel blocker, respectively), and 4-aminopyridine (1 mM, voltage-dependent K(+) channel (K(V)) blocker). Indomethacin and ketoconazole suppressed the antagonistic effects of glibenclamide and apamin and 17-ODYA those of all the K(+) channel blockers tested. l-NOARG suppressed only the antagonistic effect of glibenclamide. We suggest that K(ATP), SK(Ca), BK(Ca) and K(V) are involved in the arachidonic acid-induced relaxation of human pulmonary arteries. Cyclooxygenase metabolites are the main relaxing agents of arachidonic acid, involving K(ATP) and SK(Ca) channels. CYP-dependent metabolites modulate arachidonic acid-induced relaxation through a pathway involving K(+) channels. K(ATP) channels are involved through a NOS-dependent pathway.

ETA, mixed ETA/ETB receptor antagonists, and protein kinase C inhibitor prevent acute hypoxic pulmonary vasoconstriction: influence of potassium channels.

The aims of this study were to investigate the effects of a selective ETA (BQ-123), a selective ETB (BQ-788), and a specific mixed ETA/ETB receptor antagonist (bosentan) on the pulmonary vasoconstriction induced by hypoxia in the isolated perfused rat lung, and the role of nitric oxide, adenosine triphosphate-sensitive (KATP), large conductance Ca+-activated (BKCa) and 4-aminopyridine-sensitive voltage-gated K channels (K+) in the relaxant effects of the selective ETA receptor antagonist BQ-123 and a protein kinase C inhibitor, bisindolylmaleimide I. K+ channels were inhibited by glibenclamide, charybdotoxin, and 4-aminopyridine and nitric oxide synthase by L-NG-nitroarginine methyl ester (L-NAME). Hypoxic ventilation produced a significant pressure response (+57%, p < 0.001). BQ-123, bosentan, and bisindolylmaleimide I induced a concentration-dependent decrease of the hypoxic pressure response (p < 0.001), whereas BQ-788 did not exhibit any inhibitory effect against hypoxic pressure response. Glibenclamide, charybdotoxin, and 4-aminopyridine partially opposed the inhibitory effects elicited by BQ-123 (p < 0.05), but L-NAME did not modify these effects. The effects of bisindolylmaleimide I on hypoxic pressure response were unaffected by glibenclamide, charybdotoxin, or 4-aminopyridine. The authors conclude that (a) ETA receptors and protein kinase C are involved in the modulation of hypoxic pulmonary vasoconstriction; and (b) the ETA antagonist BQ-123 opposes hypoxic pulmonary vasoconstriction through KATP, KV, and BKCa channels, differing in this from the protein kinase C inhibitor bisindolylmaleimide I. These results suggest that BQ-123 operates through a mechanism independent of bisindolylmaleimide I-inhibited protein kinase C isoforms.

Relaxant effects of selective phosphodiesterase inhibitors on U46619 precontracted human intralobar pulmonary arteries and role of potassium channels.

We examined the influence of K+ channel antagonists on the vasorelaxation induced by theophylline (non selective PDEI), siguazodan (PDE3I), rolipram (PDE4I) and zaprinast (PDE5I) in human intralobar pulmonary arteries. All PDEI tested induced a concentration-dependent relaxation with theophylline being significantly (p < 0.05) more efficient and rolipram more potent than PDE5I and PDE3I (Emax values, expressed as a percentage of maximal relaxation by papaverine 10(-4)M, were 92% +/- 2%, 84% +/- 8%, 90% +/- 4% and 99% +/- 1%, and pD2 values were 7.30 +/- 0.35, 6.14 +/- 0.25, 5.86 +/- 0.17, and 4.85 +/- 0.47 for rolipram, siguazodan, zaprinast and theophylline, respectively). 4-Aminopyridine (4-AP, Kv, voltage dependent channel blocker, 1 mM) induced a significant increase (+17% p < 0.05) of U46619-induced vasoconstriction whereas the other K+-channels blockers, glibenclamide (KATP channels, 1 microM) charybdotoxin (predominant BKCa, large conductance Ca2+-sensitive K+ channels, 0.1 microM) and apamine (SKCa, small conductance, 0.3 microM) were without effect. The concentration response curves (CRC) for rolipram were significantly shifted to the right by glibenclamide (1 microM), charybdotoxin (0.1 microM) and 4-AP (1 mM). The CRC for siguazodan was significantly displaced to the right by 4-AP. None of the potassium channel blockers displaced the CRC for zaprinast and theophylline. Apamine was without effect on the CRC for all the PDEI used in this study. (1) PDE3, 4 and 5 are functionally present in human intralobar pulmonary arteries; (2) the vasoconstriction induced by U46619 is downregulated by 4-aminopyridine sensitive-K+ channels; (3) the relaxant effects of rolipram (PDE4I) are partly mediated through KATP, BKCa, and Kv potassium channels and those of siguazodan (PDE3I) by Kv potassium channels.