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Zitterbewegungen des Fusses bei Dorsalflexion (shaking movements of the foot upon dorsal flexion) were observed independently from each other and described in the same issue of a German peer reviewed journal by Carl Westphal (1833–1890) at the Charité in Berlin and by Wilhelm Erb (1840–1921) in Heidelberg. While Westphal used the term Fussphaenomen , Erb is credited with coining the term clonus for the phenomenon. Both scientists are immortalized by various eponyms acknowledging their respective contributions to science. Little is known however about Julius Sander (1840–1909), in those days resident at Charité, who noticed the phenomenon and presented it to his superiors, Wilhelm Griesinger (1817 −1868) and Westphal. In addition to such observations, Sander made original contributions in resuscitation physiology while working with Hugo Kronecker (1839–1914). With Kronecker, Sander published observations on life saving transfusions with inorganic salt solutions in dogs " Bemerkung über lebensrettende Transfusion mit anorganischer Salzlösung bei Hunde n" a very early work on isovolemic fluid resuscitation. The purpose of this communication is to highlight Sander's scientific contributions and to shed some light on his life, of which a German Lexicon stated that after 1870 no information on him can be ascertained anymore . [ABSTRACT FROM AUTHOR]

Previous studies on biocatalytic transformations of pinenes by cytochrome P450 (CYP) enzymes reveal the formation of different oxygenated products from a single substrate due to the multistate reactivity of CYP and the many reactive sites in the pinene scaffold. Up until now, the detailed mechanism of these biocatalytic transformations of pinenes have not been reported. Hereby, we report a systematic theoretical study of the plausible hydrogen abstraction and hydroxylation reactions of α- and β-pinenes by CYP using the density functional theory (DFT) method. All DFT calculations in this study were based on B3LYP/LAN computational methodology using the Gaussian09 software. We used the B3LYP functional with corrections for dispersive forces, BSSE, and anharmonicity to study the mechanism and thermodynamic properties of these reactions using a bare model (without CYP) and a pinene-CYP model. According to the potential energy surface and Boltzmann distribution for radical conformers, the major reaction products of CYP-catalyzed hydrogen abstraction from β-pinene are the doublet trans (53.4%) and doublet cis (46.1%) radical conformer at delta site. The formation of doublet cis/trans hydroxylated products released a total Gibbs free energy of about 48 kcal/mol. As for alpha pinene, the most stable radicals were trans-doublet (86.4%) and cis-doublet (13.6%) at epsilon sites, and their hydroxylation products released a total of ~50 kcal/mol Gibbs free energy. Our results highlight the likely C-H abstraction and oxygen rebounding sites accounting for the multi-state of CYP (doublet, quartet, and sextet spin states) and the formation of different conformers due to the presence of cis/trans allylic hydrogen in α-pinene and β-pinene molecules. [ABSTRACT FROM AUTHOR]

Acute kidney injury (AKI) relates to an abrupt reduction in renal function resulting from numerous conditions. Morbidity, mortality, and treatment costs related to AKI are relatively high. This condition is strongly associated with damage to proximal tubule cells (PTCs), generating distinct patterns of transcriptional and epigenetic alterations that result in structural changes in the nuclei of this epithelium. To this date, AKI-related nuclear chromatin redistribution in PTCs is poorly understood, and it is unclear whether changes in PTC chromatin patterns can be detected using conventional microscopy during mild AKI, which can progress to more debilitating forms of injury. In recent years, gray level co-occurrence matrix (GLCM) analysis and discrete wavelet transform (DWT) have emerged as potentially valuable methods for identifying discrete structural changes in nuclear chromatin architecture that are not visible during the conventional histopathological exam. Here we present findings indicating that GLCM and DWT methods can be successfully used in nephrology to detect subtle nuclear morphological alterations associated with mild tissue injury demonstrated in rodents by inducing a mild form of AKI through ischemia–reperfusion injury. Our results show that mild ischemic AKI is associated with the reduction of local textural homogeneity of PTC nuclei quantified by GLCM and the increase of nuclear structural heterogeneity indirectly assessed with DWT energy coefficients. This rodent model allowed us to show that mild ischemic AKI is associated with the significant reduction of textural homogeneity of PTC nuclei, indirectly assessed by GLCM indicators and DWT energy coefficients. [ABSTRACT FROM AUTHOR]

Persistent hyperglycemic state in type 2 diabetes mellitus leads to the initiation and progression of non-enzymatic glycation reaction with proteins and lipids and nucleic acids. Glycation reaction leads to the generation of a heterogeneous group of chemical moieties known as advanced glycated end products (AGEs), which play a central role in the pathophysiology of diabetic complications. The engagement of AGEs with its chief cellular receptor, RAGE, activates a myriad of signaling pathways such as MAPK/ERK, TGF-β, JNK, and NF-κB, leading to enhanced oxidative stress and inflammation. The downstream consequences of the AGEs/RAGE axis involve compromised insulin signaling, perturbation of metabolic homeostasis, RAGE-induced pancreatic beta cell toxicity, and epigenetic modifications. The AGEs/RAGE signaling instigated modulation of gene transcription is profoundly associated with the progression of type 2 diabetes mellitus and pathogenesis of diabetic complications. In this review, we will summarize the exogenous and endogenous sources of AGEs, their role in metabolic dysfunction, and current understandings of AGEs/RAGE signaling cascade. The focus of this review is to recapitulate the role of the AGEs/RAGE axis in the pathogenesis of type 2 diabetes mellitus and its associated complications. Furthermore, we present an overview of future perspectives to offer new therapeutic interventions to intervene with the AGEs/RAGE signaling pathway and to slow down the progression of diabetes-related complications. [ABSTRACT FROM AUTHOR]

Fine temperature control is essential in homeothermic animals. Both hyper- and hypothermia can have deleterious effects. Multiple, efficient and partly redundant mechanisms of adjusting the body temperature to the value set by the internal thermostat exist. The neural circuitry of temperature control and the neurotransmitters involved are reviewed. The GABAergic inhibitory output from the brain thermostat in the preoptic area POA to subaltern neural circuitry of temperature control (Nucleus Raphe Dorsalis and Nucleus Raphe Pallidus) is a function of the balance between the (opposite) effects mediated by the transient receptor potential receptor TRPM2 and EP3 prostaglandin receptors. Activation of TRPM2-expressing neurons in POA favors hypothermia, while inhibition has the opposite effect. Conversely, EP3 receptors induce elevation in body temperature. Activation of EP3-expressing neurons in POA results in hyperthermia, while inhibition has the opposite effect. Agonists at TRPM2 and/or antagonists at EP3 could be beneficial in hyperthermia control. Activity of the neural circuitry of temperature control is modulated by a variety of 5-HT receptors. Based on the theoretical model presented the "ideal" antidote against serotonin syndrome hyperthermia appears to be an antagonist at the 5-HT receptor subtypes 2, 4 and 6 and an agonist at the receptor subtypes 1, 3 and 7. Very broadly speaking, such a profile translates in a sympatholytic effect. While a compound with such an ideal profile is presently not available, better matches than the conventional antidote cyproheptadine (used off-label in severe serotonin syndrome cases) appear to be possible and need to be identified. [ABSTRACT FROM AUTHOR]

Elevated concentrations of interleukin-6 have been demonstrated to be an important key factor in COVID-19 host immune impairment. It represents an important prognostic factor of harm associated with COVID-19 infection by stimulating a vigorous proinflammatory response, leading to the so-called "cytokine storm". Therefore, immunomodulatory interventions targeting interleukin-6 receptor antagonism have been investigated as potential treatments to counterbalance the host immune dysregulation and to support the advantageous effects of corticosteroids. Tocilizumab is a recombinant humanized monoclonal antibody that has gained much interest during the COVID-19 pandemic as an interleukin-6 receptor antagonist. Various early observational studies have reported beneficial effects of tocilizumab. Moreover, consequent randomized controlled trials have subsequently shown significant positive results about tocilizumab efficacy and safety, focusing on outcomes like mortality, risk of intensive care unit admission, and the need for mechanical ventilation, while others presented conflicting findings. In this review, we first described the pathophysiology of COVID-19 infection while highlighting the role of interleukin-6. Furthermore, we also discussed the non-conclusive evidence about tocilizumab to be used as the standard of care therapy for all patients with COVID-19 pneumonia, as well as its beneficial effects in selected patients. [ABSTRACT FROM AUTHOR]

Cannabidiol (CBD), a major non-psychotropic cannabinoid found in the Cannabis plant, has been shown to exert anti-nociceptive, anti-psychotic, and anti-convulsant effects and to also influence the cardiovascular system. In this study, the effects of CBD on major ion currents were investigated using the patch-clamp technique in rabbit ventricular myocytes. CBD inhibited voltage-gated Na+ and Ca2+ channels with IC50 values of 5.4 and 4.8 µM, respectively. In addition, CBD, at lower concentrations, suppressed ion currents mediated by rapidly and slowly activated delayed rectifier K+ channels with IC50 of 2.4 and 2.1 µM, respectively. CBD, up to 10 μM, did not have any significant effect on inward rectifier I K1 and transient outward I to currents. The effects of CBD on these currents developed gradually, reaching steady-state levels within 5–8 min, and recoveries were usually slow and partial. Hill coefficients higher than unity in concentration-inhibition curves suggested multiple CBD binding sites on these channels. These findings indicate that CBD affects cardiac electrophysiology by acting on a diverse range of ion channels and suggest that caution should be exercised when CBD is administered to carriers of cardiac channelopathies or to individuals using drugs known to affect the rhythm or the contractility of the heart. [ABSTRACT FROM AUTHOR]

Exposure to or ingestion of turpentine can alter the scent of urine, conferring it a flowery, violet-like scent. Turpentine's effect on urine was initially noticed after its use either as medicine or as a preservative in winemaking. Regardless of the source of exposure, the phenomenon requires metabolic conversion of turpentine component(s) to ionone, the molecule mainly responsible for the scent of violets. The purpose of this study was to identify the presence of ionone in the urine of rats that received β-pinene, and thus to demonstrate that the postulated conversion occurs. We treated rats intraperitoneally with normal saline (negative control), β-ionone (positive control), low-dose β-pinene (1/3 of LD50), and high-dose β-pinene (1/2 of LD50). Urine samples were collected up to 72 h after administration of the compounds, followed by gas chromatography/mass spectrometry identification of the presence of ionone. β-Ionone was found in the urine of rats exposed to both low and high doses of β-pinene. In contrast, α-ionone appears unlikely to have been formed in rats exposed to either low or high doses of β-pinene. β-pinene was converted to β-ionone, followed by partial excretion in the urine of rats. β-Ionone is a minor metabolite of β-pinene. [ABSTRACT FROM AUTHOR]

Organs-on-chip are gaining increasing attention as promising platforms for drug screening and testing applications. However, lymph nodes-on-chip options remain limited although the lymph node is one of the main determinants of the immunotoxicity of newly developed pharmacological drugs. In this review, we describe existing biomimetic lymph nodes-on-chip, their design, and their physiological relevance to pharmacology and shed the light on future directions associated with lymph node-on-chip design and implementation in drug discovery and development. [ABSTRACT FROM AUTHOR]

Organs On-a-Chip represent novel platforms for modelling human physiology and disease. The lymph node (LN) is a relevant immune organ in which B and T lymphocytes are spatially organized in a complex architecture, and it is the place where the immune response initiates. The present study addresses the utility of a recently designed LN-on-a-chip to dissect and understand the effect of drugs delivered to cells in a fluidic multicellular 3D setting that mimics the human LN. To do so, we analyzed the motility and viability of human B and T cells exposed to hydroxychloroquine (HCQ). We show that the innovative LN platform, which operates at a microscale level, allows realtime monitoring of co-cultured B and T cells by imaging, and supports cellular random movement. HCQ delivered to cells through a constant and continuous flow induces a reduction in T cell velocity while promotes persistent rotational motion. We also find that HCQ increases the production of reactive oxygen species in T cells. Taken together, these results highlight the potential of the LN-on-a-chip to be applied in drug screening and development, and in cellular dynamics studies. [ABSTRACT FROM AUTHOR]

Accidental intoxications from environmental pollutants, as well as intentional self‐ and chemical warfare‐related poisonings affect millions of people worldwide each year. While many toxic agents can readily enter the central nervous system (CNS), the blood‐brain barrier (BBB) prevents the brain uptake of most pharmaceuticals. Consequently, poisoning antidotes usually cannot reach their site of action in the CNS in therapeutically relevant concentrations, and thus only provide effective protection to the peripheral nervous system. This limitation can be overcome by encapsulating the antidotes in nanoparticles (NP), which can enhance their CNS accumulation without damaging the integrity of the BBB. Among nanocarriers, polymer‐based drug delivery systems exhibit remarkable benefits, such as bioavailability, cell uptake and tissue retention. Furthermore, due to their capacity to mask unfavorable physicochemical properties of cargo drugs, polymeric NPs were able to improve BBB transport of various pharmaceuticals. However, while polymer NP‐mediated treatment of various pathological brain conditions, such as glioma and Alzheimer's disease were exhaustively studied, the application of polymeric nanocarriers for brain‐targeted delivery of antidote molecules has not been adequately examined. To display its therapeutic potential, we review the state of the art of polymer NP‐assisted CNS delivery of antidotes for various poisonings, including heavy metal and organophosphorus intoxications. While many toxins can enter the central nervous system (CNS), the blood‐brain barrier (BBB) prevents brain uptake of most antidotes. A possible solution to this problem is the encapsulation of antidote molecules in polymeric nanoparticles, which can enhance their CNS accumulation without damaging the BBB. Therefore, we review the potential of polymeric nanocarriers in the CNS delivery of antidotes for various poisonings, such as heavy metal and organophosphorus intoxications. [ABSTRACT FROM AUTHOR]

Sir Louis Francis Knuthsen (1869–1957), the physician who painstakingly listed almost all treatments known for obstinate hiccough, ascribes the holding of breath method to Philip Henry Pye-Smith, FRS (1840–1914), consultant at Guy's Hospital in London. In fact, the strategy is much older and was mentioned by greats such as Francis Bacon (1561–1626), Aristoteles (384–322 BC), and Eryximachus (late-fifth century bce). Hypoventilation to reduce central nervous system excitability was used in antiquity as evidenced by Cyriacus' treatment of Artemia, the daughter of Emperor Diocletian (≈ 244–311). She was suffering from (among others) seizures that Cyriacus was apparently controlling by tightening a scarf around her neck, as depicted by Mathias Grünewald (1460–1528) on a wing of the so-called Heller Altar now on display at the Historical Museum, Frankfurt, Germany. In modern times, around 1920, inducing hypercapnia by CO2 inhalation as therapy for hiccups was suggested and tried by a number of anesthetists, such as Americans Russel Firth Sheldon (1885–1960) and Brian Collins Sword (1889–1956) in Boston; Briton Christopher Langton Hewer (1896–1986) at St. Bartholomew's Hospital in London; Austrian Karl Doppler (1887–1947) in Vienna; and the German/Polish Arthur Dzialoszynski (1893–1977) in Berlin. Although various authors assign the scientific primate to any of them, the first mention of carbon dioxide inhalation as treatment of singultus in the scientific literature is of French origin and was made by Paris pharmacist Henri Bocquillon-Limousin (1856–1917) in his 1892 Formulaire des médicaments nouveaux et des médications nouvelles. [ABSTRACT FROM AUTHOR]

Organophosphates, useful agents as pesticides, also represent a serious danger due to their high acute toxicity. There is indication that oximes, when administered before organophosphate exposure, can protect from these toxic effects. We have tested at equitoxic dosage (25% of LD01) the prophylactic efficacy of five experimental (K‐48, K‐53, K‐74, K‐75, K‐203) and two established oximes (pralidoxime and obidoxime) to protect from mortality induced by the organophosphate paraoxon. Mortalities were quantified by Cox analysis and compared with those observed after pretreatment with a strong acetylcholinesterase inhibitor (10‐methylacridine) and after the FDA‐approved pretreatment compound pyridostigmine. All nine tested substances statistically significantly reduced paraoxon‐induced mortality. Best protection was conferred by the experimental oxime K‐48, reducing the relative risk of death (RR) to 0.10, which was statistically significantly superior to pyridostigmine (RR = 0.31). The other oximes reduced the RR to 0.13 (obidoxime), 0.20 (K‐203), 0.21 (K‐74), 0.24 (K‐75) and 0.26 (pralidoxime), which were significantly more efficacious than 10‐methylacridine (RR = 0.65). These data support the hypothesis that protective efficacy is not primarily due to cholinesterase inhibition and indicate that the tested experimental oximes may be considered promising alternatives to the established pretreatment compound pyridostigmine. The prophylactic efficacy of five experimental (K‐48, K‐53, K‐74, K‐75, K‐203) and two established oximes (pralidoxime and obidoxime) to protect from mortality induced by the organophosphate paraoxon was evaluated. Best protection was conferred by the experimental oxime K‐48, reducing the relative risk of death to 0.10, which was significantly superior to the FDA‐approved substance pyridostigmine. [ABSTRACT FROM AUTHOR]

Poisoning with organophosphorus compounds (OPCs) is a major problem worldwide. Standard therapy with atropine and established oxime-type enzyme reactivators (pralidoxime, obidoxime) is unsatisfactory. In search of more efficacious broad-spectrum oximes, new bispyridinium (K-) oximes have been synthesized, with K027 being among the most promising. This review summarizes pharmacokinetic characteristics of K027, its toxicity and in vivo efficacy to protect from OPC toxicity and compares this oxime with another experimental bisquaternary asymmetric pyridinium aldoxime (K048) and two established oximes (pralidoxime, obidoxime). After intramuscular (i.m.) injection, K027 reaches maximum plasma concentration within ∼30 min; only ∼2% enter the brain. Its intrinsic cholinesterase inhibitory activity is low, making it relatively non-toxic. In vitro reactivation potency is high for ethyl-paraoxon-, methyl-paraoxon-, dichlorvos-, diisopropylfluorophosphate (DFP)- and tabun-inhibited cholinesterase. When administered in vivo after exposure to the same OPCs, K027 is comparable or more efficacious than pralidoxime and obidoxime. When given as a pretreatment before exposure to ethyl-paraoxon, methyl-paraoxon, DFP, or azinphos-methyl, it is superior to the Food and Drug Administration-approved compound pyridostigmine and comparable to physostigmine, which because of its entry into the brain may cause unwanted behavioral effects. Because of its low toxicity, K027 can be given in high dosages, making it a very efficacious oxime not only for postexposure treatment but also for prophylactic administration, especially when brain penetration is undesirable. [ABSTRACT FROM AUTHOR]

Type I diabetes (T1D) is a T cell-driven autoimmune disease that results in the killing of pancreatic β-cells and, consequently, loss of insulin production. Using the multiple low-dose streptozotocin (MLD-STZ) model of experimental autoimmune diabetes, we previously reported that pretreatment with a specific acetylcholinesterase inhibitor (AChEI), paraoxon, prevented the development of hyperglycemia in C57BL/6 mice. This correlated with an inhibition of T cell infiltration into the pancreatic islets and a reduction in pro-inflammatory cytokines. The cholinergic anti-inflammatory pathway utilizes nicotinic and muscarinic acetylcholine receptors (nAChRs and mAChRs, respectively) expressed on a variety of cell types. In this study, we carried out a comparative analysis of the effect of specific antagonists of nAChRs or mAChRs on the development of autoimmune diabetes. Co-administration of mecamylamine, a non-selective antagonist of nAChRs maintained the protective effect of AChEI on the development of hyperglycemia. In contrast, co-administration of atropine, a non-selective antagonist of mAChRs, mitigated AChEI-mediated protection. Mice pretreated with mecamylamine had an improved response in glucose tolerance test (GTT) than mice pretreated with atropine. These differential effects of nAChR and mAChR antagonists correlated with the extent of islet cell infiltration and with the structure and functionality of the β-cells. Taken together, our data suggest that mAChRs are essential for the protective effect of cholinergic stimulation in autoimmune diabetes. [ABSTRACT FROM AUTHOR]

Organophosphorus compounds (OPCs), inhibitors of acetylcholinesterase (AChE), are useful agents as pesticides, but also represent a serious health hazard. Standard therapy with atropine and established oxime‐type enzyme reactivators (pralidoxime, obidoxime) is unsatisfactory. Better therapeutic results are obtained, when reversible AChE inhibitors are administered before OPC exposure. This review summarizes the history of such a pretreatment approach and sums up a set of experiments undertaken in search of compounds that are efficacious when given before a broad range of OPCs. The prophylactic efficacy of 10 known AChE inhibitors, either already used clinically for different indications (physostigmine, pyridostigmine, ranitidine, tiapride, tacrine, amiloride, metoclopramide, methylene blue) or developed for possible therapeutic use in the future (7‐methoxytacrine, K‐27) was compared, when administered before exposure to six chemically diverse OPCs in the same experimental setting: ethyl‐paraoxon, methyl‐paraoxon, diisopropylfluorophosphate, terbufos sulfone, azinphos‐methyl and dicrotophos. The experimental oxime K‐27 was the most efficacious compound, affording best protection, when administered before terbufos sulfone, azinphos‐methyl and dicrotophos, second best before ethyl‐ and methyl‐paraoxon exposure and third best before diisopropylfluorophosphate administration. This ranking was similar to that of physostigmine, which was superior to the Food and Drug Administration‐approved pretreatment for soman with pyridostigmine. Tiapride, amiloride, metoclopramide, methylene blue and 7‐methoxytacrine did not achieve protection. No correlation was observed between the IC50 of the reversible AChE inhibitors and their protective efficacy. These studies indicate that K‐27 can be considered a very promising broad‐spectrum prophylactic agent in case of imminent organophosphate exposure, which may be related to its AChE reactivating activity rather than its AChE inhibition. Organophosphorus inhibitors of acetylcholinesterase (OPCs) represent a serious health hazard. Standard oxime therapy is unsatisfactory. Reversible cholinesterase inhibitors administered before OPC exposure achieve better results. This review describes the history of such a pretreatment approach and summarizes experiments undertaken in search of compounds that are efficacious when given before a broad range of OPCs. These studies indicate that the experimental oxime K‐27 is a very promising broad‐spectrum prophylactic agent, which may be related to its AChE reactivating capacity. [ABSTRACT FROM AUTHOR]

Abstract: This study was performed to evaluate the protective efficacy of metoclopramide (MCP) against the organophosphates paraoxon (POX)‐ and malathion (MLT)‐induced apoptosis in the murine L929 skin fibroblasts. L929 cells were exposed to either POX (10 n m) or 1.0 μ m MLT in the absence and presence of increased concentrations of MCP. The protective effect of MCP on these organophosphate‐stimulated apoptotic events was evaluated by flow cytometry analysis after staining with annexin‐V/propidium iodide, processing and activation of the executioner caspase‐3, cleavage of the poly‐ADP ribose polymerase, fragmentation of the nucleosomal DNA and disruption of the mitochondrial membrane potential (Δψ). Our results showed that increased doses of MCP alone (≥10 μ m) did not induce apoptosis or activation of caspase‐3. Pretreatment of the cells with MCP attenuated all the apoptotic events triggered by the organophosphate compounds in a dose‐dependent manner reaching ~70–80% protection when they were preincubated at 1 and 5 μ m of the drug before the addition of POX and MLT, respectively. Interestingly, MCP did not offer a significant protective effect against the cytotoxicity of tumor necrosis factor‐α, cisplatinum, etoposide or paclitaxel, which stimulate apoptosis by various mechanisms, suggesting that the anti‐apoptotic effect of the drug is specific to organophosphates. The strong and specific anti‐apoptotic activity of subclinical doses of MCP against the cytotoxicity of organophosphate compounds suggests its potential clinical application in treating their poisoning. [ABSTRACT FROM AUTHOR]

Organophosphate (OP) poisoning is a major global health issue; while compounds from this group have been used intensively over the last century, an effective antidote is still lacking. Oxime-type acetylcholinesterase (AChE) reactivators are used to reactivate the OP inhibited AChE. Pralidoxime is the only US Food and Drug Administration approved oxime for therapeutic use but its efficacy has been disappointing. Two novel oximes (K378 and K727) were investigatedin silicoandin vitroand compared with an experimental oxime (kamiloxime; K-27) and pralidoxime.In silicothe molecular interactions between AChE and oximes were examined and binding energies were assessed. LogP (predicted log of the octanol/water partition coefficient) was estimated.In vitrothe intrinsic ability of the oximes to inhibit AChE (IC50) and their reactivation potency (R50) when used in paraoxon inhibited human RBC-AChE was determined. Molecular docking revealed that K378 and K727 bind to the peripheral site(s) with high binding energies in contrast to the central binding of K-27 and pralidoxime. LogP values indicating that the novel compounds are significantly less hydrophilic than K-27 or pralidoxime. IC50of K378 and K727 were comparable (0.9 and 1 µM, respectively) but orders of magnitude lower than comparators.R50values revealed their inability to reactivate paraoxon inhibited AChE. It is concluded that the novel oximes K378 and K727 are unlikely to be clinically useful. Thein silicoandin vitrostudies described allow avoidance of unnecessaryin vivoanimal work and contribute to the reduction of laboratory animal use. [ABSTRACT FROM PUBLISHER]

The recognition in the early 1960s by Morifusa Eto that tri-o-cresyl phosphate (TOCP) is hydroxylated by the cytochrome P450 system to an intermediate that spontaneously cyclizes to a neurotoxic phosphate (saligenin phosphate ester) ignited the interest in this group of compounds. Only the ortho isomer can cyclize and clinically cause Organo Phosphate Induced Delayed Neurotoxicity (OPIDN); the meta and para isomers of tri-cresyl phosphate are not neuropathic because they are unable to form stable cyclic saligenin phosphate esters. This review identifies the diverse biological effects associated with various cyclic and caged phosphates and phosphonates and their possible use. Cyclic compounds that inhibit acetylcholine esterase (AChE), such as salithion, can be employed as pesticides. Others are neurotoxic, most probably because of inhibition of neuropathy target esterase (NTE). Cyclic phosphates that inhibit lipases, the cyclipostins, possibly represent promising therapeutic avenues for the treatment of type 2 diabetes mellitus and/or microbial infections; those compounds inhibiting β-lactamase may prevent bacterial resistance against β-lactam antibiotics. Naturally occurring cyclic phosphates, such as cyclic AMP, cyclic phosphatidic acid and the ryanodine receptor modulator cyclic adenosine diphosphate ribose, play an important physiological role in signal transduction. Moreover, some cyclic phosphates are GABA-antagonists, while others are an essential component of Molybdenum-containing enzymes. Some cyclic phosphates (cyclophosphamide, ifosfamide) are clinically used in tumor therapy, while the coupling of therapeutic agents with other cyclic phosphates (HepDirect® Technology) allows drugs to be targeted to specific organs. Possible clinical applications of these compounds are considered. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

This short report attempts to shed light on the interesting but controversial personality of George T Dexter (ca1812 -?), the physician who first described manipulation of the female genitalia in a hysterical impressionable girl as being associated with the termination of singultus. Although his interaction with the young female patient would not meet today's ethical standards, his medical observation was valid and contributes to our understanding of the pathophysiology of singultus. He was well ahead of his colleagues who presented hiccup therapy case reports with similar or related pathophysiology mechanisms some 150 years later. [ABSTRACT FROM AUTHOR]

The article offers information on how Ionone, a molecule that shaped the history of the western civilization. It mentions that scent of violets as due to various mono-cyclical terpenoids, mainly ionones and irones, along with mentions that Ionone synthesis was first achieved in 1893 by Ferdinand Tiemann and Paul Krueger.

Pre-treatment with reversible acetylcholinesterase (AChE) inhibitors before organophosphorous compound (OPC) exposure can reduce OPC-induced mortality. However, pyridostigmine, the only substance employed for such prophylaxis, is merely efficacious against a limited number of OPCs. In search of more efficacious and broad-range alternatives, we have compared in vivo the ability of five reversible AChE inhibitors (pyridostigmine, physostigmine, ranitidine, tacrine and K-27) to reduce mortality induced by the OPC azinphos-methyl. Protection was quantified using Cox analysis by determining the relative risk (RR) of death in rats that were administered these AChE inhibitors in equitoxic dosage (25% of LD01) 30 min before azinphos-methyl exposure. Azinphos-methyl-induced mortality was significantly reduced by all five tested compounds as compared with the reference group that was only exposed to azinphos-methyl without prior pre-treatment (RR = 1). The most efficacious prophylactic agents were K-27 (RR = 0.15) and physostigmine (RR = 0.21), being significantly more efficacious than ranitidine (RR = 0.62) and pyridostigmine (RR = 0.37). Pre-treatment with tacrine (RR = 0.29) was significantly more efficacious than pre-treatment with ranitidine, but the difference between tacrine and pyridostigmine was not significant. Our results indicate that prophylactic administration of the oxime K-27 may be a promising alternative in cases of imminent OPC exposure. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

A multitude of nonpharmacological interventions to terminate hiccup belong to the public-domain hiccup “mythology” or have been described in the medical literature as case reports. While usually effective in terminating bouts of acute hiccup, they are mostly ineffective in cases of hiccupping that have been present for an extended period. The common denominator of most of these therapeutic maneuvers (some also used to terminate paroxysmal supraventricular tachycardia) is their ability to directly or indirectly increase efferent vagal activity. Among the best known “vagal maneuvers” are the oculo-cardiac reflex (Dagnini-Aschner), the carotid sinus massage, the Valsalva maneuver, stimulation of the ear/auditory canal, ice ingestion, and induction of emesis. This short report provides an overview on hiccups and attempts to identify the lesser known personalities who pioneered its treatment by vagal maneuvers. The recent introduction of electrical vagus nerve stimulation for therapy-resistant hiccup is the ultimate compliment to these pioneers. [ABSTRACT FROM PUBLISHER]

ABSTRACT Unforeseen toxic effects contribute to compound attrition during preclinical evaluation and clinical trials. Consequently, there is a need to correlate in vitro toxicity to in vivo and clinical outcomes quickly and effectively. We propose an expedited evaluation of physiological parameters in vitro that will improve the ability to predict in vivo toxicity of potential therapeutics. By monitoring metabolism, mitochondrial physiology and cell viability, our approach provides insight to the extent of drug toxicity in vitro. To implement our approach, we used human hepatocellular carcinoma cells (HepG2) and neuroblastoma cells (SH-SY5Y) to monitor hepato- and neurotoxicity of the experimental oxime K027. We utilized a trivalent approach to measure metabolism, mitochondrial stress and induction of apoptosis in 96-well formats. Any change in these three areas may suggest drug-induced toxicity in vivo. K027 and pralidoxime, an oxime currently in clinical use, had no effect on glycolysis or oxygen consumption in HepG2 and SH-SY5Y cells. Similarly, these oximes did not induce oxidant generation nor alter mitochondrial membrane potential. Further, K027 and pralidoxime failed to activate effector caspases, and these oximes did not alter viability. The chemotherapeutic agent, docetaxel, negatively affected metabolism, mitochondrial physiology and viability. Our studies present a streamlined high-throughput trivalent approach for predicting toxicity in vitro, and this approach reveals that K027 has no measurable hepatotoxicity or neurotoxicity in vitro, which correlates with their in vivo data. This approach could eliminate toxic drugs from consideration for in vivo preclinical evaluation faster than existing toxicity prediction panels and ultimately prevent unnecessary experimentation. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

ABSTRACT Poisoning with organophosphorus compounds (OPCs) poses a serious threat worldwide. OPC-induced mortality can be significantly reduced by prophylactic administration of reversible acetylcholinesterase (AChE) inhibitors. The only American Food and Drug Administration (FDA)-approved substance for such pre-treatment (to soman exposure) is presently pyridostigmine, although its efficacy is controversial. In search for more efficacious and broad-spectrum alternatives, we have assessed in vivo the mortality-reducing efficacy of a group of five compounds with known AChE inhibitory activity (pyridostigmine, physostigmine, ranitidine, tacrine and K-27), when given in equitoxic dosage (25% of LD01) 30 min before exposure to the OPC terbufos sulfone. Protection was quantified in rats by determining the relative risk of death (RR) using Cox analysis, with RR = 1 for animals given only terbufos sulfone, but no pre-treatment. All tested AChE inhibitors reduced terbufos sulfone-induced mortality significantly (p ≤ 0.05) as compared with the non-treatment group (RR = 1: terbufos sulfone only). Best in vivo protection from terbufos sulfone-induced mortality was achieved, when K-27 was given before terbufos sulfone exposure (RR = 0.06), which was significantly ( P ≤ 0.05) superior to the pre-treatment with all other tested compounds, for example tacrine (RR = 0.21), pyridostigmine (RR = 0.28), physostigmine (RR = 0.29) and ranitidine (RR = 0.33). The differences in efficacy between tacrine, pyridostigmine, physostigmine and ranitidine were not statistically significant. Prophylactic administration of an oxime (such as K-27) in case of imminent OPC exposure may be a viable option. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

During intrauterine life, hiccups are universally present, their incidence peaking in the third trimester. Alfons Mermann (1852–1908), a gynecologist from Mannheim, Germany, best known for having established the Luisenheim Woechnerinnenasyl [lying-in asylum] there in 1887, is viewed as the first physician to name and describe singultus foetalis [fetal hiccups] in a modern peer-reviewed scientific publication. This short report attempts to shed some light on the work of Dr. Mermann and to explore whether or not he was indeed the first to recognize this phenomenon. [ABSTRACT FROM AUTHOR]

ABSTRACT There is an increasing belief that organophosphorus compounds (OPCs) impair glucose homeostasis and cause hyperglycemia and diabetes mellitus. The present study was undertaken to investigate the putative diabetogenic effect of sub-lethal and sub-chronic exposure to paraoxon (POX), an extremely hazardous OPC used in pesticides. The effect of paraoxon on streptozotocin-induced diabetic rats was also examined. Each rat was injected with 100 nmol of POX 5 days per week for 6 weeks. Blood glucose levels and red blood cell acetylcholinesterase activity were measured weekly. Biochemical analysis and morphological studies were performed at the end of the experiment. The results revealed that POX neither induces nor exacerbates diabetes mellitus in experimental rats. Liver and kidney/body weight ratios revealed statistically insignificant differences when compared with controls. Biochemical analysis of urine samples showed a small but not significant increase in protein level in all groups. Urine bilirubin was significantly higher in the diabetes + POX group when compared with the control group. The number of blood cells in urine was significantly higher in the POX-treated group compared with the control group. Hyperglycemia was noted in the diabetes and diabetes + POX groups, but neither in the saline control nor in POX-treated normal rats. Electron microscopy of POX-treated pancreas did not show any morphological changes in beta cells. These results suggest that POX does not cause diabetes mellitus at sub-lethal sub-chronic exposure. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

ABSTRACT Reversible acetylcholinesterase (AChE) inhibitors can protect against the lethal effects of irreversible organophosphorus AChE inhibitors (OPCs), when administered before OPC exposure. We have assessed in vivo the mortality-reducing efficacy of a group of known AChE inhibitors, when given in equitoxic dosage before exposure to the OPC paraoxon. Protection was quantified in rats by determining the relative risk (RR) of death. Best in vivo protection from paraoxon-induced mortality was observed after prophylactic administration of physostigmine (RR = 0.30) or the oxime K-27 (RR = 0.34); both treatments were significantly superior to the pre-treatment with all other tested compounds, including the established substance pyridostigmine. Tacrine (RR = 0.67), ranitidine (RR = 0.72), pyridostigmine (RR = 0.76), tiapride (RR = 0.80) and 7-MEOTA (RR = 0.86) also significantly reduced the relative risk of paraoxon-induced death, but to a lesser degree. Methylene blue, amiloride and metoclopramide had an unfavorable effect (RR ≥ 1), significantly increasing mortality. When CNS penetration by prophylactic is undesirable K-27 is a promising alternative to pyridostigmine. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

BACKGROUND AND PURPOSE Methylene blue (MB) is commonly employed as a treatment for methaemoglobinaemia, malaria and vasoplegic shock. An increasing number of studies indicate that MB can cause 5-HT toxicity when administered with a 5-HT reuptake inhibitor. MB is a potent inhibitor of monoamine oxidases, but other targets that may contribute to MB toxicity have not been identified. Given the role of the 5-HT transporter (SERT) in the regulation of extracellular 5-HT concentrations, the present study aimed to characterize the effect of MB on SERT. EXPERIMENTAL APPROACH Live cell imaging, in conjunction with the fluorescent SERT substrate 4-(4-(dimethylamino)-styryl)- N-methylpyridinium (ASP+), [3H]5-HT uptake and whole-cell patch-clamp techniques were employed to examine the effects of MB on SERT function. KEY RESULTS In EM4 cells expressing GFP-tagged human SERT (hSERT), MB concentration-dependently inhibited ASP+ accumulation (IC50: 1.4 ± 0.3 µM). A similar effect was observed in N2A cells. Uptake of [3H]5-HT was decreased by MB pretreatment. Furthermore, patch-clamp studies in hSERT expressing cells indicated that MB significantly inhibited 5-HT-evoked ion currents. Pretreatment with 8-Br-cGMP did not alter the inhibitory effect of MB on hSERT activity, and intracellular Ca2+ levels remained unchanged during MB application. Further experiments revealed that ASP+ binding to cell surface hSERT was reduced after MB treatment. In whole-cell radioligand experiments, exposure to MB (10 µM; 10 min) did not alter surface binding of the SERT ligand [125I]RTI-55. CONCLUSIONS AND IMPLICATIONS MB modulated SERT function and suggested that SERT may be an additional target upon which MB acts to produce 5-HT toxicity. [ABSTRACT FROM AUTHOR]

Prophylactic administration of reversible acetylcholinesterase (AChE) inhibitors before exposure to organophosphorus compounds (OPCs) can reduce OPC-induced mortality. Pyridostigmine is the only FDA-approved substance for such use. The AChE-inhibitory activity of known AChE inhibitors was quantified in vitro and their in vivo mortality-reducing efficacy was compared, when given prophylactically before the exposure to the OPC diisopropylfluorophosphate (DFP). The IC50 was measured in vitro for the known AChE inhibitors pyridostigmine, physostigmine, ranitidine, tiapride, tacrine, 7-methoxytacrine, amiloride, metoclopramide, methylene blue and the experimental oxime K-27. Their in vivo efficacy, when given as pretreatment, to protect rats from DFP-induced mortality was quantified by determining the relative risk of death (RR) by Cox analysis, with RR = 1 for animals given only DFP, but no pretreatment. Physostigmine was the strongest in vitro AChE-inhibitor (IC50 = 0.012 µ m), followed by 7-methoxytacrine, tacrine, pyridostigmine and methylene blue. Ranitidine (IC50 = 2.5 µ m), metoclopramide and amiloride were in the mid-range. Tiapride (IC50 = 256 µ m) and K-27 (IC50 = 414 µ m) only weakly inhibited RBC AChE activity. Best in vivo protection from DFP-induced mortality was achieved when physostigmine (RR = 0.02) or tacrine (RR = 0.05) was given before DFP exposure, which was significantly superior to the pretreatment with all other tested compounds, except K-27 (RR = 0.18). The mortality-reducing effect of pyridostigmine, ranitidine and 7-methoxytacrine was inferior, but still significant. Tiapride, methylene blue, metoclopramide and amiloride did not significantly improve DFP-induced mortality. K-27 may be a more efficacious alternative to pyridostigmine, when passage into the brain precludes administration of physostigmine or tacrine. Copyright © 2010 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The cholinergic nervous system has been demonstrated to attenuate the inflammatory response during sepsis via the inhibitory action of acetylcholine (ACh) on macrophages. These findings were largely based on experimental sepsis models using endotoxin as the inducing agent. Herein, however, we report that the specific inhibition of acetylcholinesterase (AChE) renders animals more resistant to infection by a virulent strain of Salmonella enterica serovar Typhimurium, a Gram-negative enteric pathogen. Inhibition of AChE was induced by a subchronic exposure to paraoxon, a potent anti-cholinesterase metabolite of the organophosphorous compound parathion. Our findings indicate that inhibition of AChE enhanced survival of infected mice in a dose-dependent fashion and this correlated with efficient control of bacterial proliferation in target organs. Immunologically, inhibition of AChE enabled the animals to mount a more effective inflammatory anti-microbial response, and to secrete higher levels of interleukin-12, a key T helper type 1-promoting cytokine. The ACh-induced enhancement in resistance to infection was abrogated by co-administration of an oxime which can reactivate AChE. Hence, in a model of Gram-negative bacterial infection, cholinergic stimulation is shown to enhance the anti-microbial immune response leading to effective control of bacterial proliferation and enhanced animal survival. [ABSTRACT FROM AUTHOR]

One important risk gene in schizophrenia is neuregulin-1 ( NRG1), which is expressed in different isoforms in the brain. To determine if alterations of NRG1 are present in schizophrenia, we measured gene expression of NRG1 and its main isoforms as well as the impact of genetic variation of NRG1 in an exploratory study examining three brain regions instead of only one as published so far. In all, we examined post-mortem samples from 11 schizophrenia patients and eight normal subjects. We investigated gene expression of total NRG1 and isoforms I, II and III by real-time PCR in the prefrontal cortex (Brodmann areas 9 and 10) and right hippocampal tissue. For the genetic study, we genotyped the NRG1 polymorphism SNP8NRG221533, which is within the core haplotype of the original publication. Compared to controls, gene expression of the NRG1 isoform I was decreased and isoform II increased in the prefrontal cortex (BA10) of schizophrenia patients. There were no statistically significant differences between individuals carrying at least one C allele of SNP8NRG221533 compared to individuals homozygous for the T allele. The decreased expression of NRG1 isoform I and overexpression of isoform II may be related to deficits in receptor function as well as abnormal migration and myelination. However, our study sample was small and results of this exploratory study should be verified in a larger sample. [ABSTRACT FROM AUTHOR]

An important risk gene in schizophrenia is d-amino acid oxidase (DAAO). To establish if expression of DAAO is altered in cortical, hippocampal or thalamic regions of schizophrenia patients, we measured gene expression of DAAO in a post-mortem study of elderly patients with schizophrenia and non-affected controls in both hemispheres differentiating between gray and white matter. We compared cerebral post-mortem samples (granular frontal cortex BA9, middle frontal cortex BA46, superior temporal cortex BA22, entorhinal cortex BA28, sensoric cortex BA1–3, hippocampus (CA4), mediodorsal nucleus of the thalamus) from 10 schizophrenia patients to 13 normal subjects investigating gene expression of DAAO in the gray and white matter of both hemispheres of the above-mentioned brain regions by in situ-hybridization. We found increased expression of DAAO-mRNA in the hippocampal CA4 of schizophrenic patients. Compared to the control group, both hemispheres of the hippocampus of schizophrenic patients showed an increased expression of 46% (right, P = 0.013) and 54% (left, P = 0.019), respectively. None of the other regions examined showed statistically significant differences in DAAO expression. This post-mortem study demonstrated increased gene expression of DAAO in the left and right hippocampus of schizophrenia patients. This increased expression could be responsible for a decrease in local d-serine levels leading to a NMDA-receptor hypofunction that is hypothesized to play a major role in the pathophysiology of schizophrenia. However, our study group was small and results should be verified using larger samples. [ABSTRACT FROM AUTHOR]

Lung cancer is the most common form of cancer in the world, and 90% of patients die from their disease. The angiotensin converting enzyme (ACE) inhibitors are used widely as antihypertensive agents, and it has been suggested that they decrease the risk of some cancers, although available data are conflicting. Accordingly, we investigated the anticancer activity of the ACE inhibitor, captopril, in athymic mice injected with highly tumorigenic LNM35 human lung cells as xenografts. Using this model, we demonstrated that daily IP administration of captopril (2.8 mg/mouse) for 3 weeks resulted in a remarkable reduction of tumor growth (58%, P < 0.01) and lymph node metastasis (50%, P= 0.088). There were no undesirable effects of captopril treatment on animal behavior and body weight. In order to determine the mechanism by which captopril inhibited tumor growth, we investigated the impact of this drug on cell proliferation, apoptosis, and angiogenesis. Immunohistochemical analysis demonstrated that captopril treatment significantly reduced the number of proliferating cells ( Ki-67) in the tumor samples but was not associated with inhibition of tumor angiogenesis (CD31). Using cell viability and fluorescent activated cell sorting analysis tests, we demonstrated that captopril inhibited the viability of LNM35 cells by inducing apoptosis, providing insight about the mechanisms underlying its antitumorigenic activities. In view of these experimental findings, we conclude that captopril could be a promising option for the treatment of lung cancer. [ABSTRACT FROM AUTHOR]

A simple and reliable reversed-phase TLC method was used to determine the lipophilicity of ACE inhibitors. The TLC silica plates were saturated with paraffin using continuous development with 10% paraffin in hexane for 18 hours. The TLC silica particles covered with the paraffin are used as an inexpensive substituent of the usual RP-18 TLC stationary phase. [ABSTRACT FROM AUTHOR]

The chemical structures of certain drug candidates give only a minimum of lipophilicity. Investigation of their elution on reversed-phase materials was difficult, even when the water content of the mobile phase was changed. The dominative role of lipophilicity, either in the drugs' penetration or in the receptorial drug binding, is considered to be valid solely in the same chemical group of the various drugs. In the cases of extremely lipophobic (i.e., hydrophilic) compounds, both the determination or calculation of lipophilicity was difficult or impossible. This is the reason that a novel index, the TLC hydrophilicity parameter, should be introduced as a substitute for lipophilicity. Hydrophilicity can be preferrably determined using a planar stationary phase and an aqueous-organic mobile phase. Numerical data of hydrophilicity on silica stationary phase can be calculated using RM values, similar to the lipophilicity indices. [ABSTRACT FROM AUTHOR]

Cognitive impairment is a dramatically increasing problem affecting many individuals as well as the health system. As we have no causal treatment for the loss of memory, symptomatic treatment is needed. Influencing the ACh system is a generally accepted approach, although other therapeutic treatments are in various stages of development. The multiple target drug approach using hybrid compounds may be another optimized move forward for the treatment of cognitive disorders. Since the complex neuronal regulation is slowly being decoded, there is hope that ways will be found to stop neuronal loss and to generate new synapses. [ABSTRACT FROM AUTHOR]

Pyridostigmine (PSTG) is a carbamate inhibitor of cholinesterases. Carbamates are known to confer some protection from the lethal effects of (some) organophosphorus compounds. Recently, based on animal data, the FDA approved oral PSTG for pre-exposure treatment of soman. The purpose of the study was to quantify in vivo the effect of PSTG pre-treatment on survival in rats exposed to the organophosphate paraoxon (POX) with and without subsequent reactivator (pralidoxime) treatment. POX is a highly toxic non-neuropathic ethyl organophospate. Pralidoxime (PRX) is the enzyme reactivator used by some NATO armies. The prospective, controlled animal (rat) study included Group 1 that received 1 μmol POX (≈LD75); Group 2 that received 1 μmol PSTG followed 30 min later by 1 μmol POX; Group 3 that received 1 μmol PSTG followed 30 min later by 1 μmol POX and 50 μmol PRX; Group 4 that received 1 μmol POX and 50 μmol PRX; Group 5 that received 1 μmol PSTG; Group 6 that received 50 μmol PRX and Group 7 that received 1 μmol PSTG followed 30 min later by 50 μmol PRX. Each group contained six rats. The experiment was repeated twelve times (12 cycles). All substances were applied i.p. From surviving animals of eight cycles tail blood was taken for red blood cell acetylcholinesterase (RBC-AChE) measurements. The animals were monitored for 48 h and mortality (survival time) was recorded. RBC-AChE activities were determined. Mortality was analysed using Kaplan–Meier plots. Both PSTG and PRX statistically significantly decreased organophosphate induced mortality in the described model. While the same applies to their combination the decrease in mortality when using both PSTG and PRX is less than that achieved with their single use (but not significantly so). While certainly further work using different organophosphorus compounds and animal species are needed before a final conclusion is reached, the animal data presented does not support the combined use of PSTG and PRX. [ABSTRACT FROM AUTHOR]

Weak and reversible inhibitors of cholinesterase, when co-administered in large doses, can act in a protective manner against more potent inhibitors such as organophosphates. The clinically widely used histamine type 2 (H2) receptor blocker ranitidine is among H2 blockers the most potent inhibitor of acetylcholinesterase but roughly three to four orders of magnitude less potent than paraoxon (an irreversible organophosphate esterase inhibitor) or pyridostigmine (a reversible carbamate esterase inhibitor). We have previously shown that in vitro ranitidine confers some protection against inhibition of cholinesterases by paraoxon and that in vivo it both increases the number of rats surviving an acute paraoxon exposure and also protects to some degree the cholinesterases from organophosphate inhibition. The purpose of the study was to compare in a prospective non-blinded study, in a rat model of acute high-dose paraoxon exposure, ranitidine with pyridostigmine either administered simultaneously or 30 min. before exposure. There were 36 rats in each of the 5 groups. All substances were applied intraperitoneally. Additional analysis included data from a similar experiment carried out in 2005, in which 54 rats were exposed to paraoxon only (G1) and 54 to paraoxon+ranitidine simultaneously (G2). All groups (except controls; G6 & G7) received 1 μMol paraoxon (≈LD75); groups 2–5 received in addition to paraoxon: G2: 50 μMol ranitidine within 1 min. of paraoxon, G3: 1 μMol pyridostigmine within 1 min. of paraoxon, G4: 50 μMol ranitidine 30 min. before paraoxon, G5: 1 μMol pyridostigmine 30 min. before paraoxon. Groups 6 & 7 received only ranitidine and pyridostigmine respectively, group G1 received only paraoxon. Mortality was recorded at 30 min., 1, 2, 3, 4, 24 and 48 hr. Mortality data were compared using Kaplan-Meier plots and logrank tests. No Bonferroni correction for multiple comparisons was applied and an α≤0.05 was considered significant. All statistical analysis was performed by using SPSS 12.0 statistical software (SPSS Inc., Chicago, IL, USA). Simultaneous administration of ranitidine or pyridostigmine with paraoxon does not significantly affect mortality. Pretreatment (30 min. before) with both ranitidine or pyridostigmine statistically and significantly reduced mortality. When administered before paraoxon, pyridostigmine is statistically significantly superior to ranitidine. Both ranitidine and pyridostigmine are protective against acute paraoxon toxicity provided they are administered before paraoxon. Pyridostigmine results are statistically significantly superior to ranitidine (≤0.05). [ABSTRACT FROM AUTHOR]

The article examines the works of pharmacologist Paul Trendelenburg. A short biography of Tredelenburg is provided. His classic paper of 1917 consists of three parts: part one describes his methodology of controlled distension of the intestinal segment, part two provides a meticulous description of the recordings under physiological conditions and the third part contains a study of the effects of several pharmacological agents on the reflex.

Reports that intoxications with organophosphorus compounds such as paraoxon (POX) are frequent. How oximes are the only enzyme reactivators clinically available; Details of In vitro and in vivo studies which have shown that l-lactate reduces the inhibition of plasma acetylcholine-esteratic activity (AChEA) (in vitro and in vivo) and plasma butyrylcholine-esteratic activity (BChEA).

Presents a study which examined the utility of paraoxon sensitive phenylvalerate hydrolase to assess the severity of acute poisoning of paraoxon, an organosphophorous compound. Materials and methods; Results; Discussion.

Evaluates the effect of pralidoxime (PRX) and lactate on the inhibition of acetylcholinesterase by paraoxon. Enzyme pseudo-activity; Interaction between PRX and acetylthiocholine substrate; Protective effect of PRX.

Evaluates the effect of lactate on the inhibition of acetylcholinesterase (AChE) by paraoxon. Prevention of AChE inhibition by lactate; Factors affecting the protective effect of lactate; Inhibition of AChE activity by lactate.

We examined the influence of an experimental venous and arterial air embolism on the hearing level in laboratory mini pigs. Before and after the injection of air a threshold ABR was measured in anaesthetized mini pigs (n=15). A venous air embolism was performed in 6 animals: no changes in the hearing level or in the interpeak latencies Jewett wave V-I were observed in any of the animals before, during or after the application of air. In 9 animals the arterial embolism was done, 2 animals died and had to be excluded. In 6 animals out of 7 a hearing loss was observed starting after the injection of 40 ml air and finally ending in deafness for these 6 animals. The detected hearing loss is probably of cochlear origin, as no prolongations of the interpeak latencies of Jewett wave V-I at 90 dB HL were observed prior to the deafness. Our results show that air bubbles in the arterial circulation lead to cochlear damage ending in deafness. Our research indicates that decompression sickness, which is comparable to the arterial air embolism, is more often the cause of a sensorineural hearing loss after diving than previously believed. [ABSTRACT FROM AUTHOR]