Lethal Intoxication Research Articles

An Expanding World of Novel Psychoactive Substances: Opioids.

The abuse of novel psychoactive substances (NPS) has been increasing dramatically worldwide since late 2000s. By the end of 2015, more than 560 NPS had been reported to the European Monitoring Centre for Drugs and Drug Addiction. Although the most popular compounds are synthetic cannabinoids and psychostimulatory derivatives of cathinone (so-called β-keto-amphetamines), novel synthetic opioids have recently emerged on the recreational drug market. They include fentanyl (a potent narcotic analgesic) and its analogs (e.g., acetylfentanyl, acryloylfentanyl, carfentanil, α-methylfentanyl, 3-methylfentanyl, furanylfentanyl, 4-fluorobutyrylfentanyl, 4-methoxybutyrylfentanyl, 4-chloroisobutyrylfentanyl, 4-fluoroisobutyrylfentanyl, tetrahydrofuranylfentanyl, cyclopentylfentanyl, and ocfentanil) and compounds with different chemical structures, such as AH-7921, MT-45, and U-47700. This survey provides an overview of the pharmacological properties, pattern of use, and desired and unwanted effects of the above-listed novel opioids. Special emphasis is given to cases of non-fatal and lethal intoxication involving these compounds.

Development of the methods for atomoxetine identification suitable for the chemical and toxicological analysis

The cases of acute and lethal poisonings by atomoxetine, an antidepressant, have been registered. Therefore, development of the available and reliable methods for its chemical and toxicological analysis is the topical issue.Aim. To develop the conditions for atomoxetine detection in the presence of a number of its pharmacological and structural analogs when performing the general TLC-screening and identification of the antidepressant by UV spectrophotometry.Materials and methods. Chromatographic mobility of antidepressants in thin sorbent layers was studied in 11 mobile phases, including those recommended by TIAFT, using five types of chromatographic plates. A number of chromogenic reagents was used for visualization. The UV-spectrum of atomoxetine was studied in 0.1 Mol • L-1 solution of hydrochloric acid.Results and discussion. Chromatographic systems with the low correlation of Rf values for atomoxetine that make them suitable for the general TLC-screening have been found. The UV spectrum of atomoxetine in the acid solution had light absorption maxima at wavelengths of 270 (e = 1300; A11 = 45) and 277 nm.Conclusions. A combined use of three mobile phases: methanol – 25 % ammonia solution (100 : 1.5), cyclohexane – toluene – diethylamine (75 : 15 : 10), and toluene – acetone – 25 % ammonia solution (45 : 45 : 7.5 : 2.5) provides a reliable atomoxetine detection in the presence of a number of its pharmacological and structural analogs when performing the general TLC-screening. The presence of specific light absorption in the UV region of the spectrum for atomoxetine makes the UV spectrophotometry method suitable for identification of the antidepressant in toxicological studies.metry method suitable for identification of the antidepressant in toxicological studies.

Effectiveness of isosorbide dinitrate in cyanide poisoning as a function of the administration timing

BackgroundBetter and safer antidotes against cyanide poisoning are needed. Prior study has shown a favorable effect of isosorbide dinitrate (ISDN) on the survival of cyanide-poisoned rabbits when administered as early as 1 min after poisoning. The aim of the current study was to further evaluate the efficacy of intravenous ISDN administered in clinically relevant timing for first responders.MethodsA comparative animal study using 24 rabbits in 4 randomized study groups was performed. Animals were poisoned with intravenous potassium cyanide (1 mg/kg). Animals in Group 1 served as controls and received no treatment. Groups 2–4 animals were treated intravenously with ISDN (50 μg/kg) after poisoning; one group after 3 min, another group after 5 min and the last after 7 min. Animals were observed for 30 min after poisoning. The study endpoints included survival rate, clinical status, blood pressure, pulse per minute, blood lactate and pH.ResultsFive of 6 animals (83.3%) from every treatment group survived the whole observation period while all control untreated animals died. All the rabbits collapsed immediately after exposure, showing rapidly deteriorated vital signs with lactic metabolic acidosis (peak blood lactate levels of 18.1 to 19.0 mmol/L on average at 10 min post exposure). Vital signs, clinical scores, and blood gases of treated rabbits gradually improved.ConclusionPoisoned rabbits showed improved short-term survival following the administration of ISDN up to 7 min after lethal cyanide poisoning of. We see a potential for ISDN as an antidote against cyanide poisoning.

Diagnosis of aluminum phosphide poisoning using a new analytical approach: forensic application to a lethal intoxication.

Aluminum phosphide (AlP) is an effective and cheap pesticide that is commonly used worldwide, but it is also a common cause of human poisoning and carries a high mortality rate. AlP reacts with moisture in air, water, and hydrochloric acid in the stomach to produce phosphine (PH3) gas. Two routes of exposure are ingestion of AlP and inhalation of phosphine generated by the action of moisture on AlP. Absorbed phosphine is rapidly metabolized into phosphite and hypophosphite. A method is described for the analysis of the phosphine metabolites in various biological matrices. The method involves reacting the sample with zinc and aqueous H2SO4 in a volatile organic analysis vial. The metabolites were transformed into phosphine gas and then analyzed by headspace gas chromatography coupled with mass spectrometry (HS-GC-MS). This method is capable of detecting quantities of PH3 as low as 0.2μg/mL in a sample. After validation, the method was applied to animal experiments and a real case of human AlP intoxication. This approach has the advantage of detecting metabolites of PH3, in case the PH3 was converted, and can be considered a useful additional tool for the diagnosis of AlP poisoning in forensic science.

Evaluation of the Ecstasy influence on tramadol and its main metabolite plasma concentration in rats.

Tramadol is prone to be abused alone, or in combination with 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy). It was reported that 95% of people with a history of substance abuse in the United States used tramadol in 2004. According to the WHO report in 2016, there was a growing number of tramadol abusers alone or in combination with psychoactive substances such as MDMA in particular in some Middle East countries. Higher concentrations of tramadol in plasma may lead to adverse drug reactions or lethal intoxication. In this study, the effect of MDMA on the pharmacokinetics of tramadol was examined in male rats. The effect of MDMA on Tmax, Cmax, area under the curve, elimination rate, and half-life of tramadol and its metabolites was examined. Two control and two treatment groups were designed. The treatment groups received MDMA 18 h before the administration of tramadol. Jugular vein blood samples were analyzed by high-performance liquid chromatography with fluorescent detector to determine the concentrations of tramadol and its metabolites. Independent-sample t-test was used to define the differences between pharmacokinetic parameters of control and treatment groups. When tramadol administered intraperitoneally, the absorption rate of this drug was reduced, and a lower Cmax (40%) with longer Tmax (eight-fold) was achieved. MDMA exerted greater inhibitory effects on cytochrome P450 3A4 (CYP3A4) than on cytochrome P450 2D6 (CYP2D6). The M2 metabolite ratio was reduced by half, and because of the inhibition of M2 production, the M1 plasma concentration slightly increased. According to the obtained data, MDMA treatment affected the absorption, distribution and metabolism phases of tramadol. This treatment increased the concentration of tramadol if administered intravenously and can latent the absorption of tramadol in oral route. However, MDMA was introduced as CYP2D6 inhibitor; in this study, MDMA inhibited CYP3A4 isoenzymes as well. This finding is important for the compounds that are metabolized through CYP3A4. It can be proposed that in abusers of MDMA who only receive tramadol for medical or nonmedical purposes in short intervals, the dangers of the intravenous administration of tramadol should be considered, and if tramadol is administered orally, the desired effect may not be achieved at the routine dose.

Cyanotoxins: producing organisms, occurrence, toxicity, mechanism of action and human health toxicological risk evaluation.

Cyanobacteria were present on the earth 3.5 billion years ago; since then they have colonized almost all terrestrial and aquatic ecosystems. They produce a high number of bioactive molecules, among which some are cyanotoxins. Cyanobacterial growth at high densities, forming blooms, is increasing in extension and frequency, following anthropogenic activities and climate changes, giving rise to some concern for human health and animal life exposed to cyanotoxins. Numerous cases of lethal poisonings have been associated with cyanotoxins ingestion in wild animal and livestock. In humans few episodes of lethal or severe human poisonings have been recorded after acute or short-term exposure, but the repeated/chronic exposure to low cyanotoxin levels remains a critical issue. The properties of the most frequently detected cyanotoxins (namely, microcystins, nodularins, cylindrospermopsin and neurotoxins) are here critically reviewed, describing for each toxin the available information on producing organisms, biosynthesis/genetic and occurrence, with a focus on the toxicological profile (including kinetics, acute systemic toxicity, mechanism and mode of action, local effects, repeated toxicity, genotoxicity, carcinogenicity, reproductive toxicity; human health effects and epidemiological studies; animal poisoning) with the derivation of health-based values and considerations on the risks for human health.

A Salt-Water Aquarium can be a Dangerous Hobby:A Case Report of Palytoxin Intoxication after Dermal Contact with Poisonous Coral

Palythoa toxica is a coral that is often sold to aquarium holders. It contains one of the most toxic substances known to human: palytoxin. It is important for clinicians to recognize this potential lethal intoxication. A 39 year old man presented to the Emergency Department (ED) complaining of rigors, dyspnea, dizziness, atypical chest pain, tremor, and dysarthria. Medical history taking revealed that he was a professional coral dealer. He recalled accidental dermal exposure to mucus of Palythoa toxica four hours before symptoms started. His laboratory tests showed signs of muscular and cardiac damage. He was admitted to the hospital and had a full recovery. Intoxications with palytoxin are potentially lethal. Since the Palythoa coral is often sold to new aquarium holders there is probably an underreporting of cases as many patients and doctors would not link the symptoms to coral exposure. In the setting of an emergency department, physicians should be aware of the symptoms of palytoxin intoxication, including patients with rhabdomyolysis, and ask patients with relevant symptoms about potential contact with corals.

Evaluation of the Role of Toxicological Data in Discriminating Between H2 S Femoral Blood Concentration Secondary to Lethal poisoning and Endogenous H2 S Putrefactive Production.

Hydrogen sulfide is a colorless gas and has a strong odor of rotten eggs. It is absorbed by the upper respiratory tract mucosa, and it causes histotoxic hypoxemia and respiratory depression by exerting an inhibitory effect on cytochrome oxidase. To evaluate the role of toxicological data in distinguishing between the H2 S blood concentration secondary to lethal poisoning and the endogenous H2 S produced during putrefaction, we compared the postmortem H2 S concentrations of six fatal H2 S poisoning cases (8.7-28.6 mg/L) with the postmortem concentrations of endogenous H2 S of 12 subjects who died from other causes (traffic-related deaths) (2.2-32.7 mg/L). These results will be of interest to the forensic community as it underlines the importance of considering circumstantial evidence along with the toxicological and pathological findings in the identification of H2 S lethal poisoning.

Emerging toxicity of 5,6-methylenedioxy-2-aminoindane (MDAI): Pharmacokinetics, behaviour, thermoregulation and LD50 in rats

MDAI (5,6-Methylenedioxy-2-aminoindane) has a reputation as a non-neurotoxic ecstasy replacement amongst recreational users, however the drug has been implicated in some severe and lethal intoxications. Due to this, and the fact that the drug is almost unexplored scientifically we investigated a broad range of effects of acute MDAI administration: pharmacokinetics (in sera, brain, liver and lung); behaviour (open field; prepulse inhibition, PPI); acute effects on thermoregulation (in group-/individually-housed rats); and systemic toxicity (median lethal dose, LD50) in Wistar rats.Pharmacokinetics of MDAI was rapid, maximum median concentration in serum and brain was attained 30min and almost returned to zero 6h after subcutaneous (sc.) administration of 10mg/kg MDAI; brain/serum ratio was ~4. MDAI particularly accumulated in lung tissue. In the open field, MDAI (5, 10, 20 and 40mg/kg sc.) increased exploratory activity, induced signs of behavioural serotonin syndrome and reduced locomotor habituation, although by 60min some effects had diminished. All doses of MDAI significantly disrupted PPI and the effect was present during the onset of its action as well as 60min after treatment. Unexpectedly, 40mg/kg MDAI killed 90% of animals in the first behavioural test, hence LD50 tests were conducted which yielded 28.33mg/kg sc. and 35mg/kg intravenous but was not established up to 40mg/kg after gastric administration. Disseminated intravascular coagulopathy (DIC) with brain oedema was concluded as a direct cause of death in sc. treated animals. Finally, MDAI (10, 20mg/kg sc.) caused hyperthermia and perspiration in group-housed rats.In conclusion, the drug had fast pharmacokinetics and accumulated in lipohilic tissues. Behavioural findings were consistent with mild, transient stimulation with anxiolysis and disruption of sensorimotor processing. Together with hyperthermia, the drug had a similar profile to related entactogens, especially 3,4-metyhlenedioxymethamphetamine (MDMA, ecstasy) and paramethoxymethamphetamine (PMMA). Surprisingly subcutaneous MDAI appears to be more lethal than previously thought and its serotonergic toxicity is likely exacerbated by group housing conditions. MDAI therefore poses greater risks to physical and mental health than recognised hitherto.

Ethylene glycol poisoning

Ethylene glycol, which is most commonly encountered in antifreeze, causes acidosis and renal failure and is a frequent cause of lethal poisoning in companion animals, particularly cats. Initial signs including neurological effects and vomiting are non-specific and may be overlooked. Signs progress as renal failure develops. The aims of therapy in ethylene glycol poisoning are to prevent metabolism of the parent compound and the production of toxic metabolites, typically through the use of ethanol; reverse electrolyte and acid/base disturbances; and maintain the glomerular filtration rate. Antidotal therapy should be started as soon as possible after ingestion for the best chance of survival, because ethylene glycol is rapidly absorbed and metabolised, and once renal failure occurs treatment options are limited. Haemodialysis can be effective but is rarely available. Prognosis is poor in animals with renal failure, seizures or coma.

Evaluation of the role of toxicological data in discriminating between H2S femoral blood concentration secondary to lethal poisoning and endogenous H2S putrefactive production

Hydrogen sulfide is a colorless gas and has a strong odor of rotten eggs. It is absorbed by the upper respiratory tract mucosa and it causes histotoxic hypoxemia and respiratory depression by exerting an inhibitory effect on cytochrome oxidase. To evaluate the role of toxicological data in distinguishing between the H2S blood concentration secondary to lethal poisoning, and the endogenous H2S produced during putrefaction, we compared the post-mortem H2S concentrations of six fatal H2S poisoning cases (8.7–28.6mg/L) with the post-mortem concentrations of endogenous H2S of 12 subjects who died from other causes (traffic-related deaths) (2.2–32.7mg/L). These results will be of interest to the forensic community as it underlines the importance of considering circumstantial evidence along with toxicological and pathological findings in the identification of H2S lethal poisoning.

Role of coconut oil and soda bicarbonate in gastric lavage in the management of celphos poisoning

Context: Celphos poisoning is one of the most common and lethal poison with no antidote available till now. Aims: To evaluate the effectiveness of new treatment regimen and interventions to reduce the mortality from celphos poisoning. Settings and Design: A profile of 30 patients with alleged intake of celphos tablets who got admitted in intensive care unit (ICU) was studied. Materials and Methods: In all the 30 patients with alleged celphos poisoning, extensive gastric lavage was done with a mixture of coconut oil and sodium bicarbonate solution. Strict monitoring, both invasive and noninvasive was done and symptomatic/supportive treatment was carried out on a patient-to-patient basis. Statistical Analysis: At the end of the study, all the data were compiled systematically and statistical analysis was carried out using the nonparametric tests and value of P < 0.05 was considered significant. Results: Majority of the patients were young with a mean age of 20.14 ± 3.62 years and had good educational level. Most of the patients presented clinically with cardiovascular signs and symptoms (60%), followed by respiratory distress (13.33%) and little higher incidence of multiorgan symptomatology (16.67%). The mean stay of the patients in ICU was 5.62 ± 1.24 days and the survival rate was 40%. Conclusions: With the treatment regimen we have formulated, we were able to save 40% of our patients and recommend the use of this regimen by all the intensivists and physicians.

A race against time in lethal aluminum phosphide intoxication: a case report

Aluminum phosphide (AP) is a condition that results in death in case of use for suicide purpose. The phosphine gas, which is released as a result of aluminum phosphide intake, has high level of toxicity. It leads to cellular level hypoxia and inhibition of oxidative phosphorylation. Aluminum phosphide intoxication may cause metabolic acidosis, arrhythmia, acute respiratory distress syndrome, and shock. High-dose intakes may lead to death within hours. 22 year-old female patient was taken to our emergency service because of the suicide attempt with 6000mg aluminum phosphide tablet. We aimed to share our experience with our aluminum phosphide intoxication, which has no known antidote and leads to rapid death in follow-up. We aim to present our experiences with our case of intoxication from aluminum phosphide, which causes high mortality after the intake. 22 year-old female patient was transferred to our hospital due to suicide attempt with 6000mg aluminum phosphide tablet. The patients have no known comorbidities, medicine use or allergic history. We believe that, in preventing the high mortality rate in aluminum phosphide intoxication, metabolic acidosis, arrhythmia, ARDS and measures against the shock and the hemodialysis in early period should be performed. Although its efficiency has not been clearly proved and its use has not entered into algorithms, the use of MgSO4 and N-Acetyl-Cysteine in supportive care is an option for such cases. Further studies and proven treatment methods are needed in AP toxicity.

The specific features of the distribution of 4-metoxyhydroxybenzene in the organism of the warm-blooded animals suffering lethal intoxication

This work was designed to study the distribution of 4-metoxyhydroxybenzene in the organism of the omnivorous warm-blooded animals (rats) after the intragastric administration of this poisonous compound at a dose three-fold greater than the LD50 value. The administered 4-metoxyhydroxybenzene was isolated from the organs and blood of the experimental animals by exposing the biological tissues to acetone with subsequent purification on a silica gel L 40/100 mcm using a hexane:dioxane:propanol-2 (20:5:1) as the mobile phase. The identification and quantitation of 4-metoxyhydroxybenzene were carried out with the use of TLC, GC-MS, and UF-spectrophotometry. It was shown that the administered 4-metoxyhydroxybenzene remained unmetabolized in the internal organs and blood of the poisoned experimental animals. The largest amounts of 4-metoxyhydroxybenzene were found in the stomach contents (2584,92±117,47), brain (59.49±6.05), contents of small intestines (28.21±3.77), and kidneys (26.13±1.64).

Management of 2, 4- Dichlorophenoxyacetic Acid Intoxication by Hemodialysis: A Case Report

Background: The herbicide 2, 4-dichlorophenoxyacetic acid (2, 4-D) can cause moderate to lethal poisoning. Although urine alkalization has been recommended as the main treatment, hemodialysis (HD) may be more effective in severe cases. Case: On 24th June 2014, a 53- year-old man ingested a high amount of 40% 2, 4-D. He suffered from mouth and epigastric burning sensation, vomiting and nausea. He was treated, in Emam Reza’s Hospital of Mashhad University Of Medical Sciences, Mashhad , Iran, with maintenance daily fluid infusion plus 10 meq/L NaHCO3. Up to 9 hours after exposure, he became progressively stuporous. He developed diarrhea and hypotension, BP=100/60, unresponsive to volume replacement therapy. He received regular hemodialysis (HD) with bicarbonate for three hours. At the end of HD, his blood pressure rose to 110/70 and the level of consciousness began to improve. Four hours later, he was fully conscious with stable blood pressure (130/80 mmHg). Conclusion: HD may be an effective, safe and fast method for 2, 4-D high dose intoxication induced coma.

Cleistanthus collinus poisoning: experience at a medical intensive care unit in a tertiary care hospital in south India.

Background & objectives:Ingestion of Cleistanthus collinus causes hypokalemia and cardiac arrhythmias leading to mortality in most cases. We undertook this retrospective study to evaluate the clinical presentation and predictors of outcome in critically ill patients admitted with C. collinus poisoning.Methods:The case records of 56 patients admitted to the medical intensive care unit (MICU) of a tertiary care teaching hospital in south India (2000-2014) with C. collinus poisoning were retrospectively analysed.Results:The mean age of patients was 36.7±13.3 yr; there were 30 males. Salient clinical manifestations included hypokalemia (58%), neutrophilic leucocytosis (48.2%), acute kidney injury (AKI) (42.9%), acute respiratory failure requiring mechanical ventilation (AcRFMv) (32.1%), shock (21.4%); cardiac arrhythmias and neuromuscular weakness (19.6% each); 21 patients (37.5%) had adverse outcome. Longer time-lapsed from consumption to reaching emergency room [median (interquartile range)] (hours) [49 (22-97) vs. 28 (7-56), P=0.038]; higher acute physiology and chronic health evaluation II (APACHE II) score at presentation [14 (8.25-14.75) vs. 2 (0-6) P<0.001]; and presence of the following [odds ratio (95% confidence intervals)] at initial presentation: shock [37.40 (4.29-325.98), P=0.001]; AcRFMv [26.67 (5.86-121.39), P<0.001]; elevated alanine aminotransferase [5.71 (1.30-25.03), P=0.021]; metabolic acidosis [5.48 (1.68-17.89), P=0.005]; acute kidney injury (AKI) [5 (1.55-16.06), P=0.007]; hyponatremia [4.67 (1.25-17.44), P=0.022]; and neutrophilic leucocytosis [3.80 (1.02-14.21), P=0.047] predicted death. A significant (P<0.001) increasing trend in mortality was observed with increasing International Program on Chemical Safety Poisoning Severity Score (IPCS-CSS) grade.Interpretation & conclusions:C. collinus is a lethal poison associated with high mortality for which there is no specific antidote. Careful search and meticulous monitoring of the predictors of death and initiating appropriate corrective measures can be life saving.

Investigation of Lethal Poisonings among Dead Bodies Referred to Regional Office of Iranian Legal Medicine Organization in Shiraz

Background:Death due to acute poisoning is of medical, legal and social significance. This study was designed to investigate lethal poisonings among dead bodies referred to a regional office of Iranian Legal Medicine Organization (ILMO). Methods:This was a retrospective descriptive-analytical study on dead bodies referred to Fars province regional office of ILMO in Shiraz, Iran, during April 2013 to the end of March 2014. For data analysis, only subjects with poisoning as the definitive cause of death were included. Results:During the study period, 2,594 autopsies were conducted in Fars province office of ILMO, among which poisoning was found to be the cause of death in 147 autopsies (5.7%). Eighty-eight cases (59.9%) were men. The majority of subjects aged 20 to 30 years (50.3%). The greatest number of subjects (73.5%) was unmarried persons. Regarding the occupation, most subjects were unemployed (49.7%) followed by housewives (19.7%). Over half of the cases (54.42%) had died within less than 6 hours after the poisoning. The majority of cases were found dead at home (73.5%), while the rest had died in outpatient department or hospital wards. Suicide cases were far more common than unintentional cases (75.5% vs. 24.5%). Suicidal intention was significantly higher in subjects with lower educational status (P = 0.033). The most common causes of poisoning were pharmaceutical products (66.7%) followed by aluminum phosphide (10.9%) and other types of pesticides (7.2%). Conclusion:Lethal poisonings is mostly seen in young adults, and those with lower educational level and unemployment. Suicidal intention is the main cause of lethal poisonings.

Child poisonings with methadone in France: A 6-year prospective national survey since the availability of capsules in 2008

Background. Methadone for opiate substitution was available only in syrup formulation prior to 2008. In 2007, the French Health Authorities made solid forms available. A national survey was performed in order to evaluate the modification of child poisonings induced by such a new pharmaceutical formulation. Methods. A prospective study was set up (April 15, 2008 to April 15, 2014) with the analysis of cases of unintentional ingestion of methadone by patients under 18 years old and managed by the 10 French poison control centers at the national level. As soon as a new pediatric exposure was recorded in the informatics data bank of the Poison Centers, a telephone survey was performed by the Marseilles’ Poison Center to obtain the evolution and all the necessary details. Results. 87 cases of child poisonings with the 2 forms were reviewed (syrup, 56 patients; capsules, 31 patients). Comparison shows that patients were similar for both formulations (no significant difference concerning age [median 2 years], sex ratio [M/F 0.85], previous history, and ingested quantities of methadone). There was a similar severity profile with both formulations proving that methadone can lead to lethal child intoxications (1 death with capsules and 4 with syrup). The relative risk of pediatric accidents is also the same with 2 formulations, leading the health authorities, in collaboration with laboratories, to design and distribute flyers. The aim was to inform patients who are also parents about the high danger risk of their treatment for children, whatever the formulation of methadone present in the house. Discussion. The results of this survey were similar to those of another national study by the French Poison Centers concerning adult suicide attempts with methadone. Both prospective studies led to the conclusion that methadone must be considered as a dangerous molecule for patients and their families. The recent availability of a solid formulation in France did not change the profile of poisonings with this opiate substitute treatment.

Lethal Lullabies: A History of Opium Use in Infants.

Poppy extract accompanied the human infant for more than 3 millenia. Motives for its use included excessive crying, suspected pain, and diarrhea. In antiquity, infantile sleeplessness was regarded as a disease. When treatment with opium was recommended by Galen, Rhazes, and Avicenna, baby sedation made its way into early medical treatises and pediatric instructions. Dabbing maternal nipples with bitter substances and drugging the infant with opium were used to hasten weaning. A freerider of gum lancing, opiates joined the treatment of difficult teething in the 17th century. Foundling hospitals and wet-nurses used them extensively. With industrialization, private use was rampant among the working class. In German-speaking countries, poppy extracts were administered in soups and pacifiers. In English-speaking countries, proprietary drugs containing opium were marketed under names such as soothers, nostrums, anodynes, cordials, preservatives, and specifics and sold at the doorstep or in grocery stores. Opium's toxicity for infants was common knowledge; thousands of cases of lethal intoxication had been reported from antiquity. What is remarkable is that the willingness to use it in infants persisted and that physicians continued to prescribe it for babies. Unregulated trade, and even that protected by governments, led to greatly increased private use of opiates during the 19th century. Intoxication became a significant factor in infant mortality. As late as 1912, the International Hague Convention forced governments to implement legislation that effectively curtailed access to opium and broke the dangerous habit of sedating infants.

Tumor necrosis factor inhibition increases the revascularization of ischemic hind-limbs in diabetic mice.

Tumor necrosis factor (TNF) is first identified as a mediator of lethal endotoxin poisoning. The anti-TNF therapy in the treatment of rheumatoid arthritis is based on the recognition of the role of TNF as the master regulator. Type II diabetes is characterized with altered stem cells and reduced vasculogenesis. Therefore, we aimed to determine if TNF inhibitor would improve vasculogenesis in ischemic hind-limbs of diabetic mice. Fifty male type 2 diabetic and their control (8-10weeks old mice) were used, and ischemia was induced in the hind-limbs of all mice for 28days. Vessel density was assessed by high-definition microangiography at the end of the treatment period. After 4weeks, vessel density displayed no difference between the ischemic and the non-ischemic legs in control mice. However, in diabetic mice, the ischemic hind-limb vessel density was significantly decreased. Interestingly, diabetic mice displayed a significant improved vasculogenesis when treated with TNF inhibitor. Moreover, this data was confirmed by capillary density determined by immunostaining. TNF inhibitors are able to improve the formation of microvessels in response to ischemia in type 2 diabetes.