Role of the medial prefrontal cortex in the effects of rapid acting antidepressants on decision-making biases in rodents

Major depressive disorder is a significant and costly cause of global disability. Until the discovery of the rapid acting antidepressant (RAAD) effects of ketamine, treatments were limited to drugs that have delayed clinical benefits. The mechanism of action of ketamine is currently unclear but one hypothesis is that it may involve neuropsychological effects mediated through modulation of affective biases (where cognitive processes such as learning and memory and decision-making are modified by emotional state). Previous work has shown that affective biases in a rodent decision-making task are differentially altered by ketamine, compared to conventional, delayed onset antidepressants. This study sought to further investigate these effects by comparing ketamine with other NMDA antagonists using this decision-making task. We also investigated the subtype selective GluN2B antagonist, CP-101,606 and muscarinic antagonist scopolamine which have both been shown to have RAAD effects. Both CP-101,606 and scopolamine induced similar positive biases in decision-making to ketamine, but the same effects were not seen with other NMDA antagonists. Using targeted medial prefrontal cortex (mPFC) infusions, these effects were localised to the mPFC. In contrast, the GABA_A agonist, muscimol, induced general disruptions to behaviour. These data suggest that ketamine and other RAADs mediate a specific effect on affective bias which involves the mPFC. Non-ketamine NMDA antagonists lacked efficacy and we also found that temporary inactivation of the mPFC did not fully recapitulate the effects of ketamine, suggesting a specific mechanism.Subject terms: Prefrontal cortex, Preclinical research, Depression, Reward     

Anion-induced water flux as drug release mechanism through cationic Eudragit RS 30D film coatings

The objective of this study was to investigate the anion-controlled drug release mechanism through the cationic coating polymer Eudragit RS 30 D as a function of the anion attraction toward the polymer's quarternary ammonium group (QAG), anion valence, and film composition. The mechanism was investigated by dissolution testing, determination of chloride ion exchange using ion chromatography, plasticizer leaching by means of differential scanning calorimetry, and water uptake by Karl Fischer titration. All experiments were performed on coated theophylline micro tablets or isolated films of various compositions using 0.01 M sodium nitrate, sodium sulfate, disodium succinate, sodium acetate, and succinic acid as dissolution media. The mechanism of drug release involved an immediate penetration of dissolution medium into the polymer followed by an instant exchange of chloride against the medium's anion species at completely different rates compared with the drug release. Dependent on the attraction of the anion toward the QAGs, a water flux was induced by back and forth exchanging anions. Strong attraction (nitrate, sulfate) resulted in a low water flux while weak attraction resulted in a high flux (acetate, succinic acid). The water flux increased at increasing number of QAGs. Plasticizer acted as a diluent in respect of the number of QAGs, thus higher plasticizer concentrations led to lower drug release.     

Cyclosporine exacerbates ketamine toxicity in zebrafish: Mechanistic studies on drug–drug interaction

Cyclosporine A (CsA) is an immunosuppressive drug commonly used in organ transplant patients to prevent allograft rejections. Ketamine is a pediatric anesthetic that noncompetitively inhibits the calcium‐permeable N‐methyl‐d ‐aspartic acid receptors. Adverse drug–drug interaction effects between ketamine and CsA have been reported in mammals and humans. However, the mechanism of such drug–drug interaction is unclear. We have previously reported adverse effects of combination drugs, such as verapamil/ketamine and shown the mechanism through intervention by other drugs in zebrafish embryos. Here, we show that ketamine and CsA in combination produce developmental toxicity even leading to lethality in zebrafish larvae when exposure began at 24 h post‐fertilization (hpf), whereas CsA did not cause any toxicity on its own. We also demonstrate that acetyl l ‐carnitine (ALCAR) completely reversed the adverse effects. Both ketamine and CsA are CYP3A4 substrates. Although ketamine and CsA independently altered the expression of the hepatic marker CYP3A65 , a zebrafish ortholog of human CYP3A4 , both drugs together induced further increase in CYP3A65 expression. In the presence of ALCAR, however, CYP3A65 expression was normalized. ALCAR has been shown to prevent ketamine toxicity in mammal and zebrafish. In conclusion, CsA exacerbated ketamine toxicity and ALCAR reversed the effects. These results, providing evidence for the first time on the reversal of the adverse effects of CsA/ketamine interaction by ALCAR, would prove useful in addressing potential occurrences of such toxicities in humans. Published 2017. This article is a U.S. Government work and is in the public domain in the USA.     

Perfluorooctane sulfonate induces apoptosis in lung cancer A549 cells through reactive oxygen species‐mediated mitochondrion‐dependent pathway

Perfluorooctane sulfonate (PFOS) is a widespread environmental contaminant that is detected in the lung of mammals. The mechanisms underlying PFOS‐induced lung cytotoxicity remain unclear. The main purpose of this study was to evaluate the cytotoxic effects of PFOS on human lung cancer A549 cells and its possible molecular mechanism. A549 cells were treated with PFOS (0, 25, 50, 100 and 200 μm ) and the cellular apoptosis, mitochondrial membrane potential as well as intracellular reactive oxygen species were determined. In this study, PFOS induced a dose‐dependent increase in A549 cell toxicity via an apoptosis pathway as characterized by increased percentage of sub‐G1, activation of caspase‐3 and ?9, and increased ratio of Bax/bcl‐2 mRNA expression. In addition, there was obvious oxidative stress, represented by decreased glutathione level, increased malondialdehyde level and superoxide dismutase activity. N‐Acetylcysteine, as an antioxidant that is a direct reactive oxygen species scavenger, can effectively block PFOS‐induced reactive oxygen species generation, mitochondrial membrane potential loss and cell apoptosis. These data indicate that PFOS induces apoptosis in A549 cells through a reactive oxygen species‐mediated mitochondrial dysfunction pathway mechanism. Copyright © 2012 John Wiley & Sons, Ltd.     

Nitrite reduction by the red cell membrane: a mechanism with a biological role?

The possible role of nitric oxide (NO) metabolites in vivo has gained much interest in recent years, in particular, the interaction of these species with red blood cells. We investigated the potential for the membrane of red blood cells to act as a nitrite reductase site. Using both EPR (electromagnetic resonance spectroscopy) and ozone based chemiluminescence we were able to demonstrate NO generation from nitrite by the red cell membrane. The exact components responsible for this action are yet to be elucidated, but the response was unchanged by L‐NMMA suggesting that eNOS is not involved. Reduction at the membrane could provide an entry route for NO into the red cell where it could produce potentially bioactive species e.g. nitrosylated proteins (RSNOs). If the nitrite reduction occurred on the outer surface of the red cell membrane it is also feasible that some NO may escape auto capture by that red cell, however in whole blood it is likely to be rapidly metabolised. In conclusion, this mechanism could provide a route by which nitrite, acting as a substrate, could be reduced to NO and form other, more biologically accessible species.     

Cytotoxic and apoptotic activities of the plancitoxin I from the venom of crown‐of‐thorns starfish (Acanthaster planci) on A375.S2 cells

This study reports on a cytotoxic toxin derived from the venom of the crown‐of‐thorns starfish Acanthaster planci (CAV). The protein toxin was isolated through both ion‐exchange and gel‐filtration chromatography, and characterized by sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS–PAGE) and mass spectrum analyzes. The CAV was identified as plancitoxin I protein. The mechanistic role of the CAV toxin was explored in human malignant melanoma A375.S2 cell death. The results indicated that after incubation with CAV toxin, cells significantly decreased in A375.S2 cell viability and increased in the lactate dehydrogenase (LDH) level in a dose‐dependent manner. The assays indicated that CAV toxin promoted reactive oxygen species (ROS) production, induced nitric oxide (NO) formation, lost mitochondrial membrane potential (ΔΨm) and induced inter‐nucleosomal DNA fragmentation in A375.S2 cells. The molecular cytotoxicity of the CAV toxin was tested through evaluation of the apoptosis/necrosis ratio by double staining with annexin V‐FITC and a propidium iodide (PI) assay. The results suggested that CAV toxin induced a cytotoxic effect in A375.S2 cells via the apoptotic procedure, and may be associated with the regulation of the p38 pathways. Copyright © 2014 John Wiley & Sons, Ltd.     

Antimycin A shows selective antiproliferation to oral cancer cells by oxidative stress‐mediated apoptosis and DNA damage

The antibiotic antimycin A (AMA) is commonly used as an inhibitor for the electron transport chain but its application in anticancer studies is rare. Recently, the repurposing use of AMA in antiproliferation of several cancer cell types has been reported. However, it is rarely investigated in oral cancer cells. The purpose of this study is to investigate the selective antiproliferation ability of AMA treatment on oral cancer cells. Cell viability, flow cytometry, and western blotting were applied to explore its possible anticancer mechanism in terms of both concentration‐ and exposure time‐effects. AMA shows the higher antiproliferation to two oral cancer CAL 27 and Ca9‐22 cell lines than normal oral HGF‐1 cell lines. Moreover, AMA induces the production of higher reactive oxygen species (ROS) levels and pan‐caspase activation in oral cancer CAL 27 and Ca9‐22 cells than in normal oral HGF‐1 cells, providing the possible mechanism for its selective antiproliferation effect of AMA. In addition to ROS, AMA induces mitochondrial superoxide (MitoSOX) generation and depletes mitochondrial membrane potential (MitoMP). This further supports the AMA‐induced oxidative stress changes in oral cancer CAL 27 and Ca9‐22 cells. AMA also shows high expressions of annexin V in CAL 27 and Ca9‐22 cells and cleaved forms of poly (ADP‐ribose) polymerase (PARP), caspase 9, and caspase 3 in CAL 27 cells, supporting the apoptosis‐inducing ability of AMA. Furthermore, AMA induces DNA damage (γH2AX and 8‐oxo‐2′‐deoxyguanosine [8‐oxodG]) in CAL 27 and Ca9‐22 cells. Notably, the AMA‐induced selective antiproliferation, oxidative stress, and DNA damage were partly prevented from N‐acetylcysteine (NAC) pretreatments. Taken together, AMA selectively kills oral cancer cells in an oxidative stress‐dependent mechanism involving apoptosis and DNA damage.     

4‐Aminoquinoline Derivatives as Potential Antileishmanial Agents

The leishmanicidal activity of a series of 4‐aminoquinoline ( AMQ ) derivatives was assayed against Leishmania amazonensis. This activity against the intracellular parasite was found stronger than for L. amazonensis promastigotes. Neither compound was cytotoxic against macrophages. The compound AMQ ‐j , which exhibited a strong activity against promastigotes and amastigotes of L. amazonensis (IC₅₀ values of 5.9 and 2.4 μg/mL, respectively) and similar leishmanicidal activity to reference drugs, was chosen for studies regarding its possible mechanism of action toward parasite death. The results showed that the compound AMQ ‐j induced depolarization of the mitochondrial membrane potential in promastigotes and in L. amazonensis‐infected macrophages, but not in uninfected macrophages. Furthermore, the depolarization of the mitochondrial membrane potential was dose dependent in infected macrophages. We have established that promastigotes and L. amazonensis‐infected macrophages treated with AMQ ‐j were submitted to oxidative stress. This is in line with the increase in the level of reactive oxygen species (ROS). Leishmania amazonensis‐infected macrophages treated with AMQ ‐j did not show a significant increase in the production of nitric oxide. Our results indicate the effective and selective action of AMQ ‐j against L. amazonensis, and its mechanism of action appears to be mediated by mitochondrial dysfunction associated with ROS production.     

Inhibitory effects of amiloride on the current mediated by native GABAA receptors in cultured neurons of rat inferior colliculus

1. The diuretic amiloride is known to modulate the activity of several types of ion channels and membrane receptors in addition to its inhibitory effects on many ion transport systems. However, the effects of amiloride on some important ion channels and receptors, such as GABA_A receptors, in the central nervous system have not been characterized. 2. In the present study, we investigated the functional action of amiloride on native GABA_A receptors in cultured neurons of rat inferior colliculus using whole‐cell patch‐clamp recordings. 3. Amiloride reversibly inhibited the amplitude of the GABA‐induced current (I_GABA) in a concentration‐dependent manner (IC₅₀ 454 ± 24 μmol/L) under conditions of voltage‐clamp with a holding potential at ?60 mV. The inhibition depended on drug application mode and was independent of membrane potential. Amiloride did not change the reversal potential of I_GABA. Moreover, amiloride induced a parallel right‐ward shift in the concentration–response curve for I_GABA without altering the maximal value and Hill coefficient. 4. The present study shows that amiloride competitively inhibits the current mediated by native GABA_A receptors in the brain region, probably via a direct action on GABA‐binding sites on the receptor. The findings suggest that the functional actions of amiloride on GABA_A receptors may result in possible side‐effects on the central nervous system in the case of direct application of this drug into the cerebrospinal fluid for treatment of diseases such as brain tumours.     

Functional impact of the hyperpolarization‐activated current on the excitability of myelinated A‐type vagal afferent neurons in the rat

1. The hyperpolarization‐induced, cation‐selective current I_h is widely observed in peripheral sensory neurons of the vagal and dorsal root ganglia, but the peak magnitude and voltage‐ and time‐dependent properties of this current vary widely across afferent fibre type. 2. Using patch clamp investigations of rat isolated vagal ganglion neurons (VGN) identified as myelinated A‐type afferents, we established a compendium of functional correlates between changes in membrane potential and the dynamic discharge properties of these sensory neurons as a result of the controlled recruitment of I_h using the current clamp technique. 3. Two robust reponses were observed in response to hyperpolarizing step currents: (i) upon initiation of the negative step current, there was a rapid hyperpolarization of membrane potential followed by a depolarizing voltage sag (DVS) towards a plateau in membrane potential as a result of steady state recruitment of I_h; and (ii) upon termination of the negative step current, there was a rapid return to the pretest resting membrane potential that often led to spontaneous action potential discharge. These data were strongly correlated (r² > 0.9) with a broad compendium of dynamic discharge characteristics in these A‐type VGN. 4. In response to depolarizing step currents of increasing magnitude, the discharge frequency of the A‐type VGN responded with increases in the rate of sustained repetitive discharge. Upon termination of the depolarizing step current, there was a post‐excitatory membrane hyperpolarization of a magnitude that was strongly correlated with action potential discharge rate (r² > 0.9). 5. Application of the selective hyperpolarization‐activated cyclic nucleotide gated (HCN) channel blockers ZD7288 (10 μmol/L) or CsCl (1.0 mmol/L) abolished I_h and all of the aforementioned functional correlates. In addition to reducing the excitability of the A‐type VGN to step depolarizing currents. 6. Because there is increasing evidence that the HCN channel current may represent a valid target for pharmacological intervention, the quantitative relationships described in the present study could potentially help guide the molecular and/or chemical modification of HCN channel gating properties to effect a particular outcome in VGN discharge properties, ideally well beyond merely selective blockade of a particular HCN channel subtype.     

Acetyl L‐carnitine targets adenosine triphosphate synthase in protecting zebrafish embryos from toxicities induced by verapamil and ketamine: An in vivo assessment

Verapamil is a Ca²⁺ channel blocker and is highly prescribed as an anti‐anginal, antiarrhythmic and antihypertensive drug. Ketamine, an antagonist of the Ca²⁺‐permeable N‐methyl‐d ‐aspartate‐type glutamate receptors, is a pediatric anesthetic. Previously we have shown that acetyl l ‐carnitine (ALCAR) reverses ketamine‐induced attenuation of heart rate and neurotoxicity in zebrafish embryos. Here, we used 48 h post‐fertilization zebrafish embryos that were exposed to relevant drugs for 2 or 4 h. Heart beat and overall development were monitored in vivo . In 48 h post‐fertilization embryos, 2 mm ketamine reduced heart rate in a 2 or 4 h exposure and 0.5 mm ALCAR neutralized this effect. ALCAR could reverse ketamine's effect, possibly through a compensatory mechanism involving extracellular Ca²⁺ entry through L‐type Ca²⁺ channels that ALCAR is known to activate. Hence, we used verapamil to block the L‐type Ca²⁺ channels. Verapamil was more potent in attenuating heart rate and inducing morphological defects in the embryos compared to ketamine at specific times of exposure. ALCAR reversed cardiotoxicity and developmental toxicity in the embryos exposed to verapamil or verapamil plus ketamine, even in the presence of 3,4,5‐trimethoxybenzoic acid 8‐(diethylamino)octyl ester, an inhibitor of intracellular Ca²⁺ release suggesting that ALCAR acts via effectors downstream of Ca²⁺. In fact, ALCAR's protective effect was blunted by oligomycin A, an inhibitor of adenosine triphosphate synthase that acts downstream of Ca²⁺ during adenosine triphosphate generation. We have identified, for the first time, using in vivo studies, a downstream effector of ALCAR that is critical in abrogating ketamine‐ and verapamil‐induced developmental toxicities. Published 2016. This article is a U.S. Government work and is in the public domain in the USA.     

A convenient synthesis of [11C]paraquat and other [N‐methyl‐11C]bisquaternary ammonium compounds

[¹¹C]Paraquat was synthesized by the reaction of [¹¹C]methyl triflate with the mono‐triflate salt of 1‐methyl‐[4,4′]bipyridinyl. The product was selectively separated from the precursor by a microcolumn of Chelex 100 ion exchange resin. The method was applied to the synthesis of a variety of [N‐methyl‐¹¹C]bisquaternary ammonium compounds. This is the first reported use of a chelating cation exchange resin for the selective purification of organic dications. Copyright © 2002 John Wiley & Sons, Ltd.     

17β‐Oestradiol Protects Primary‐Cultured Rat Cortical Neurons from Ketamine‐Induced Apoptosis by Activating PI3K/Akt/Bcl‐2 Signalling

Numerous studies in rodents have indicated that exposure to ketamine during the period when synaptogenesis is highly active induces neurodegeneration. Thus, there is a growing need to develop strategies to prevent ketamine‐induced brain injury in the developing brain. Oestradiol is a neuroactive steroid that prevents neuronal cell death in different experimental models by activating cell survival signals and inhibiting apoptotic signals. The main goal of this study was to investigate the neuroprotective effects of 17β‐oestradiol against ketamine‐induced apoptotic neurodegeneration in primary‐cultured cortical neurons. The data revealed that 17β‐oestradiol (0.1 μM) in combination with ketamine (100 μM) increased cell viability in the MTT assay and reduced the number of apoptotic cells detected by TUNEL and Hoechst 33258 staining. To elucidate a possible mechanism by which 17β‐oestradiol exerts its neuroprotective effect, we investigated the PI3K pathway using an inhibitor of PI3K, LY294002. The protective effects of 17β‐oestradiol were abrogated by LY294002. Furthermore, we found that 17β‐oestradiol not only induced phosphorylation of the PI3K substrate Akt, but also increased the expression of Bcl‐2, which down‐regulated ketamine‐induced caspase‐3 activity and inhibited neuronal apoptosis. These data demonstrate that 17β‐oestradiol exerts a neuroprotective effect against ketamine‐induced neuronal apoptosis by activating the PI3K/Akt/Bcl‐2 signalling pathway. Therefore, 17β‐oestradiol appears to be a promising agent in preventing or reversing ketamine's toxic effects on neurons at an early developmental stage.     

Zebrafish larva as a reliable model for in vivo assessment of membrane remodeling involvement in the hepatotoxicity of chemical agents

The easy‐to‐use in vivo model, zebrafish larva, is being increasingly used to screen chemical‐induced hepatotoxicity, with a good predictivity for various mechanisms of liver injury. However, nothing is known about its applicability in exploring the mechanism called membrane remodeling, depicted as changes in membrane fluidity or lipid raft properties. The aim of this study was, therefore, to substantiate the zebrafish larva as a suitable in vivo model in this context. Ethanol was chosen as a prototype toxicant because it is largely described, both in hepatocyte cultures and in rodents, as capable of inducing a membrane remodeling leading to hepatocyte death and liver injury. The zebrafish larva model was demonstrated to be fully relevant as membrane remodeling was maintained even after a 1‐week exposure without any adaptation as usually reported in rodents and hepatocyte cultures. It was also proven to exhibit a high sensitivity as it discriminated various levels of cytotoxicity depending on the extent of changes in membrane remodeling. In this context, its sensitivity appeared higher than that of WIF‐B9 hepatic cells, which is suited for analyzing this kind of hepatotoxicity. Finally, the protection afforded by a membrane stabilizer, ursodeoxycholic acid (UDCA), or by a lipid raft disrupter, pravastatin, definitely validated zebrafish larva as a reliable model to quickly assess membrane remodeling involvement in chemical‐induced hepatotoxicity. In conclusion, this model, compatible with a high throughput screening, might be adapted to seek hepatotoxicants via membrane remodeling, and also drugs targeting membrane features to propose new preventive or therapeutic strategies in chemical‐induced liver diseases. Copyright © 2016 John Wiley & Sons, Ltd.     

Illicit ketamine induced frequency of micturition in a young Malay woman

Issues. The growing use of illicit ketamine among young adults poses a public health concern in Malaysia. In contrast to medical use of ketamine, illicit use has been reported to produce adverse effects on the urinary tract and, in particular the bladder. Approach and Key Findings. This case report describes a young Malay woman who developed severe bladder symptoms (urinary frequency) after consuming illicit ketamine. A history of illicit ketamine use was initially missed, and she was consequently diagnosed and treated for a urinary tract infection. Her symptoms persisted despite several courses of antibiotics. The patient was subsequently referred to an urologist where cystoscopic examination and biopsy of the bladder found changes consistent with interstitial cystitis. This was despite the absence of haematuria. Renal function was normal. Implication. The patient's ketamine use was the most likely cause for the urinary symptoms and bladder changes. Conclusion. Illicit ketamine use may lead to severe urinary tract problems that can be irreversible even after ketamine has ceased. Early diagnosis is critical although difficult when ketamine use is not divulged during the consultation with the physician. Physician consideration of this new clinical entity is important, particularly in cases where the symptoms do not resolve with usual treatment.[Robson N, Vicknasingam B, Narayanan S. Illicit ketamine induced frequency of micturition in a young Malay woman. Drug Alcohol Rev 2010;29;334–336]     

Effects of ketamine, MK-801, and amphetamine on regional brain 2-deoxyglucose uptake in freely moving mice.

Although the pathophysiology of schizophrenia remains unclear, behavioral effects in humans induced by N-methyl-D-aspartate (NMDA) antagonists, such as ketamine, provide direction for formulating new pharmacologic models of the illness. The purpose of the present study was to clarify the roles of NMDA receptor antagonism, as well as dopamine-releasing properties of ketamine, in regional brain metabolic activity and behavioral responses in mice. The effects of acute administration of ketamine (30 mg/kg, i.p.) were compared with those of the more selective non-competitive NMDA antagonist MK-801 (0.3 and 0.5 mg/kg, i.p.), and amphetamine (4 mg/kg, i.p.) on regional brain [14C]-2-deoxyglucose (2-DG) uptake, by using a high resolution autoradiographic technique in the freely moving mice. Both ketamine and MK-801 induced substantial and similar neuroanatomically selective alterations in regional 2-DG uptake. Remarkable increases in 2-DG uptake in response to the NMDA antagonists were seen in limbic cortical regions, hippocampal formation, nucleus accumbens, select thalamic nuclei, and basolateral amygdala. The behavior of mice given amphetamine was similar to that of mice given MK-801. However, the brain activity patterns induced by amphetamine were distinctly different from those observed after ketamine and MK-801 treatment. These results suggest that generalized behavioral activation and increased dopamine release are insufficient to account for the ketamine-induced alterations in regional brain metabolism, and that the effects of ketamine on 2-DG uptake are likely related to a reduction in NMDA receptor function. The data also suggest that ketamine-induced changes in 2-DG uptake may provide a useful paradigm for translational research to better understand the pathophysiology of schizophrenia.     

Design,Synthesis, and Biological Evaluation of Novel Quinazoline Derivatives as Anti‐inflammatory Agents against Lipopolysaccharide‐induced Acute Lung Injury in Rats

Quinazoline has been reported to exhibit multiple bioactivities. The aim of this study was to discover new quinazoline derivatives with preventive effect on lipopolysaccharide‐induced acute lung injury via anti‐inflammatory actions. Thirty‐three 4‐amino quinazolin derivatives were synthesized and screened for anti‐inflammatory activities in lipopolysaccharide‐induced macrophages. The most potent four compounds, 6h, 6m, 6p , and 6q , were shown dose‐dependent inhibition against lipopolysaccharide‐induced TNF‐α and IL‐6 release. Then, the preliminary structure–activity relationship and quantitative structure–activity relationship analyses were conducted. To further determine the effects of quinazolines on acute lung injury treatment, lipopolysaccharide‐induced acute lung injury model was employed. Male Sprague Dawley rats were pretreated with 6m or 6q before instillation of lipopolysaccharide. The results showed that 6m and 6q, especially 6q , obviously alleviated lung histopathological changes, inflammatory cells infiltration, and cytokines mRNA expression initiated by lipopolysaccharide. Taken together, this work suggests that 6m and 6q suppressed the lipopolysaccharide‐induced acute lung injury through inhibition of the inflammatory response in vivo and in vitro, indicating that quinazolines might serve as potential agents for the treatment of acute lung injury and deserve the continuing drug development and research.     

Intranasal Ketamine and Its Potential Role in Cancer‐Related Pain

Cancer‐related pain continues to be a significant therapeutic challenge, made more difficult by contemporary opioid use and diversion concerns. Conventional treatment using a tiered approach of nonsteroidal antiinflammatory drugs (NSAIDs), opioids, and adjuvant agents is limited; and alternatives are needed for patients with rapidly progressing pain and those who develop hyperalgesia and tolerance to opioids. Ketamine, an N‐methyl‐d ‐aspartate (NMDA) selective antagonist, has historically been used for anesthesia in adult and pediatric populations but has also been investigated for depression, bipolar disorder, and general and postoperative pain management. As an analgesic, low‐dose ketamine decreases morphine requirements and rates of nausea and vomiting, suggesting a potentially beneficial role in cancer‐related pain. Ketamine is typically administered intravenously and has a rapid onset of action with a relatively short half‐life (2–3 hours) but is inconvenient for use in an ambulatory setting. Oral bioavailability is low and erratic, limiting application of this route for chronic use. Intranasal administration has a number of potential advantages, including avoidance of first‐pass hepatic metabolism, no need for venous access, ability to repeat doses quickly, and rapid absorption. Although early studies of intranasal ketamine are promising in a number of indications, information is more limited in its use as an adjunct in cancer‐related pain. We review the background, rationale, pharmacokinetics, and clinical and safety data using intranasal ketamine as an adjunctive agent and its potential in cancer‐related pain.     

Actions of ketamine on synaptic transmission in frog sympathetic ganglia.

The effects of ketamine, a clinically used general anaesthetic, on isolated paravertebral sympathetic ganglia were investigated with extracellular and intracellular techniques. Ketamine, in concentrations of 10^?5M–10^?3M, reversibly blocked orthodromically induced action potentials. In concentrations which completely abolished the nicotinic response, ketamine did not entirely depress the muscarinic and noncholinergic components of ganglionic transmission. Ketamine depressed the postsynaptic membrane sensitivity to acetylcholine which was determined by comparing the responses to iontophoretically applied acetylcholine before and after ketamine. Concentrations of ketamine less than 10^?3M, which effectively blocked ganglionic transmission, did not significantly alter the passive membrane properties of the postsynaptic membrane. At 10^?3M, ketamine acted to simultaneously depolarize the postsynaptic membrane and increase the effective membrane resistance by decreasing the membrane conductance to potassium. In concentrations greater than 10^?3M, ketamine acted non-selectively to block reversibly the nicotinic, muscarinic and non-cholinergic ganglionic responses. These results demonstrate that ketamine. in addition to its strong central action, also has a direct depressant action upon peripheral synaptic transmission.